Gregory Petsko in Genome Biology: The first 10 years

Gregory A Petsko

Published by BioMed Central in 2010

ISBN 978-0-9540278-5-8

© 2000-2010 BioMed Central

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"An addictive series of science OP-ED commentaries... using current issues to illuminate issues important in the profession and in the relationship of science to society"

Virginia Walbot, Stanford University

"If only the people who ran our nations had the Petsko combination of wit and sense..."

Sir David Baulcombe, University of Cambridge

"Petsko can always be counted on to leave me with a smile while offering a fresh perspective on issues facing the genome biologist, be they trends in genomics research, scientific interaction in the age of social networking, science policy in our politicized era, or life science funding"

Marc S Halfon, State University of New York at Buffalo

"As no other, Petsko knows how to place modern biology into the larger picture of today's society. A welcome and often brilliant view"

Alex Griekspoor, bioinformaticist and author of 'Papers'

"Elegantly phrased, witty, original and always to the point, the Petsko columns set the ultimate standard for fellow-columnists like me"

Piet Borst, University of Amsterdam

Gregory Petsko in Genome Biology: The first 10 years

Foreword

2000

The Grail problem (9 June 2000)

Dog eat dogma (28 July 2000)

The dark side (15 September 2000)

Perpetual motion of the worst kind (13 October 2000)

Seek and ye shall maybe find (10 November 2000)

Count me out (8 December 2000)

2001

The buckyball effect (10 January 2001)

Homologuephobia (8 February 2001)

Size doesn't matter (28 February 2001)

The slide rule and the calculator (6 April 2001)

The Rosetta Stone (1 May 2001)

Location, location, location (6 June 2001)

Model behavior (4 July 2001)

Design by necessity (1 August 2001)

Hell is a karaoke cruise (31 August 2001)

September 11, 01 (26 September 2001)

Winter, plague and pestilence (23 October 2001)

A piece of the action (22 November 2001)

A Christmas Carol (28 December 2001)

2002

If you can't take any more of this, please press two (28 January 2002)

The father of us all (22 February 2002)

What's in a name? (26 March 2002)

Grain of truth (25 April 2002)

Our own petards (29 May 2002)

No place like Ome (26 June 2002)

Summer reading (29 July 2002)

Fish tale (27 August 2002)

An Asilomar moment (25 September 2002)

The guards themselves (25 October 2002)

Banana republic (26 November 2002)

Everything I need to know about genomics, I learned from Yogi Berra (31 December 2002)

2003

Funky, not junky (29 January 2003)

Still no flying cars (27 February 2003)

Judgement call (28 March 2003)

War and peace (28 April 2003)

Ira (19 May 2003)

A new recruit for the army of the men of death (27 June 2003)

Galileo's stepchildren (24 July 2003)

The road worrier (28 August 2003)

The usual suspects (22 September 2003)

Sleeping dogs (23 October 2003)

For the good of the state (27 November 2003)

Live and let diet (22 December 2003)

2004

Bad chemistry (2 February 2004)

Good chemistry (26 February 2004)

Doctor Dunsel (29 March 2004)

The Ascent of Man? (26 April 2004)

Pharmacogenomics arrives (28 May 2004)

Powerless to stop myself (23 June 2004)

A drop in the bucket (22 July 2004)

Fame is a bubble, but not for some (24 August 2004)

Twilight of a hero (28 September 2004)

The emperor's new shibboleth (29 October 2004)

Color blind (26 November 2004)

Identity crisis (15 December 2004)

2005

Tsunami (31 January 2005)

Feet in mouth disease (28 February 2005)

Who owns the data? (31 March 2005)

A matter of life and death (28 April 2005)

How may you help me? (27 May 2005)

Eighty years ago (30 June 2005)

The life aquatic (28 July 2005)

Trinity (30 August 2005)

Half right (30 September 2005)

H5N1 (1 November 2005)

Who steals my identity steals trash (2 December 2005)

Foxes and hounds (3 January 2005)

2006

Let's get our priorities straight (1 February 2006)

Sweden has the right idea (1 March 2006)

The system is broken (30 March 2006)

Instructions for repair (28 April 2006)

The next epidemic (31 May 2006)

The ninth wave (30 June 2006)

Facts and figures (28 July 2006)

Senior moments (1 September 2006)

Fly's time (29 September 2006)

Transformation (1 November 2006)

Do the math (30 November 2006)

A model worth considering? (29 December 2006)

2007

Jumping the shark (31 January 2007)

And the second shall be first (26 February 2007)

A day in the life of a genome biologist in the not-too-distant future (29 March 2007)

It can't happen here - can it? (30 April 2007)

Inconvenient truths (31 May 2007)

An idea whose time has gone (2 July 2007)

A truly titanic figure in science (31 July 2007)

My worries are no longer behind me (3 September 2007)

Strange days (1 October 2007)

They fought the law and the law won (2 November 2007)

What if Watson had said "Apes evolved from man"? (30 November 2007)

Medicine man (28 December 2007)

2008

The story they missed (31 January 2008)

The right to be wrong (29 February 2008)

Going to the dogs (31 March 2008)

Not debatable (30 April 2008)

The new Manichaeans (29 May 2008)

It is alive (23 June 2008)

Having an impact (factor) (29 July 2008)

Biodefense versus bioterrorism (1 September 2008)

When bubbles burst (29 September 2008)

Meta-morphosis (03 November 2008)

The wisdom, and madness, of crowds (01 December 2008)

A seat at the table (31 December 2008)

2009

Life is a Ponzi scheme (27 January 2009)

Many happy returns (27 February 2009)

Too big to succeed? (30 March 2009)

Guilt by association (29 April 2009)

Render unto Darwin (01 June 2009)

What my genome told me - and what it didn't (29 June 2009)

Wimps? What wimps? (29 July 2009)

Nation of twits (28 August 2009)

An issue to remember (29 September 2009)

The dog days of autumn (4 November 2009)

Advice and dissent (24 November 2009)

A harsh climate (30 December 2009)

2010

Rising in the East (29 January 2010)

Lost in translation (26 February 2010)

No stone unturned (29 March 2010)

The devil's in the details (30 April 2010)

And they said it wouldn't last... (5 May 2010)

Hand-made biology (30 June 2010)

When the pie is too small (30 July 2010)

The past is a foreign country (27 August 2010)

About the Author

About Genome Biology

Foreword

Greg Petsko, a renowned structural biochemist at Brandeis University, aside from his various additional or honorary academic roles, has another guise: he is Genome Biology’s columnist, regularly serving up a taste of life and the world of science, as he sees it, since the journal’s launch in 2000. Perhaps best compared to the style of Sydney Brenner’s long-running ‘Loose Ends and False Starts’ (later simplified to ‘Loose Ends’) column in Current Biology, Greg’s column is a monthly offering of topical science discussion, written in the wittiest, provocative and sometimes even perverse style. Not only does Greg challenge dogma and drive discussion among Genome Biology’s readers, but he also boasts an impressive fan base. Greg’s columns, as testament to how popular they are, are often found in our ‘most highly accessed’ listings and I should confess to being rather bemused, when first joining Genome Biology, to be told by attendees at a conference I was attending that the best thing Genome Biology had going was Greg’s column! This feedback has since been repeated many-a-time and some go further, proposing that Greg may like to discuss a certain issue. My role at Genome Biology becomes increasingly clear.

I share with my many colleagues who have worked with Greg over the years, a great fondness, not just for Greg, but also for his monthly perspective on whatever topic is in his sights. My personal favorites have to be the ones penned (or maybe pawed) by the guest writers Mink and Clifford (the lamb chops are in the post!); although the Bush/Cheney-focused columns during the aforementioned administration are a very close second.

I continue to be amazed by Greg’s dedication to the journal — few could go the distance of a monthly column; where the ideas come from, I don’t know - and I hope (as do his many followers, I’m sure) that he’ll continue to be a mainstay of life at Genome Biology, offering up, as only Greg can, a taste of how things should be, for some time to come.

Clare Garvey
Editor, Genome Biology
October 2010

P.S. Greg’s latest columns can be found here, on the Genome Biology website.

The Grail problem

Genome Biology 2000, 1:comment002.1

The Holy Grail is a familiar metaphor in science. A current Holy Grail is the complete sequence of the human genome, but there seems to be one for every field of biology. In biophysics, it is the prediction of the three-dimensional structure of a protein from its amino acid sequence alone. But what if, when someone claims that this Grail is found, we - like the hero of the film Indiana Jones and the Last Crusade - can't be sure it's the right one? Something like that could happen in structure prediction unless we refine our measure of correctness for a predicted structure.

Genome sequencing projects have created a heavy demand for protein structure prediction. Structure prediction at present relies on modeling based on data collected from the many proteins for which both sequence and structure are known (reviewed by Baker, Nature 2000, 405:39-42). When the sequence identity between a protein of known structure and the putative homolog is high (about 50% or greater), most existing modeling methods work well. The difficulty arises in the most interesting cases, when sequence identity to proteins of known structure is low or absent. No completely reliable methods for structure prediction exist for these cases at present. New methods and claimed improvements to existing ones are always evaluated on test systems in the same way: the predicted structure is superimposed onto the true one so as to minimize the root-mean-square deviation in atomic coordinates - a measure of the difference in position - between all pairs of equivalent atoms (which may be alpha carbons or all backbone atoms; side-chains are usually excluded). This single number, the root-mean-square or rms deviation, is then reported as the measure of how well the predicted and actual structures agree.

The use of the rms deviation as a measure of the quality of a structure prediction has its origins in the early days of protein crystallography, when there was considerable interest in the precision of experimentally determined protein structures. Two different structures of the same protein solved, for example, in two different laboratories, or by the same laboratory in two different crystal forms, would be superimposed and the rms deviation would be calculated. Well-determined structures at high resolution often yield rms deviations of less than 0.5 Angstroms in such a comparison.

But predicted structures are not experimental ones, and the rms deviations between models of homologous protein structures and real ones are typically between 2 and 4 Angstroms, even in the best cases. And for the far more difficult problem of taking an arbitrary polypeptide chain and folding it up into the correct structure ab initio, by brute force calculation, the best available methods usually produce numbers even larger. All of which raises the same question as in the Indiana Jones Grail situation: how do we tell the true Grail from a false one? What constitutes 'good enough' agreement between a predicted structure and the real one to demonstrate that the prediction method works? No one expects de novo folding to get within 0.5 Angstroms rms deviation, but is 2 Angstroms good enough? What about 3?

I believe that a fundamental difficulty faced by the whole folding field - one shared with structural biology in general - is that it has never solved this Grail problem. The use of a single number to represent the disagreement between hundreds or thousands of pairs of numbers is of no statistical validity. Consider two predicted-observed structure pairs, each of which has an rms deviation of 4 Angstroms. Are they of equal quality? Suppose one pair has a roughly 4 Angstrom difference between every one of its superimposed sets of atoms, while the other has most of the equivalent atoms about 1 Angstrom apart except for a small number (say in a few loops) where the deviation is 10 Angstroms, making the overall value 4. We would certainly prefer the latter prediction, but the rms deviation alone would never allow us to decide that. Yet this is usually the only measure that is reported. That is just silly.

There are a few simple changes to this custom that would help give the field of structure prediction (and structure comparison) some much-needed numerical credibility. One is for referees to reject, out of hand, manuscripts that report only the rms deviations between pairs of structures. The maximum and minimum deviations in the whole set should be given, and I would recommend reporting the most commonly observed deviation as well. Best of all would be a histogram of the deviations; I see no reason why we should not enforce that as a requirement in all publications.

But even with these improvements, I don't think any number or set of numbers is the best indication that the Grail of always being able to predict a protein structure from its sequence has been found, because we still have no good sense of what number constitutes 'close enough'. But there is an obvious method of evaluation that will allow any structure prediction method to be assessed. It is simply to demand that the method produce a model that can be used to solve the corresponding protein crystal structure by the method of molecular replacement.

Molecular replacement is a common crystallographic tool for solving the structures of proteins that are similar in fold to ones that have already been determined. The crystallographer calculates the diffraction patterns expected for the known structure when it has been placed in all possible orientations in the unit cell of a theoretical crystal of the unknown protein, and compares the observed and calculated diffraction patterns. A likely solution is defined as one where the two patterns agree within some specified numerical criteria. But there is a further, absolute test as well: the correct solution allows the unknown structure to be completed (that is, refined to crystallographic convergence, when the observed and calculated diffraction patterns match each other as closely as possible) by automatic refinement methods combined with manual model rebuilding.

Such a test can be set up for any computational method that claims to be able to solve the ab initio folding problem or to improve on existing methods of modeling weakly similar structures. It is well-defined and easy to carry out. And when a computational procedure comes along that passes this test for helical proteins and all-beta-sheet proteins and proteins with mixed secondary structures and proteins with multiple domains, we will know that the true Grail has been found at last.

Published: 9 June 2000

Dog eat dogma

Genome Biology 2000, 1:comment1002.1

It is human nature to inflate one's ideas and contributions. It is also human nature to hang onto one's ideas long after they have outlived their usefulness, in much the same way that a parent will still support a child who has grown up to be a menace to society. Both traits are at work whenever a scientist makes sweeping statements. The more general one's insight or discovery can be claimed to be, the greater its seeming importance. And having gone out on that proverbial limb, a scientist will do much to avoid conceding that it may be less than it was thought to be, which is why so many outdated concepts have more lives than a cat.

Few statements in biology have been as sweeping as the 'Central Dogma of Molecular Biology': DNA makes RNA makes protein. Its name is always capitalized, like the Constitution of the United States or the Magna Carta. It is usually stated without qualification. It was referred to, from its inception, as a dogma rather than a theory. (Even Darwin had the modesty to call evolution a theory.) Scientists don't usually produce dogmas; that is nominally the province of religions, and even the briefest study of history will suggest that, in addition to admitting of no contradiction, dogmas tend to be accompanied by lots of other fun things, such as inquisitions and wars.

The Central Dogma was beloved of students because it was easy to remember and had no stated exceptions, like any good dogma. Sadly, it has fallen on hard times of late. The discovery of reverse transcriptase provided an inconvenient example of the synthesis of DNA from RNA. An attempt was made to re-establish dogma status by explaining that the phrase 'DNA makes RNA makes protein' really referred to the flow of genetic information, not the actual steps of synthesis. Then along came RNA editing, in which guide RNAs or enzyme action modify some messenger RNAs such that the final protein sequence cannot be deduced from the gene sequence alone. Alternative splicing didn't help either: it could be argued that it represents a case of RNA making itself, then making a bunch of different proteins. And then there was that inconvenient stuff about RNA catalysis, which suggested that there was once an RNA world in which RNA made protein without DNA getting into the act at all. To account for all this, the Central Dogma now would have to go something like this: 'DNA makes RNA makes protein, but sometimes RNA can make DNA and other times RNA makes RNA, which makes proteins different from what they would be if only DNA made the RNA, and once upon a time RNA made protein, probably, but no-one knows for certain'. Or, if you prefer your dogmas pithy: 'DNA makes RNA makes protein, except when it doesn't'.

Perhaps it is best to retire the Central Dogma, and before suggesting a replacement remind ourselves that, because it was a dogma, all of the exceptions - from reverse transcription to RNA catalysis to editing of the message - were initially dismissed as artifacts and had more trouble gaining acceptance than perhaps they should have from the quality of the experimental work. Skepticism in science is a good thing, but dogmas breed cynicism (which is not) and lead to reactionary thinking. Just ask Galileo.

Still, dogmas have their uses. Students, as stated earlier, find them very helpful. They provide a convenient encapsulation of the perceived wisdom of the moment. They are usually easier for lay people to understand than laboriously qualified statements. And they provide a clearly visible target for that most interesting breed of scientist, the iconoclast, to shoot at - rather like policemen's hats. So, I might as well suggest that genomics has a dogma that is more profound, I think, than the Central Dogma, and more robust to boot.

The Central Dogma of Genomics derives from structural biology. Concisely stated, it is: 'sequence determines structure determines function'. Chaperone-mediated protein folding does not violate this dogma, because chaperones do not induce in proteins a fold that is different from one adopted when the proteins are allowed to fold on their own in dilute solution - chaperones just expedite the folding or prevent unwanted aggregation. Post-translational modification of the structure by limited proteolysis, phosphorylation, glycosylation and the like also does not violate the dogma, because the sequence and structure of the protein determine the nature of such modifications, and the sequence and structure of the protein after modification determines what the consequences of that modification will be. The dogma is vague about which sequence is referred to, which is useful because it forces us to think about it. Upon reflection, it is clear that the relevant sequence must be that of the protein, not the DNA or RNA, and specifically that of the protein following any modifications that may be made on the pathway to full expression of function. That is a very important conclusion, because it means the task of genome sequencing cannot be considered complete until genome-wide methods for detecting and characterizing changes in the protein sequence have been developed and applied.

The dogma asserts that it should be possible, ultimately, to deduce the function of a protein from its structure. Belief in the truth of this statement lies at the heart of structural genomics, which endeavors to determine structures for all of the gene products in a given organism. Yet here the dogma can be accused of oversimplification. Protein-protein interactions and protein localization within the cell can have profound influence on protein function. But I believe it is sound to argue in rebuttal that these things also depend directly on the sequence and structure of the protein in question.

The Central Dogma of Genomics is a concise summary of the basic assumptions that underlie this field. Though they are cast as a dogma, we would do well to bear in mind that they are only assumptions, albeit ones with good legs to stand on. If the seeds of eventual overthrow are sown anywhere, they may be in the word 'function'. For, unlike most important words in science, function is a word whose meaning is highly situational. But that's another column.

Published: 28 July 2000

The dark side

Genome Biology 2000, 1:comment1003.1

Francis Crick once said that if you can't study function you had better study structure. He probably meant that studying function was hard but structure provided a powerful entry into the problem. But I like to think that he actually was giving us his version of "Once you start down that path, forever will it dominate your destiny," advice given about the danger of the Dark Side of the Force, in the movie Star Wars: The Empire Strikes Back. For if there is a dark side to the structure/function relationship, it is to be found when we search for function.

We will all face the dark side before long, as the emphasis in genomics shifts from identifying and sequencing genes to the problem of determining what their products do. Leaving aside the formidable technical challenges posed by that problem, there remains the prospect that the job, as commonly considered, is impossible: because the term 'function' means very different things to different people, and a given gene product might have almost as many 'functions' as there are scientists studying it. There is its biochemical function: the chemical or physical process it carries out when isolated from the cell and studied in vitro. There is its cellular function - signal transduction protein, translation inhibitor, transcription factor, and so on - which may depend on its location in the cell, what other molecules it is bound to, when in the cell cycle it is expressed, and so on. Then there is its larger biological function, which is most often defined by the pheno-type that is observed when it is deleted or mutated: growth control, or immune regulation, or involvement in morpho-genesis, to name but a few possibilities. The layers are almost infinite, especially for genes in metazoan organisms.

Consider actin. Its biochemical function is to bind ATP and hydrolyse it, but it is not very good at that on its own. The ATPase activity can be modulated by the binding of other molecules - a common phenomenon in biochemistry. One could also say that the 'real' function of actin is to self-polymerize, forming filaments. This brings us closer to the cellular roles of actin, but these are legion: essential component of the cytoskeleton, 'railroad track' along which vesicles and other cellular constituents run, anchor for myosin in muscle contraction, target for the mushroom toxin phalloidin, rigidifier of microvilli, backbone of the acrosome, inhibitor of DNase I, and many more. When can we say we know what the 'function' of the actin gene is?

Clearly any attempt to understand function, however defined, on a genome-wide scale is going to require the combined expertise of many different kinds of scientist. Geneticists, biochemists, computational biologists, cell biologists, structural biologists - all of these, and more, will have to work together if we are to appreciate the myriad parts that proteins play in living cells. This raises a serious cultural problem (one that I shall address next month), but it also implies something about how we train people. We need people with specialized skills to carry out technically complex experiments, but we also need people who can speak in a language other than that of their own field so that they can communicate their results effectively to specialists in different fields. The dark side will overwhelm us unless we also train enough generalists who can help us put the data from all these disciplines together.

Anyone who doubts the dangers of overspecialization should consider the giraffe (Figure 1). The tallest mammal, it is marvelously adapted to solve the physiological problems posed by its enormous neck. Its blood circulation has been studied by, among others, Alan Hargens of NASA and T.J. Pedley of Cambridge University. Central arterial blood pressure is about 250 mmHg in a giraffe (as opposed to 100 mmHg in us), implying a pressure of 400 mmHg in the feet. But the giraffe escapes swollen ankles by virtue of a very tight skin (the earliest known support stockings?). The work done by its heart is 2.5 times greater per unit mass than in other mammals, but the giraffe heart is 2.5 times bigger (it weighs over 13 kilos). There is an intricate network of valves in the veins and blood vessels of the neck, which prevents the giraffe's brain from being filled or emptied of blood too quickly. One highly specialized vessel near the brain acts as a sponge, slowly absorbing blood to the point where pressure warns the animal to lift its head before damage occurs. Marvelous engineering; perfect adaptation. And yet... if a giraffe were to fall flat on its side, it would not be able to get up. Giraffes must rest while standing; they seldom sit on the ground as it would be too awkward for them to rise and flee from predators. Because of its great size, a giraffe should be relatively safe from predation, but this is not the case. Normally, giraffes absorb most of the water they need from the food they eat. But when a giraffe needs to drink from a water hole, it has to spread its legs wide so that its head can reach the water. In this position, it is easy prey for lions.

Like the giraffe, many of us are marvelously developed technically, but the complexity and sophistication of our technology could make us vulnerable to changing fads and the appearance of new techniques. Excessive emphasis on training scientists with highly specialized skills could produce a generation of biologists who cannot talk to one another at anything but a superficial level. Chemistry has already fallen prey to this, as did physics before it. Biology could be next. That would be a tragedy, because the great strength of biology has always been its grand unity.

In this, as in so much else in this time of rapid change, genomics is a two-edged sword. On the one hand, the quantity and diversity of data genomics produces demand that we bring forth broadly trained scientists to integrate and explain the data. On the other hand, by rewarding those who furnish the data with jobs and research grants, it fuels the drive towards increased specialization that is inherent in any maturing field.

Star Wars tells us that fear and anger led to the Dark Side, but impatience and insecurity lead to the dark side of genomics - namely the balkanization of biology. Impatience is dangerous, because it will take longer to train scientists who are broadly educated. Such students will need more course work and will spend less time on their research than those who concentrate on one thing. Insecurity threatens us by preventing us from taking the seemingly risky path of becoming adept in more than one field or crossing disciplines in our training and our work. If we are not to have the dark side dominate our destiny, we must encourage - and even reward - those students who choose not to become technique-oriented. We must encourage - and even reward - those faculty members, especially the junior ones, who develop programs to train such students and who choose research that fosters such training. At the risk of overworking the giraffe metaphor, we have to make interdisciplinary research and training worth sticking one's neck out for.

Published: 15 September 2000

Perpetual motion of the worst kind

Genome Biology 2000, 1:comment1004.1

"The fact-gathering tendency is apparent not just in structural genomics, but also in functional genomics (to identify the role of each gene in the genome) and proteomics (with similar aim for each protein in the cell or organism). Evidently, there are enough facts to keep biologists busy gathering them for decades. So when will they have time to think?"

Nature 2000, 403:345

"The speed of acquiring data is now exceeding our ability to comprehend it and put it into the proper biological context."

Science News 2000, 157:284

In the history of human communications, first, there was mail. It gave us news of things and connected us with people, but mostly it brought us work to do ("Pay this bill!"; "Correct these proofs!"; "Answer this query!"). We didn't mind, because it was exciting to receive mail: it was tangible proof that we mattered to someone out there. Then along came the telephone. It was exciting for the same reasons, plus it made connections with people less formal and more rapid. True, it brought us more work to do, but we didn't mind too much. But - and this should have made us feel slightly uneasy - the volume of mail did not decrease appreciably. Next there was the fax machine. It could send hard copies as fast as a telephone call. But the faxes we received mostly brought us more work to do - from impatient, demanding people (have you noticed how many fax cover sheets say 'URGENT FAX', no matter what the fax's content?), people who seemed to believe that just because they faxed us something, we had to do whatever it was they wanted immediately. And - this was the scary part - the volume of mail and the number of phone calls did not decrease appreciably.

Finally, there came e-mail. E-mail was great. We could communicate with anyone, anywhere, at our leisure and as informally or formally as we liked. We could send documents and figures as well as messages; we were wired. And yet, our e-mail correspondents didn't want us to reply at our leisure. They had e-mailed us; didn't we know that meant we had to answer right now? And the attached documents came in a time-consuming array of incompatible formats. We were expected to read enormous documents that no one would ever have faxed to us, and then reply to them immediately - after all, they had been e-mailed. And despite all this the volume of mail and the number of phone calls and faxes has not decreased to a manageable level.

Although 'introductory thermodynamics 101' was quite a few years ago for me, doesn't all this contradict The Law of Conservation of Matter? Each new technology increases the total amount of work we have to do and the speed at which we are expected to do it. And as if being smothered in work to do weren't bad enough, now we are about to drown in data. The genomics revolution is flooding us with data at a rate unprecedented in human history. The banks of DNA sequencers at Celera and the Sanger Center - inter alia - can turn out the complete genome sequence of a prokaryote in one day. But we need time to study these data. Time to digest them. Time to think deeply about what they mean. Yet we won't have that time because we're too busy gathering yet more data, trying to keep up, trying to dig out from under all the stuff to do that our wonderful new technologies are piling on top of us.

If I could change one thing about modern science, it would be this constant busyness. It robs us of so many things: the peaceful contemplation of our results; the time to get to know our students better; the challenge of planning an experiment carefully instead of just rushing to get more data; the simple joy of working with our own hands. It exhausts us, emotionally as well as intellectually and physically. And genomics is only going to make it worse, if in no other way than simply by increasing the pressure for more results, faster. If we don't do something about it soon, we will wake up one morning to find that science has become work instead of fun. (And personally, I've never wanted to work for a living.)

If you read the old scientific literature, it's astonishing how much depth of analysis there is in the best of it. Our scientific forebears could draw amazingly perceptive conclusions from a handful of data. We accumulate orders of magnitude more data with techniques they might have drooled over, but we can't seem to match their ability to make sense of it all: we're too busy. Yet if we don't find the time to think about all the data that genomics is pouring out, we'll miss the opportunity - and the fun - of figuring out what it all means.

I can't really see any way of turning the clock back to a simpler time, but I do have a proposal for a solution. It's radical, but desperate times call for desperate measures. I think we should agree as a community to designate one month a year solely for the purpose of catching up and having time to think. February seems like a sensible choice: in much of the scientific world it's a pretty depressing month, weather-wise, so why not make it good for something. During February, no journals could be published, no papers submitted, no papers sent out to reviewers. No one would be allowed to send mail, e-mail, fax, or make a phone call, that required anyone to do anything in the nature of additional work. No scientific meetings could be held. Supplies and equipment could be ordered, experiments could be done, papers could be written and read, but no new work could be dumped onto anybody in the scientific community. In March all the busyness would start up again, but we would know that every year we would have one month to look forward to: a month when we could get the piles of work somewhat under control, reacquaint ourselves with our students and families, and just think.

There would need to be severe penalties for violating this community-wide agreement, or else the temptation to slip back into the old ways might prove too strong. Funding agencies could cut off research support to anyone who broke the rules - but a lot of work is funded by industry instead, and governments police things too much for my taste anyway. Ostracism is a possibility, but scientists tend to be gentle and forgiving people, so ostracism would be tough to enforce. I am completely opposed, both morally and intellectually, to capital punishment, but I might just be willing to make an exception in this case. I think the matter is so important that we can all agree that no disciplinary action would be too harsh.

Published: 13 October 2000

Seek and ye shall maybe find

Genome Biology 2000, 1:comment1005.1

The other day I became what George Orwell might have called an unperson. I was searching the US National Library of Medicine's Medline database for an article that I wrote a number of years ago. I wanted to cite it in a paper I was writing (hardly anyone else cites it these days, so I like to; besides, it actually was relevant), and it was easier just to download the citation than to dig it out of my reference database since I was logged on to Medline anyway. But I couldn't find it. Searching with my name, the names of my coauthors, the journal and year, the title keywords - all failed. Anyone who saw the classic, creepy 1960s television series The Twilight Zone will understand how I felt. I actually went to my files and dug out the reprint so I could be certain I really had written the paper and wasn't in the grip of some grotesque delusion. (At my age, it never hurts to check one's memory.)

It took me a while to realize what had happened. The paper was published in Science, a journal that covers all scientific disciplines, and although the subject matter was a new technique that we applied to structural biology, the title might have led one to conclude that the paper was about computer science. Someone obviously did conclude that, and so the reference was never entered into Medline, which focuses on medicine and the basic life sciences. Anyone searching for past publications on that topic who used only Medline to conduct the search would, in all probability, never learn that our work had been done.

The experience caused me to consider another of the consequences of the 'Age of Genomics': we are all becoming conditioned to rely on databases, and to believe that they constitute a complete repository of the available relevant information. This belief is largely justified for sequence databases (with the significant exception of some sequence data from the private sector), a fact that has contributed to a much less justified faith in other databases.

Nowhere is this phenomenon more apparent than in the blind trust students - and, let's face it, the rest of us - place in computerized literature searches. There is no denying their value. Assembling a collection of references for a research article or review is orders of magnitude faster using such tools than it would be by hand. But this efficiency comes with a hidden cost: many of the literature databases, especially the free ones, limit their coverage in ways that are not obvious to the casual user. I don't mean to pick on Medline specifically, but it is the most widely-used literature database, at least in the US, so it is useful to consider it as an example. As my experience indicates, not every article that belongs in Medline finds its way there.

Nor does every journal. The Journal of the American Chemical Society is not covered, despite the fact that every issue contains more than a dozen articles on biological chemistry. Most other chemistry journals are also omitted. And a number of 'physics-related' journals such as Acta Crystallographica are also not comprehensively covered, despite the fact that they contain important articles on structural biology methods and results. These are all excellent journals, yet the best advice one could give a modern young life-scientist is to avoid publishing in them if one is trying to build a reputation, because papers published there risk invisibility.

Then there is the matter of history. Reference databases do not go back to the dawn of time. Medline goes only as far back as the 1960s for most journals, and the bulk of entries more than about twenty years old have no abstracts and so are less likely to be useful. Many search systems that access Medline do not search the entire database, and many other databases contain only the entries for the past ten or twenty years. It's bad enough that so many scientists today don't know the older literature - and so are more likely to reinvent the wheel - but it's far worse to realize that it won't be long before that literature won't ever be cited. There is a joke in science that papers more than ten years old aren't worth reading, but soon this may be no laughing matter.

I think there are two things that can help this situation. First, the scientific community needs to pressure database curators to be as inclusive as possible. This means not only a broad coverage in terms of journals, but also deep coverage into the older literature and more careful decisions about which articles belong in which database. Indeed, it is arguable that genomics, being interdisciplinary by its very nature, needs literature databases that cover nearly all of the physical and life sciences. Second, young scientists need to check periodically (pun intended) that their work has found its way into the proper databases. Doing a regular search for one's own oeuvre and notifying database curators of omissions and errors would help prevent out-of-body experiences like mine. In the end, we are all going to be subject to the vagaries of such information repositories. Databases are our new servants, but they are also our new masters.

Published: 10 November 2000

Count me out

Genome Biology 2000, 1:comment1006.1

The following is a transcript of testimony before the Supreme Court of the State of Florida, United States of America. Eugene Finder, lawyer on behalf of the Human Genome Organization, is arguing his case before the assembled justices, who are questioning him.

Gene Finder: ...and so, Your Honors, I hope that the evidence will convince you that if the decision of the Secretary of State to certify the count is upheld, the number of genes in the human genome will be smaller than anyone ever imagined.

Justice Skeptical: Just how much smaller?

Gene Finder: We don't know yet. That's why we're asking you to delay certifying the official count until we're sure what the correct number is.

Justice Ambivalent: What do you mean you don't know yet? The draft human genome sequence has been available for months. The automated counting of genes has been going on since then. How hard is it to count something properly?

Gene Finder: Uh, well, Your Honors, a large part of the problem is that we don't exactly know what constitutes a legitimate gene. We can identify sequences of DNA that have long open reading frames and things that look like start and stop codons, but we don't know if they're actually transcribed. Some sequences have several apparent start codons embedded in the first couple of exons; we don't know which, if any, is the right one.

Justice Credulous: Can't you just go by the distance to the promoter region? If there's a nearby promoter, doesn't that signify intent on the part of the sequence to be a transcribed gene?

Gene Finder: It might, Your Honor, if we knew what a good promoter looked like in a higher eukaryote, but there are arguments about that. Does a gene need a complete promoter to be a functional gene, or would an incomplete promoter -what we're starting to call 'dimpled promoters' - be enough to signify intent? We also don't know how far away from the start signal a promoter can be in a higher eukaryote and still work. Which brings me to the intron problem.

Justice Credulous: Intron problem? Does that have something to do with Palm Beach County?

Gene Finder: Uh, no, Your Honor; that's a different case. Introns are intervening sequences. We used to think introns didn't code for anything. But some genes have things that look like good start signals in introns, and we now know of several genes that are intron-encoded. We propose, by the way, that such a cryptic start signal should be called a 'chad'.

Justice Ambivalent: You mean genes within genes? That would complicate the machine-based counting of genes, wouldn't it?

Gene Finder: Yes, Your Honor. That is why my client, who has bet a lot of money on there being more than 40,000 genes in the human genome, wants a manual recount, including such disputed genes. We believe that until a universally-agreed automatic method is developed, careful scrutiny of each potential gene by a human being is the right way to go.

Justice Credulous: Wait a minute, can't we just use homology to expressed genes from lower organisms as a criterion?

Gene Finder: We could use it, and we are doing so, but we don't know what weight to give it in drawing conclusions. Just because there is a homolog in a lower organism doesn't mean the gene is functional in humans. It may be a pseudo-gene. We anticipate that many apparent genes will have to be excluded from the final count because of irregularities such as non-functional promoters, cryptic stop signals, and so on.

Justice Credulous: So if you did that, could we at least count - sorry for the pun - on being able to come up with a total?

Gene Finder: Not in time. We have to delay the certification. If we certified now, on the basis of the little we know about what it takes to make a human gene, the number of genes in the human genome would be less than 40,000. Not only would my client lose her bet, but the figure would mean that we as human beings are only three times more complicated than a fruitfly, in genetic terms. I think that would be very hard for people to accept.

Justice Ambivalent: Well, besides including genes with dimpled promoters and genes where the intent of the sequence is unclear, is there any other way to ensure that all genes have been fairly counted?

Gene Finder: Yes, Your Honor. My client believes that we must also learn how to take into account alternative splicing.

Justice Credulous: Is that like the situation in a ballot, where people punch two candidates instead of voting for only one?

Gene Finder: Very much like it, Your Honor. But alternative splicing can produce many more than two gene products from a single gene. For example, work by Fettiplace at Wisconsin and Fuchs at Johns Hopkins, among others, has shown that mechanosensory hair cells of the vertebrate inner ear contribute to acoustic tuning through feedback processes involving voltage-gated ion channels in the basolateral membrane and mechanotransduction channels in the apical hair bundle. The specific number and kinetics of calcium-activated (BK) potassium channels determine the resonant frequency of electrically tuned hair cells. Kinetic variation among BK channels appears to arise through alternative splicing of mRNA for the slo gene and combination with modulatory beta subunits. It's hard to know how many splice variants of these channels may be involved, but it is possible that a single gene may produce dozens or even hundreds of slightly different proteins in the auditory system. And who knows how often that sort of thing happens in other tissues? We know that many genes, especially genes encoding receptors, are alternatively spliced. Do they count as one gene or two?

Justice Skeptical: I don't think you should count your chickens before ...

Gene Finder: Exactly, Your Honor, thank you. Some of these variants were first detected in chickens. But it gets worse, Your Honors. We don't even know how to predict from the sequence whether a gene will be alternatively spliced, or if so, how many different splice variants it will produce. Not enough people are working on that problem. And if we could do that, when we have a gene that produces, say, six alternative transcripts, do we count it as one gene or many? We need a ruling from Your Honors on this matter before we can go forward and certify a final gene count.

Justices: Don't count on it.

Published: 8 December 2000

The buckyball effect

Genome Biology 2001, 2:comment1001.1

In the spirit of the season, I've been wondering what happens to old toys when new ones arrive during the holidays (I know, the Toy Story movies explored this question from the point of view of the toys, but bear with me). After all, the old toys are the ones the children once couldn't do without, yet there aren't enough hours in the day to play with all of them plus the new ones, so something must get neglected, at least relatively. At the end of November last year, I met someone who reminded me about this, and made me realize the connection between the discarded toys and the effect of genomics on what is 'hot' in biology.

There are a number of reasons that academic scientists travel as much as they do. One reason is to experience that sense of being valued that only accrues to someone away from his or her home institution (familiarity breeding, if not outright contempt, a kind of devaluation of the currency of one's repute). Another is to discover new people with interesting ideas. I was giving a seminar at Temple University in Philadelphia when I was introduced to David R. Dalton, an organic chemist who proved to be a delightful and stimulating conversationalist. For some reason we got around to discussing fads in science and he promptly remarked "Yes, the Buckyball Effect!"

I knew what buckyballs are: buckminsterfullerenes or fullerenes for short. The term describes a range of recently found (mid-1980s) forms of carbon including C_60, a roundish molecule made of 60 carbon atoms arranged in a truncated icosahedron (one of the 13 Archimedian solids), like the vertices of a soccer ball. Such molecules were named after Buckminster Fuller, who invented the geodesic dome, which has a similar structure. But I had never heard of the Buckyball Effect.

"Oh, that's my own term," Dalton said. He went on to explain that he had always wondered what happens to old scientific areas of investigation when a new one comes along. Within a year or two of the discovery of buckyballs by Smalley and his associates, there were hundreds of people working on them in labs all over the world. But before they started working on buckyballs, all of these people were working on something else, something that they believed was important (or at least, something that they told the funding agencies was important). What happened to all of those projects? After all, he said, one can't do everything. If a lot of effort goes into a new area, a number of old areas once thought important enough to warrant funding and research activity must get neglected in comparison. Did these areas suddenly become less important? Were they never really all that important? And if they were important and still are important, how will that work get done now?

Genomics, it seems to me, provides a classic example of the Buckyball Effect. So great has been the publicity afforded to genomics research, and so generous does the funding for it appear, that it has become the hottest area of biology almost overnight. Granted, genome sequencing is losing some of its novelty, but the pull will only increase as genomics morphs into proteomics and structural genomics and functional genomics.

What is the origin of this faddish behavior? Are scientists lemmings in whom the herd instinct is stronger than their love for a particular subject? Do they have the attention span of five-year-olds? Is it the charm of the unfamiliar? Or is something more subtle at work? Much of the attractive power of a hot new field comes, of course, from the promise of easier access to funding. Most scientists tend to choose the subjects of their work - or at least slant the way they present those subjects - according to the advice 'Deep Throat' gave to journalists Woodward and Bernstein during the Watergate investigation: "Follow the money." But I think there's a deeper draw too. Scientists like to work in hot fields because to do so enhances their importance, and their sense of self-importance. One is so much better dinner-party company if one is working on something that the lay public has heard of and believes to be interesting and worthwhile. One feels somehow superior to other scientists who are working in fields that have less cachet - and the transition from hot field to backwater can occur with startling swiftness in biology these days.

But the field as a whole pays a heavy price for this constant shifting of mobs of researchers into the latest fad. Older areas that were important and still are important lose talented people, funding (it is, after all, a zero-sum game, and don't let anyone tell you differently), and visibility. In response to these losses they can become defensive, conservative, and inner-directed. Because everything in science is cyclical, eventually most of these fields will come back into fashion, but when they do there will be a dearth of good researchers working there. Just ask the virologists, who languished for decades until oncogenes were discovered. Or the microbiologists, who were believed passe until drug-resistant pathogens began exploding over the health-care landscape.

It seems to me that we ought to learn from these and countless other examples. Funding agencies need to resist the temptation to pour most of their resources into the newest fields. It's happening too much at the US National Institutes of Health, which is rapidly becoming uninterested in microbial genetics, microbial physiology, mechanistic enzymology, and fundamental biophysics, to name but a few areas, at the expense of genomics in all its guises and research involving human cells or targeted at human disease. If present trends continue, it will soon cede title to such areas almost entirely to the National Science Foundation, a great organization but one with far fewer resources and a much broader community to spend them on.

It's also happening in universities, which, despite their mandate to preserve traditional areas of investigation whenever these have value, are rushing to throw their own resources at genomics-based initiatives, to the serious neglect of 'older' subjects that are less fashionable. To be sure, the less faddish fields can survive partially by allying themselves with genomics or adopting genome-wide approaches, but the Buckyball Effect still applies. What about the important, fundamental work in those fields that is not being done because everyone in it is rushing headlong towards genomics? Were those subjects never as important as their proponents once claimed? Shifts in emphasis are inevitable and healthy, but if we want to have the rigorous underpinning in chemistry, physics and biochemistry that must underlie the 'new' genome-based biology - if it is to have the intellectual impact we expect of it - the old toys must not be forgotten.

Published: 10 January 2001

Homologuephobia

Genome Biology 2001, 2:comment1002.1

I might as well start by admitting that I don't like the preferred spelling of the word homologue. That 'ue' at the end seems gratuitous to me, rather like the pretentious 'e' that sometimes shows up on the names of expensive business establishments ('Gift Shoppe'; 'The Olde Tavern'). But every time I type 'homolog', my word processor flags it as an incorrect spelling, flaunting its smug superiority at me by underscoring the word in wavy red lines.

Well, maybe I can't spell homolog (although for the purpose of this column I am going to spell it the way I want to), but I can at least use it correctly. And that seems to be a rare thing these days. One of the downsides of genomics is that it has caused biologists to use a lot of new words, some that have recently been made up and others that were not in common use before. The former add unnecessary and undesirable jargon to our discourse; the latter muddy the waters by being frequently misused.

The creation of new terms seems to be an irreversible trend, but I wish it could be stopped. Genomics is best carried out by multidisciplinary teams, but meaningful communication between scientists of different backgrounds is not aided by the use of jargon words that are not easy to understand from their context. Medicine is famous for this, of course, but at least physicians have the excuse of wanting to build a wall of mystery around their profession to provide themselves with the distance and authority they believe they need to deal with patients effectively. Scientists have no such justification; in fact, they should eschew anything that separates them from the public, who, after all, pay for their research. The rationale I hear most often is that of economy of expression, and I concede that brevity is often desirable, but not at the expense of ease of understanding. Do we really lose so much time and word-space by substituting 'programmed cell death' for 'apoptosis', a word no one is even sure how to pronounce?

A physicist who wants to enter biology has to learn a new way of thinking; do we have to make them learn a whole new language too? The words 'ortholog' and 'paralog' (note that my spelling is at least consistent) in my view add nothing to our subject, and by replacing easily understandable simple phrases they cause us to forget our assumptions and substitute the appearance of erudition for an attempt to be clear to everybody. I fail to see that ours is a better world for the invention of the term 'proteomics' either, especially since it seems to mean different things to almost everyone who is trying to do it. And why on earth do we need 'metabolomics', which doesn't even sound nice, or 'transcriptome' (which is clearly a dense book of American academic records)? Instead of wasting their time deciding to replace perfectly good units like the atmosphere and the kilocalorie and the Angstrom with daft ones like the Pascal and the kiloJoule and the nanometer, the International Union commissions on nomenclature should be substituting plain English expressions for the unruly mob of new terms that have descended upon us.

But even worse than a silly new word is an old one that is seldom used correctly. It happens with phrases all the time. Shakespeare never wrote 'to gild the lily'; he wrote 'to gild refined gold, to paint the lily'. Bogart never said 'Play it again, Sam'; he said 'You played it for her, you can play it for me. Play it'. No real harm is done by that sort of thing. But the misuse of a technical term can obscure meaning. No word provides a more compelling an example of this problem than 'homolog'. Biologists look at a sequence and say 'protein X is 43% homologous to protein Y'. Well, it's not. The two sequences can be 43% identical or they can be 43% similar, but they can't be 43% homologous. There is no such thing as percent homology. The meaning of homologous is 'related by divergent evolution from a common ancestor'. That's the only thing it means. You can't be partially homologous: that would be like being partially dead, or partially pregnant. You're either homologous or you're not.

If one gives a percent homology when talking about the relationship between two sequences, the reader or listener has no idea whether what is meant is identity or similarity - and the difference matters a lot. Two sequences that are 43% identical clearly belong to homologous proteins; two sequences that are 43% similar may be less than 20% identical, a gray area in which proteins are not obviously descended from a common ancestor. In such ambiguous cases only structural similarity can confirm the evolutionary connection between sequences, but we won't know whether we need it if we say they are 43% homologous. We must reserve the word homolog for those cases where its precise meaning applies; if we don't, we lose the distinction between numerical relationship of sequences and the underlying genetic history of the proteins.

Functional relationship is another problem altogether, which is why I find the words 'ortholog' and 'paralog' more harmful than helpful. When we say that two molecules perform the same function, we imply either that each has only one function or that we know all of their functions and that they all overlap. I doubt we can be certain of either situation for even a handful of proteins in the genomes of higher organisms. Experimental replacement of one gene by the other in an organism is no guarantee either, for the two proteins may share a common function but have other functions that differ. The modular nature of protein construction makes this sort of situation quite likely. In the end, the real problem with obscure new words and misused old ones is the same: they make it seem as though we understand more than we do. And if genomics has one key thing to teach us, it's that we actually understand very little.

Published: 8 February 2001

Size doesn't matter

Genome Biology 2001, 2:comment1003.1

So now we know. The first 'official' count of the number of genes in the human genome is in, and the total is smaller than almost anyone had imagined. Sorting out the pseudogenes from the real ones will take some time, so the number may increase a bit, but it seems clear that the genome of Homo sapiens contains fewer than 40,000 genes, with the final number probably being closer to 30,000. Quibble about the exact count if you will, but the total will probably not approach even half the 80,000-100,000 estimate that was widely bandied about when the Human Genome Project began.

What a blow to our collective ego as a species! Thirty thousand genes is only 50% more than the 19,000 in the genome of the nematode worm Caenorhabditis elegans. It is just a bit more than double the 13,000 genes in the fruitfly Drosophila melanogaster. And it is only five times the number of genes in a unicellular microbe, the budding yeast Saccharomyces cerevisiae. I teach undergraduates, so the idea that human beings are not even an order of magnitude more complex than a fungus is not incredible to me, but it still begs the question: how could we have evolved as such complex beings with such a minimalist genome? Does size truly not matter?

Well, the first lesson from the human genome sequence would seem to be that the number of coding sequences doesn't matter as much as we thought. There is still a crude relationship between the complexity of the organism and the number of genes: no bacterium whose genome has been sequenced to date has a gene count even as large as that of yeast, and metazoa all seem to have tens of thousands of genes instead of a few thousand. Yet the preliminary reports of some other vertebrate genomes, such as that of the puffer fish, suggest a gene count that may exceed that of the human genome, and some plant genomes are also shaping up to be quite large. Clearly, the correlation between complexity and gene number is a loose one.

But the size of the proteome is another thing altogether. No one knows how many different proteins make up the complete ensemble of human gene products, but current estimates range from 100,000 to several times this number (of course, we should remember that the number of human genes was once estimated to be that large too). This is in stark contrast with the situation for simpler organisms. For most bacteria, the relationship between genes and proteins is approximately 1:1, as indicated by the number of proteins that can be resolved on big two-dimensional gels. Yeast and other microbial eukaryotes would seem to be similar in this respect. But for metazoa, especially vertebrates and even more especially mammals, there is considerable expansion of the proteome relative to the genome.

One place where mechanisms for this are evident is in the immune system, where polymorphisms in the V, J, and D regions, somatic mutations, and recombination can combine to produce, potentially, billions of different immunoglobulins from a set of genes many orders of magnitude smaller in number. From this lesson we can begin to imagine some of the mechanisms by which a small number of genes can give rise to mind-boggling complexity at the level of the cell or the animal.

The first of these is by various forms of editing of the message. Cells of higher organisms clearly treat mRNA in much the same way my word-processor can treat text. Messages can be cut and pasted in many different ways (alternative splicing), and individual words and phrases can be modified or replaced (RNA editing). There are no good estimates for the number of human genes that are subjected to either of the these procedures, but whenever it happens, multiple gene products - often of quite different sequence and, presumably, function - are produced from a single coding region of DNA. Available data suggest that the frequency of such manipulation increases dramatically as one goes 'up' the evolutionary scale towards humans. One conclusion we can draw from this is that we desperately need methods to scan a gene sequence and to know whether alternative splicing and/or editing is likely, and, ideally, what the results of such modifications will be. It seems clear that the key to how to do this will lie in understanding the role of the non-coding regions of the genome, which no one in their right mind should ever refer to again as 'junk' DNA (unless it is with tongue planted firmly in cheek).

Of course, the non-coding regions are also where much of the regulation of gene expression is controlled, through the binding of enhancers and other modulators of transcription. Relative to other eukaryotes, this part of the human genome is very large, so that the total number of base pairs is in the billions even though the number of genes is only a few tens of thousands. I suspect that expansion of the non-coding part of the genome is very important for the evolution of complexity, since it scales well with the apparent sophistication of the organism. Increasing the size of regulatory elements would allow for a greater number of combinatorial possibilities for gene expression, thus permitting a wide range of phenotypes from a smaller set of instructions.

This consideration, though obvious, has, I think, profound consequences - because it suggests to me that the real issue isn't even the number of proteins that can be produced from a single transcript. The real issue is the number of distinct protein functions that a given gene can encode. Here we are on shakier ground, but the evidence is mounting rapidly that this number could be large, and word-processing of the message is only one of several mechanisms by which functional possibilities are expanded. Post-translational modifications, such as limited proteolysis, phosphorylation and methylation, can clearly alter the function of a protein, in some cases by serving as a reversible switch. Ligand binding can do the same - the small GTPases have different cellular functions in their GTP-bound and GDP-bound states, for example. So can binding to a membrane or another protein: the resulting conformational rearrangements can cause a complete change in what a given gene product can do. The location within the cell in which a protein is found can also determine its function: witness the number of proteins that can act as transcription factors once they are translocated to the nucleus, usually after some covalent modification such as phosphorylation or following the release of some inhibitory partner. It seems clear that we cannot claim to have enumerated the functions of a gene until we have established the totality of the modifications and interactions that its protein product(s) can undergo, and the precise locations in which they occur.

Yet even this is unlikely to suffice. Recently, it has become clear to many biologists that, at least for some proteins, the concept of a single 'active site' is too simplistic. Consider the case of the extracellular cytokine neuroleukin and the housekeeping glycolytic enzyme phosphoglucose isomerase (PGI). The second enzyme in the pathway from glucose to pyruvate, PGI would appear to be an example of a simple gene product with one function: to convert glucose-6-phosphate to fructose-6-phosphate. Neuroleukin, a potent cytokine in the development of the central nervous system, would also appear to be an example of one gene - one function. But appearances, in genomics, are deceptive, for PGI and neuroleukin are the same molecule.

Leaving aside for the moment the obvious question of how an intracellular metabolic enzyme with no signal sequence gets out of the cell in the first place, the question of what it is doing out there is tough to answer. This is not a case of alternative splicing or post-translational modification, because purified PGI from a cloned gene will function just fine in a neuroleukin assay. We call this phenomenon 'moonlighting': the taking of a second job by a protein whose function we thought we knew. And PGI, astonishingly, seems to have two more jobs besides (when does it ever sleep?). It also moonlights as autocrine motility factor (AMF), a role in which it causes tumor cells to become motile, and as DMM, a mediator of the differentiation of leukemia cells. Specific receptors have been isolated for some of its functions.

PGI is not the only eukaryotic enzyme that moonlights. Thrombin, the enzyme whose action causes blood to clot, also functions as a cytokine through binding to a specific receptor. Methionine aminopeptidase doesn't only remove the amino-terminal methionine residue from newly synthesized proteins; it also serves as a specific cofactor in the translational machinery of the ribosome. In all of these cases, the non-enzymatic functions of these proteins are independent of their catalytic action and reside in regions of the protein surface distinct from the 'active site'. Many more examples of moonlighting are turning up all the time, and the phenomenon may explain a curious fact, namely that the average size of a given protein increases as one goes from bacteria to higher organisms. The grafting of non-enzymatic signaling and regulatory functions onto the polypeptide chain as organisms became multicellular would allow the genome size to remain relatively small while expanding the size of the gene products only modestly (for a further account of moonlighting, read the 1999 review by Connie Jeffery: Trends Biochem Sci 1999, 24:8-11).

Thus we have at least four potential mechanisms by which a small number of genes can give rise to many times that number of functions: word-processing of the message; post-translational modification, ligand binding, and localization; combinatorial protein-protein association and regulation of expression; and moonlighting. Taken together, they easily allow 30,000 genes to produce 150,000 'different' proteins at the level of function. In fact, the more one thinks about it, the more one suspects that, for Homo sapiens, the number of gene functions - as distinct from genes - may be seriously underestimated. Any bids for a million?

Published: 28 February 2001

The slide rule and the calculator

Genome Biology 2001, 2:comment1004.1

Now that the race to sequence the human genome is over, with both sides engaging in the most patently phony display of amity since the negotiations that ended the Vietnam War, we can put aside petty political considerations and try to answer the most profound question that this monumental achievement raises: who won?

It's exactly the same question that I found myself asking at the conclusion of the first cricket match I ever saw, but is a lot easier to answer. The obvious answer, and the one offered by most pundits, is that we all won. We have the sequence, and we can go ahead with all the exciting science it will enable us to do. We have it faster and at a lower cost than if the private competition had not stepped in and made use of the public project's data and, because of newer technology, forced the public initiative to change its strategy and accelerate its pace. This argument has considerable merit. Celera Genomics, the private company, acknowledges that it made use of the publicly available sequence data from the Human Genome Project in assembling the fragments of sequence produced by its whole-genome shotgun-sequencing strategy. The Human Genome Project acknowledges that the arrival of Celera on the scene caused it to abandon its original goal of producing a complete, highly accurate sequence slowly and drove it instead to generate a draft sequence of lower quality as rapidly as possible. From these facts, it is possible to conclude that each side needed the other and, since they ended up publishing simultaneously, the race could be considered to have ended in a dead heat.

But when other facts are taken into account, this conclusion - which is the one the public project would dearly like accepted - seems simplistic. The private effort did not really need the public data. Celera has shown repeatedly that its whole-genome shotgun-sequencing method is capable of assembling an accurate draft sequence entirely on its own, even for multi-chromosomal genomes far larger than those of bacteria. Craig Venter and Ham Smith, the inventors of this approach, clearly devised a superior strategy to that used by all of the public initiatives. The slowness of the public projects to recognize this superiority is, in retrospect, hard to understand. Celera's technology was also superior. By assembling huge banks of automated sequencing machines and employing massive computational resources to assemble fragments of the genome into their proper order on each chromosome, the private initiative was - and is - able to sequence any genome many times faster, and at least an order of magnitude cheaper, than by traditional methods.

The power of the technology has not yet made its full impact felt, but it will. If Celera were to turn the full force of its sequencing capabilities on a single problem, it could sequence the entire yeast genome in less than a day. Genomes the size of mouse, chimpanzee or human can be done in draft form in at most a few months. This is transforming technology. It changes our entire perspective on data-gathering in biology. It is so fast, and potentially so cheap (less than a million dollars for yeast), that it demands that we start to ask which genomes we would like to have sequenced, not which ones we can afford to have sequenced. It frees us to consider the use of genome sequencing as a routine tool in basic medical science and evolutionary and developmental biology. As we contemplate this power, it becomes clear that Celera only used the human project's published data because it would have been stupid not to.

None of this is intended to minimize the considerable contributions of the public effort. After all, the publicly funded researchers started the whole thing. They mobilized the support of governments and the public as a whole for the effort, gathered the resources needed, mapped the genome, and developed many important early-stage technologies. Now they want to finish the job they originally started: to produce a high-quality, complete genome sequence for the human genome. They have earned the right to do so. But it's unclear that they should ever do another genome by the same methods. Celera's technology is clearly the way to go in the future, and the best use of public funds would be to contract companies like Celera to produce desired genome sequences with a condition of the contract being immediate public availability of the data. As a for-profit entity responsible to its shareholders, a company like Celera would probably find such a revenue stream attractive. My recommendation would be for the Human Genome project to set aside a large sum for such contracts and then convene a panel of biologists to establish priorities for which genomes to sequence.

What, then, should the public project do with itself after it finishes the complete human sequence? Gathering data on single-nucleotide polymorphisms (SNPs) and other individual genetic characteristics may make some sense, but I think most of the interesting work in this area will probably be done more rapidly in the private sector because of possible commercializable medical applications. A better goal for the human initiative would be to produce and make available the cDNA clones of all human genes for research use. They could do the same for other important higher organisms such as the mouse, the fly, the worm and the dog, and for important microbial organisms as well. I think it would also be a good idea for them to turn their attention to proteomics and functional genomics. They can develop techniques for both of these efforts, and can - and should - carry out analysis of protein structure and function for organisms of no medical or commercial importance, as these are unlikely to be investigated privately. But if they try to compete with the private sector for genome-wide analysis of medically related and industrially useful organisms, they are likely to find themselves once again losing the race. The public programs will, of course, do something. It would be unreasonable to expect them to do what Senator Aiken of Vermont urged the US to do in the middle of the Vietnam War (and what the US should clearly have done) - declare victory and go home.

In retrospect, it would have been very smart for the public sequencing initiative to have done just that when Celera announced its intention to compete. But the public effort had too much pride invested, and I think also greatly underestimated the power of the Celera technology. My guess is, however, that the real reason it made what I consider the wrong response to the challenge of the private initiative is that it saw its mission in too narrow terms. The researchers viewed their objective as simply to sequence the human genome. In much the same way, the makers of slide rules saw their function as simply to manufacture slide rules. Had they seen their mission more broadly - say, to facilitate calculations - they would have developed the electronic calculator themselves, or at least marketed it when it was developed by others. But they didn't, and now they and their product are primarily historical artifacts. Had the public effort seen its mission as the provision of tools and data that would enable the human genome sequence to be obtained, no matter by whom, they would have stepped aside for Celera at the appropriate time or truly joined forces with it. Their best hope for escaping irrelevance now is to take the widest possible view of their future goals.

Perhaps it would not have mattered had they judged things correctly. No organization willingly contributes to its own demise. (This is why the police are unlikely to completely eradicate crime.) Organizations are like organisms: they do whatever they can to survive. Public genome projects, and the big-science philosophy they have spawned, will be with us for a long time to come. We can't expect them to put themselves out of business. But we can demand that they do not stick to that business when they should get out, and that they become as adaptable in this age of genomics as we individual biologists have had to become.

Editor's note: The author has declared that he has no financial or commercial interest in Celera Genomics.

Published: 6 April 2001

The Rosetta Stone

Genome Biology 2001, 2:comment1007.1

Aristotle, who got almost everything about science wrong, got quite a lot about writing and oratory right. (Perhaps the moral of this is that we might be better off if many scientists became literary critics instead... but I digress.) One of his comments seems to me particularly relevant to big science in general and genomics in particular: he asserted that the most important thing is to find the correct metaphor.

Few things can cause so much trouble, especially in scientific discourse, as metaphor. The world is full of nitpickers and literalists who take perverse delight in pointing out inconsistencies between some obscure or trivial aspect of the metaphor and its counterpart. Reminding them that it is only a metaphor, and therefore not meant to be taken literally, accomplishes nothing: in addition to taking the metaphor too seriously, such people have an unfortunate tendency to take themselves too seriously as well. Yet we persist in using metaphor, particularly when we try to explain or justify scientific research to the general public, because the power of metaphor is so great. Metaphors allow us to bypass jargon and connect what we do with the everyday experience of the public who pay for our research and trust that what we do will help, not harm them. Get the metaphor right and we can mobilize public support even for the biggest and most expensive projects.

But if the metaphor is wrong, the consequences can be disastrous. Take the United States' "War on Cancer", announced by the Nixon Administration in the 1970s with all the fanfare that normally accompanies the dispatching of troops. Good intentions, on the part of both politicians and scientists, were behind this project, but as we all know, the road to hell is paved with those. War seemed to be the right metaphor for the anti-cancer project: it was, after all, a matter of life and death, and cancer had long been viewed with all the fear and hostility normally accorded an enemy. But I think it was the wrong metaphor, and in this case tragically wrong. Wars are perceived as having definite end-points, and usually must be won totally or else are deemed lost. This was never possible for the War on Cancer. Cancer is not a single disease. Every cancer has its own peculiarities, and the causes and treatments for it usually do not apply to most other cancers. This fact alone made a clear-cut victory in the war impossible. It also made a rapid victory even in a few key battles improbable. Thus, the metaphor of a war raised expectations that could never be met.

True, the research that the cancer war spawned in the 1970s is now paying off with new approaches to cancer diagnosis and treatment thirty years later, but lay people do not connect today's breakthroughs with investigations that began so far back. Three decades is too long for a war. And yet the right metaphor would not only have avoided the disappointments that the war analogy produced, it would also, I think, have allowed that long-term connection to be understood. Suppose we had called it the Cancer Campaign, for example - that metaphor conveys a very different image, of a process that evolves over time and has many stages. Or the Cancer Initiative. I sincerely doubt that either of these metaphors would have been less effective than war in securing the funding increase that was obtained; the importance of the project spoke for itself.

When the human genome sequencing project was started, a number of different metaphors were used to galvanize public and private support. The most common was that the sequence would represent a blueprint for building a human being. Another popular one likened the sequence to an encyclopedia. These metaphors were, I believe, very badly chosen. They convey the impression that the genome sequence can be understood easily and used readily. As we know, nothing could be farther from the truth. And now we have a gaggle of 'me too' big-science projects in its wake, which are being sold on the basis of their value in drug design (The Structural Genomics Project) or gene therapy (The Functional Genomics Project), or other immediate needs. Science isn't really like that. No one project can take us smoothly to improvements in human health. Even the biggest and best provide but a few pieces of the puzzle.

This argument suggests what I think is the best metaphor for the genome project and its progeny. Arguably the greatest pure puzzle ever solved by human ingenuity was the decipherment of Egyptian hieroglyphics by Thomas Young and Jean-Francois Champollion. After all, the language of one person is completely meaningless to someone who has not been taught its alphabet, rules of grammar and vocabulary. It would thus seem impossible to decipher a 'lost' language, yet that is precisely what was done for hieroglyphics by Young and Champollion.

The key to solving the puzzle was, as every schoolchild knows, the discovery of the Rosetta Stone. Unearthed in 1799 when a group of French soldiers at Fort Julien in the town of Rosetta in the Nile delta were demolishing an ancient wall, the stone contained the same text inscribed in three different languages: hieroglyphics, demotic (a script replacement for hieroglyphics that evolved in Egypt around 600 BC and which was equally obscure), and Greek, which any scholar of that era could read. The Greek text represented the key to deciphering the other two languages, but because hieroglyphics turned out to be a phonetic language after all (not a pure picture language as was commonly assumed) it was a far from trivial task. (There's a wonderful chapter on how it was done in Simon Singh's marvelous The Code Book (1999), a history of cryptography from ancient Egypt to the present day.)

If we imagine that understanding human biology and using that understanding to cure disease and improve the quality of life is a task every bit as difficult as being able to decipher hieroglyphics (our first metaphor), then scientists are modern versions of Young and Champollion (second metaphor); the results of scientific research constitute the Rosetta Stone that will eventually enable us to solve the mystery (third and most important metaphor), and the genome sequence is one script on the tablet (fourth metaphor). Proteomics would provide another inscription, as would the three-dimensional structures of all the gene products, and so forth. Just as any one of the inscriptions would not have been enough, any one project - even the genome project - is not enough on its own; we need a number of different approaches, and the data from all of them. Individual 'small science' projects can aid in deciphering individual words or letters; the goal of each of the 'big science' genome-wide projects is to provide entire blocks of text in different languages that can, ultimately, all be put together to crack the code.

I like this metaphor because it seems to me to evoke many of the actual characteristics of the scientific endeavor. It enables anyone to realize that no single project can provide the single answer. It suggests the difficulty of the task and the long struggle that may be required. And it also conveys some of the excitement and romance of the challenge. Best of all, the metaphor is elastic: we can continue to use it to explain each new effort and to help the public chart our progress.

The wrong metaphor oversells what we do and raises hopes unfairly in people who trust us to make their lives better. The right metaphor helps them understand the torturous path between basic scientific discoveries and medicines or products, without robbing them of the hope that such a path will eventually be traversed. Maybe Aristotle had something useful to offer science after all.

Published: 1 May 2001

Location, location, location

Genome Biology 2001, 2:comment1008.1

My father always said one should buy the cheapest house in the best neighborhood one could afford. He reasoned that the quality of the neighborhood would ensure that the value of the property would increase with time, and the relatively low price of the house would mean that it would not be overpriced and so would have a high percentage return. When I once questioned this advice on the grounds that the cheapest house might be cheap because it was poorly constructed or in need of repairs, he responded that one could always sell a relatively low-priced house to someone else if the neighborhood was good. "The only thing that really matters," he said, "is location." Years later I had a friend who bought and sold commercial property. He seemed to do well at it, and I asked him what his secret was. He replied with a maxim that he claimed was followed by everyone who was successful in the real-estate business. "The three most important words in real estate," he said, "are location, location, location."

Soon, if you ask cell biologists what they would most like to know about the products of the genes they are studying, you may get the same response. If you asked them now, most would probably say "The structures" or "The function(s)," but for proteins for which structural information is already available either "Location" or "The proteins it interacts with" are, I think, also very good choices. And I wager that before long these two alternatives will be almost synonymous, not only with each other but also with beginning to know the function.

I believe we can now make the categorical statement that there is no such thing as a freely floating protein in a eukaryotic cell. Everything is tied up: in complexes with other macromolecules, in cargo vesicles, by attachment to membranes, or as passengers on actin railroads in the cytoskeleton. Perhaps prokaryotes can be accurately described as bags of enzymes (though I wouldn't bet on that) - but eukaryotic cells are organized. In fact, it is increased organization, not increased gene number, that is the real hallmark of the complexity of eukaryotic cells. (The fission yeast Schizosaccharomyces pombe, whose genome has just been sequenced, has fewer genes than the bacterium Pseudomonas aeruginosa.) And the key to this organization is location. In eukaryotic cells, proteins are targeted to the sites where they are needed in a dynamic fashion. Changes in targeting are used to alter protein function at the cellular level, even when the biochemical function of the gene product does not change.

Nowhere is this fact more evident than in signal transduction pathways. The number of protein kinases in, say, the human genome is large, but it is nowhere near the number of protein kinase substrates. Since we do not appear to have one kinase for each substrate, kinases must have less than absolute specificity. But in that case, how are they prevented from phosphorylating the 'wrong' protein at an inappropriate time? Location is one answer. If the kinase is targeted to the same location as its 'correct' substrate, a location different from that for any other potential substrate, then the action of that kinase can be made specific in a dynamic fashion, changing as needed by simply relocalizing kinase and/or substrate.

Or consider the small monomeric GTPase Tem1 from the budding yeast Saccharomyces cerevisiae. A member of the Ras superfamily, Tem1 is an essential gene product in yeast. It is involved, inter alia, in termination of M phase of the cell cycle. Many yeast proteins have been subjected to a systematic investigation of their interactions with other proteins by genome-wide two-hybrid analysis. Tem1 is one of these, and it has been found to interact physically with 24 different yeast gene products. Now the average protein-protein interface has been shown, by crystal structure determination of many complexes, to be at least 400 square Angstroms in contact area. If we assume that Tem1 can be approximated by a sphere of 25 Angstroms radius, then the protein has about 2,000 square Angstroms of surface area available for interaction at any one time. (Tem1 is not really spherical and its surface is far from smooth, but for our purposes these oversimplifications don't matter.) One concludes from this simple consideration that no more than about four proteins can possibly bind to Tem1 at the same time, so how do we account for the fact that 24 proteins are able to do so? Differences in the timing of gene expression can account for some of the control of specificity, but most of that control has to come from targeting of Tem1, and its partners, to different locations in the cell at different times.

Although the most frequently employed targeting mechanism seems to be phosphorylation or the binding to a phosphorylated site on another protein, two other common types of targeting are by binding to membranes and binding to scaffold proteins. It is often difficult to recognize either a scaffold protein or something that will bind to one from examination of the sequence or even the structure of a protein, although some scaffolds (say, a protein with seven SH3 domains) are obvious. More work on the computational identification of possible sites of protein-protein interaction is clearly needed. Membrane-binding modules, on the other hand, can often be detected by sequence-gazing (although new ones are turning up all the time, and some of them are also used to bind other proteins instead). Covalent attachment of a protein to a lipid molecule that in turn localizes the protein to the membrane, as in the case of Ras, which is farnysylated at its carboxyl terminus, is also common. I have always been uncomfortable with the idea that these lipid anchors just insert into membranes willy-nilly by virtue of their hydrophobicity. I doubt that membranes in eukaryotic cells are really just random soups of lipids; that likelihood seems as remote to me as the possibility that eukaryotic cells are random soups of proteins. I think that membranes will be found to have many patches where specific lipids congregate, forming islands that target the lipid anchors, and lipid binding domains, of proteins not just to the membrane but to very specific places on the membrane. Control of the location and size of these patches by enzymatic modification and hydrolysis of phospholipids is likely to be a major area of research in the genomic era. So is the question (which in my view has received too little attention) of how proteins come off the membrane when they are to be targeted to a new location. Much more work is needed on all this.

Which brings me to my final thought: that understanding location and how it is used to control the action of gene products means a lot more than just doing the yeast two-hybrid screen on all the proteins in a genome. It is the dynamics of localization that matter: not just where something is, but when it is there. It does you very little good to buy the cheapest house in the best neighborhood if the following year your neighbors' houses disappear and are replaced by a shopping mall, or a prison. Ask anyone who has ever bought property for investment purposes and they will tell you that it is folly to assume that neighborhoods will always stay the same. For too long we have made that same assumption, unconsciously, in our thinking about how proteins function in the cell. But in the age of genomics we will all have to consider location as something that is not only the key to much of biology, but something we, like real estate agents, can never take for granted.

Published: 6 June 2001

Model behavior

Genome Biology 2001, 2:comment1009.1

"I am not a doctor, and you are not ill;" says Selim to Osmin in Voltaire's Philosophical Dictionary (1694), "but it seems to me I should be giving you a very good prescription if I said to you: 'Put not your trust in all the inventions of charlatans ... and believe that two and two make four.'" I've always liked this advice, but it seems to me that most scientists are prone to believing - or perhaps hoping is a better word - that two and two can, sometimes, with the aid of the right technology, make five.

Three examples of this misguided faith have caught my attention recently. The first was a report that the extremely sophisticated (and extremely expensive) 'stealth technology' that supposedly allows US military aircraft to evade detection by enemy radar can be defeated by inexpensive - and commonly available - networks of mobile phone towers. The second is a fascinating book by Bruce Schneier: Secrets and Lies: Digital Security in a Networked World (John Wiley & Sons, US and UK; 2000). Schneier, an authority on computer security, wrote the book because he had come to the conclusion that, contrary to the belief of those who invest a fortune in fancy encryption and authentication methods, it is impossible to build a totally secure system. Computer security systems rely on bug-ridden or unstable hardware and software, and their creators and users are fallible and unreliable human beings. Schneier's advice is, "put not your trust in mathematics." He would have been delighted with Samuel Johnson's remark that there is no problem the mind of man can set that the mind of man cannot solve. His is an entertaining - and sobering - look at a catalog of disasters, foulups and frauds, and a marvelous record of a journey that took him from idealist to a pragmatist.

The third example is more subtle, but perhaps equally telling. It also reminds us that, when it comes to depending on technology, we would all do well to be more pragmatic. It comes from the burgeoning science of structural genomics. In the latest issue of Nature Structural Biology, Vitkup et al. (Nat Struct Biol 2001, 6:482-484) attempt to calculate how many protein structures will need to be determined in order to meet the stated goal of obtaining useful, three-dimensional models of all proteins by a combination of experimental structure determination and comparative model building. They evaluate different strategies for optimizing information return for effort invested, and conclude that the strategy that maximizes structural coverage requires about seven times fewer structure determinations compared with the strategy in which targets are selected at random. With a choice of reasonable model quality and the goal of 90% coverage, they extrapolate that it would take approximately 16,000 carefully selected structure determinations to provide information allowing the construction of useful atomic models for the vast majority of all proteins. They further point out that, in practice, unless there is global coordination of target selection, the total effort is likely to increase by a factor of three.

This is a nice analysis and its conclusions are very important for the field, but that isn't the point I want to make here. What I found striking is their assumption, which I think is right, that the goal of the structural genomics initiative will be seen to have been met when enough structures have been done to allow all other structures to be modeled from them. In other words, we are putting our trust in homology modeling.

Given the two examples I mentioned earlier, I think it is worth considering whether this trust in technology is justified. Homology modeling aims to produce a reasonable approximation to the structure of a protein using the known structure of a homolog: a protein related to it by divergent evolution from a common ancestor. Structures that have diverged too far cannot be modeled reliably; the arrangements in space of their secondary structure elements tend to shift too much. In practice, structures with more than about 40% amino-acid sequence identity, and with no large insertions or deletions in their aligned sequences, can usually be used to produce homology models roughly equivalent to a medium-resolution (about 3 Angstroms resolution) experimental structure. Vitkup et al. aim for approximately that degree of reliability.

What can be done with such models? Well, it is more instructive to consider what cannot be done with them. They can be used to determine which amino acids are in the catalytic site or molecular recognition site if those sites are in the same place in the modeled and experimentally observed protein structures, but they cannot be used to find new binding sites that have been added by evolution. At present, there is no reliable way to interrogate a purely modeled structure and locate such sites from first principles. Further work in this area is urgently needed. Homology models cannot be used to study conformational changes induced by ligand binding, pH changes, or post-translational modification. At present, computational tools to generate such changes from a starting model are not robust. Again, more work is needed here. Homology models also cannot be docked together to produce good structures of protein-protein complexes; not only are the docking algorithms unreliable, but the likelihood of significant conformational changes when proteins associate makes it impossible to know whether one is docking the right structures. In short, many, if not most, of the things that biologists want to do with a protein structure cannot be done with confidence using homology models alone.

This is not to say that such models are useless. But it is meant to inject a cautionary note to the frenetic salesmanship that surrounds genome-wide structure determination. There will still be a huge amount of structure-based work to be done on important proteins, real work using real proteins and based on experimentally determined structures. The homology models will be very helpful in determining those structures, but will not replace them for most things of interest. And it is unclear that the structural-genomics initiatives will produce those structures: structures with ligands or cofactors bound, structures at different pH values, structures of modified proteins and structures of protein-protein complexes. Such work will be done by individual investigators, who need the support of research funding that may be siphoned off into genome-wide programs if we put too much trust in high-throughput technology.

In the US we are dealing with the after-effects of a bubble economy in internet company stocks. In Japan, a similar bubble of asset price inflation, chiefly in property, has long since burst with consequences that are still being felt. Scientific research has its bubbles too, but they come not from inflated prices but from inflated expectations. If we put too much trust in any one technology and neglect the important things that are less glamorous and require harder and longer efforts, we are in danger of failing to follow Selim's prescription. As the euphoria over all things genomic continues, we would all do well to remind ourselves that two plus two still equals four, and always will.

Published: 4 July 2001

Design by necessity

Genome Biology 2001, 2:comment1010.1

They're back. I suppose we should have always known they'd be back. As in those children's games played with tiny hammers, no sooner have you pounded them down in one place that they pop up somewhere else. I am referring, of course, to the anti-evolutionists. I suppose they're not really back, because they never actually went away. They simply get a little quieter for a while when their argument du jour is soundly refuted, but they don't go away. Before long they find some other, seemingly new, irrefutable argument that they cling to the way a drowning man clutches at a straw. The simile is apt, I think; there is a curious element of desperation about their behavior. It resembles that of the test pilot in Thomas Wolfe's The Right Stuff (Bantam Doubleday: 1980): aircraft malfunctioning, frantically radioing, "I've tried A! I've tried B!! What do I try next??"

One of the things they tried was asserting that evolution violates the Second Law of Thermodynamics. Life, they argued, is characterized by systems much more ordered than their surroundings. It could not have arisen spontaneously; that would violate the Second Law, which demands an increase in entropy, or disorder, in spontaneous processes. Unfortunately, what the Second Law actually demands is that the entropy of the universe, not the entropy of the process, must increase. The ultimate source of the free energy needed to build ordered systems on earth is, of course, the sun, which is constantly cooling down and gaining entropy, just as the Second Law requires.

They also tried the probability argument: the concentration of key chemical species in the primordial soup must have been too low for the reactions needed to form amino acids, or small peptides, or bits of RNA, to have had other than a minuscule probability of taking place. I tried this argument on a group of biochemistry graduate students as a comprehensive exam question, and got a number of simple, logical answers that did not require creationism: chemicals could have been concentrated in melting ice deposits, or adsorbed into clays and thus brought together. It really is not a problem at all. The best answer I got was from a student who said, "So what?" Her point was that the probability might indeed have been infinitesimally small, but there are trillions upon trillions of stars - and presumably planets - in the universe, and the extraordinarily lucky chance only had to occur once, here. That would mean we are alone, the only planet with life anywhere, but maybe that's the way it is. I loved that answer because it recognizes the arrogance and paucity of imagination of what biologist Richard Dawkins called the "argument from personal incredulity", which is at the heart of all anti-evolutionary reasoning: if I can't imagine how it could have happened, then it couldn't have happened.

The new idea sprung from this dry well is called Intelligent Design, and it has caught on among creationists like the summer's blockbuster movie. In essence, this theory (and one of the clever things about it is that it presents itself not as doctrine but theory - just another theory, like the theory of evolution, and by implication, entitled to equivalent consideration) argues that living things contain systems so complex that evolution by natural selection could not have produced them. The intellectual underpinning for this theory is Michael Behe's claim (in Darwin's Black Box: The Biochemical Challenge to Evolution; Simon & Schuster: 1996) that certain biological systems are "irreducibly complex", meaning that they are composed of several well-matched, interacting parts that work together to provide the basic function, and that the removal of any one of these parts would cause the system to fail. Behe's illustrative example was a well-designed, minimalist mousetrap. (We will ignore the fact that evolution has produced an even better mousetrap - the cat.) Biological examples of seemingly irreducibly complex systems might be the vertebrate eye, or the immune system, or the system for thrombostasis. Phillip E. Johnson (Defeating Darwinism by Opening Minds; InterVarsity Press: 1997) and William Dembski (The Design Inference: Eliminating Chance through Small Probabilities; Cambridge University Press: 1998), among others, argue that irreducibly complex biological systems could not evolve by slight successive modifications to a precursor system, with any precursor that was missing a part being by definition nonfunctional; they must therefore have arisen through design by a higher intelligence. Proponents of Intelligent Design rarely specify who the eponymous designer was - that would be bad for the supposedly scientific nature of their argument - but it's pretty obvious Whom they have in mind because they are, for the most part, evangelical Christians.

Until recently, the evolution versus creationism political debate tended to be fought out at the state and local levels in the United States, but there are signs that the battlefield is shifting. Last summer, proponents of Intelligent Design held a briefing to educate members of congress and their staffs on the supposed failures of Darwinism and the moral decay that its teaching has led to. On 13 June of this year the US Senate voted 91-8 in favor of an amendment to the comprehensive public education bill that defines "good science education" as preparing students "to distinguish data or testable theories of science from philosophical or religious claims that are made in the name of science". The amendment further states that "where biological evolution is taught, the curriculum should help students to understand why this subject generates so much controversy, and should prepare the students to be informed participants in public discussions regarding the subject." At first glance the amendment, which was written by Intelligent Design proponents, seems innocuous - but it isn't. If it were, the first part would be "to distinguish scientific claims that are made in the name of religion or philosophy", not the reverse. And there's more: earlier in the same congressional session, a group of conservative lawmakers had stripped a science-testing provision out of a counterpart to the Senate bill in large part because of concerns that the tests would include evolution-related questions.

So they're back, but the argument they are back with doesn't stand up against the evidence of genomics. Comparison of the human genome sequence with those from other animals and from fungi and bacteria reveals that most human genes, even those coding for the parts of "irreducibly complex" systems like the eye, have obvious homologs in creatures that evolution predicts were ancestral to us. Rhodopsin, the visual photosensor (to take but one example) is strikingly similar to other seven-transmembrane helical proteins in bacteria, some of which also sense light, although others perform different functions. Irreducibly complex systems can evolve gradually in biology in part because their precursors do not have to perform the exact same function: the ancestral mousetrap could have been a cheese tray. And the argument that mutating the cheese tray into a mousetrap would be impossible because then one would lose the function of the cheese tray clearly fails when genomic evidence is considered. All the genomes sequenced to date contain many examples of duplicated genes. Frequently whole sets of genes are duplicated, and this phenomenon is more prevalent the higher up the evolutionary ladder one climbs.

Genetic observation of synthetic lethality for many nonessential genes shows that vital functions are often shared by more than one protein, and sometimes by more than one pathway. Redundancy is a hallmark of living systems. Backup systems abound: when one protein or pathway fails, another can often take over. Redundancy also allows natural selection to tinker with a gene, or a system composed of many genes, without necessarily losing one function to gain another. Genomics further reveals that 'silent' genetic information is also more common than we had imagined. Apparently it isn't so bad to keep nonfunctional things around; the old notion that this is inefficient and would therefore be selected against may require reevaluation. Perhaps any 'waste' of metabolic energy in synthesizing and maintaining these segments of DNA is more than compensated for by the possibility that they will eventually mutate into something useful. Genomics has taught us that living things are messy, redundant, seemingly inefficient and that nature doesn't give a damn about any of that. The only thing that matters is utility. If something works, if it satisfies some necessity, then it has a good chance to survive, and evolve.

I am surprised that Intelligent Design mavens have so much trouble with the concept of design not by a higher intelligence but rather by trial-and-error satisfying necessity. It ought to be very familiar to them. The vast majority of people promoting Intelligent Design are social and economic conservatives, and if they only took a minute to consider their own favorite solution to most problems - the free market - they would see that an irreducibly complex system can easily arise without intelligent design. Consider the enormously complex structure that is free-market capitalism, inarguably the most efficient system ever for producing, delivering and pricing goods and services. No one designed it. It developed over centuries through slight, successive modifications to the precursor system. Its parts are interdependent, well-matched and fully interacting. It contains many systems, such as that required to produce and deliver my daily newspaper, wherein removal of any one part would cause that system to fail. Yet it came about through gradual evolution, not through the top-down imposition of a grand design.

Attempts to supersede the competitive market with designed, hierarchical systems have all failed thus far, communism being the latest in a long line of such failures. It was inevitable, I think, that planned economies would fail, not because they are necessarily morally inferior but because they are impossible. To design an economic system and run it requires the constant, instantaneous gathering and assimilation of vast amounts of information. Such coordination and integration is beyond any one person, or any group of people. But it is not beyond the market, which performs this miracle continually, through what the great economic philosopher Friedrich A. Hayek called "the spontaneous extended order of human cooperation". The necessity of making a profit in order to survive and grow is the only thing needed to produce a working system of immense complexity and extended order. 'Intelligent' design of a mandated arrangement of human social and economic interactions by a central authority has never produced anything remotely comparable. Necessity is not only, as the proverb puts it, the mother of invention. Necessity is also the only designer we need to explain the world that genomics has shown to us.

Published: 1 August 2001

Hell is a karaoke cruise

Genome Biology 2001, 2:comment1011.1

My brother Bryan and I were driving somewhere a few months ago when we passed a sign that advertised 'Karaoke Cruises'. For a moment we just looked at each other, and then he said "Can you imagine being trapped on a boat with a bunch of people doing karaoke at every meal? With no way to escape because you're at sea?" I shuddered. "It sounds like a definition of hell," I agreed. Which got me thinking. Over the centuries, people have defined hell in a variety of picturesque and imaginative ways. A favorite of mine is Sartre's "Hell is other people", a sentiment that every university professor can appreciate (it's also the name of a rock group, by the way - but I digress). My thought was this: what would constitute a definition of hell for a scientist in the post-genomics era? I submit the following as some possibilities, but would welcome additional suggestions from readers.

Hell is

... claiming that the number of genes in the human genome is N only to have your biggest rival announce that it is N/5.

... waking up at night with the terrible feeling that all that 'junk' DNA must be doing something.

... finding, for every one of the genes you're interested in, not a single BLAST hit.

... discovering that your favorite gene has absolutely nothing to do with cancer, Alzheimer's, or any other human disease.

... doing a BLAST search on your favorite gene and finding ten hits, all of which are annotated 'ORF of unknown function', and all of which are found only in obscure prokaryotes without a history of genetic analysis.

... falling in love, scientifically speaking of course, with an organism whose genome has not been sequenced and which is so understudied that its genome may not get sequenced until 2050.

... having announced that the number of genes in the human genome is N only to have your biggest rival claim that it is really 5N.

... having your grant not funded because it does not take sufficient account of the tools and results of genomics, then spending six months to revise it so that it does, and having it rejected again because it is no longer 'hypothesis-driven research'.

... having your political leaders, or your mother, ask you where all the promised big benefits to human health are now that the human genome has been sequenced.

... trying to write a grant for proteomics research and realizing that you have no idea what proteomics really is.

... studying a human gene that turns out to be expressed only in the appendix.

... realizing that you took all the wrong courses at the university. You took mathematics, physics, chemistry and biology; in the era of genomics you should have taken economics, computer science, sociology, business management, ethics and abnormal psychology.

... trying to do stem-cell research in the United States under the Bush administration.

... having grown up as a physicist with the sense of entitlement to funding for your big science projects and access to the corridors of power, only to find yourself suddenly living in the age of genomics, when biology is king.

... having been involved in sequencing the human genome and, when asked how many genes there are in it, having to say "Who knows?"

Published: 31 August 2001

September 11, 01

Genome Biology 2001, 2:comment1012.1

I was in a car driving past the Pentagon about an hour before the hijacked plane hit it. By the time it hit, I was at the National Science Foundation, a mile or two away. The first indication that something horrible was happening was an NSF staff member who told us that an airplane had just crashed into one of the towers of the World Trade Center. My first thought was that a terrible accident had occurred. Eighteen minutes later, when the second plane plowed into the other tower, we all knew that it was no accident. Death had come out of the sky, not by chance, but by the malevolent design of evil men. When the towers collapsed, one after the other, in an eerily quiet, vertical fall that resembled the controlled implosion of a derelict hotel, the casualty list included more than the passengers and crew of the aircraft, the office workers in the buildings and the heroic firemen and policemen who had rushed inside to aid in the evacuation. Dead also was our American sense - false as it may have been - of isolation from the madness welling up in remote parts of the world, and of invulnerability by virtue of that isolation and our mighty technology. In a few terrible seconds, our world changed into an infinitely more frightening and unpredictable one.

Thus far I have resisted the urge to stare endlessly at the images of the planes crashing and the towers collapsing. They have a strange video-game or disaster-movie quality, almost as though they were staged as part of some monstrous entertainment. It is the individual stories that drive the reality home: the man who got out safely from one of the towers, only to go back in to help others escape; he died with them when the building fell. The man who didn't go to work that day because he had to drive his daughter to day-care; all 700 employees of the company he owned perished. The con artists who, within a day of the tragedy, began soliciting donations from gullible elderly people for fake charities to aid the victims. Or the fundamentalist preachers who immediately claimed that this horror - which, they seem to forget, was visited impartially on the devout as well as on non-believers - was divine punishment for a society that they claimed had become increasingly secular. But as we mourn the dead, try to comfort the bereaved, and look for answers to the questions of who did this for what possible, twisted reason, there are a few things that seem clear.

One is that this should put forever to rest the notion that our behavior is completely, or even largely, determined by our genes. Genetic makeup does not direct a person to kill himself deliberately for no more advantage than the possible glory of martyrdom for a pseudo-religious cause. It does not direct that same person to slaughter indiscriminately thousands of innocent men, women and children, including some who practice the same religion. These actions are prompted by warped ideas planted by evil people who desire power over others and the things such power can bring them. They are the result of conscious decisions made by human beings to act against the instincts for survival and nurture that our genome does give us. Neither does our genetic makeup direct us to put our lives at risk by rushing into a flaming skyscraper to fight the fire or help others to escape. It does not direct us to give our blood or our time to aid the injured and displaced. These actions are prompted by noble ideals that have evolved as we have sought to free ourselves from the strictures of our nature. They are the result of conscious decisions made by human beings to act for something larger than themselves. And if we can so easily go against our genetically programmed instinct for survival, for good or evil purposes, then there is hope that we can in time learn to overcome our instinct for violence, and our instinct for greed, and our instinct for selfishness.

The second conclusion I draw from these awful events is that our quest to understand ourselves, which is what prompted the human genome project in the first place, has never been more important. People do abominable things for many reasons, but one reason is that they have been led to do so by their belief in what is untrue. Science has as its goal the discovery of the way things really are, and there is no better weapon against the sort of misinformation and perverted philosophy that led to the terrorism of September 11, 01. Of course, to be an effective weapon, the results of our work must be freely available and must also be explained to those who are not scientists in the clearest and least patronizing fashion. Only then can science displace the lies and half-truths that are used to shape the minds and hearts of people desperate to understand. Put another way, we've tried everything else: maybe it's time we tried the truth.

It was a man of exceptional grace, courage and intelligence who uttered the words that I find the most comforting at this time. Mohandas Gandhi said, "When I despair, I remember that, all throughout history, the way of truth and love has always won. There have been tyrants and murderers and for a time they can seem invincible, but in the end they always fall. Remember this, always."

Published: 26 September 2001

Winter, plague and pestilence

Genome Biology 2001, 2:comment1013.1

Germ warfare. A new terror from an old idea - almost as old, perhaps, as war itself. During the Middle Ages armies besieging a city would sometimes hurl the corpses of plague victims over the ramparts in an attempt to infect the population within the walls. In 1864, during the American Civil War, a group of Confederate spies (today they would be called terrorists) based in Canada attempted to spread yellow fever through the cities of the North via the clothing of the disease's victims. An outbreak of human anthrax occurred in Sverdlovsk, Union of Soviet Socialists Republic (now Ekaterinburg, Russia) in April 1979. Soviet officials attributed this to consumption of contaminated meat, but Western governments believed it resulted from inhalation of spores accidentally released from a nearby biological weapons research facility. Almost twenty years later, Paul Jackson of the Los Alamos National Laboratory and Paul Keim at Northern Arizona University, together with associates from the U.S. and Russia, obtained tissue samples from the corpses of 11 victims and applied new methods they had developed for efficiently extracting high-quality total DNA from these samples. Extracted DNA was analyzed using PCR to determine whether it contained sequences specific to Bacillus anthracis. Results demonstrated that the entire complement of B. anthracis toxin and capsular antigen genes required for pathogenicity were present in tissues from each of the victims, so the sequences did not come from a vaccine strain of B. anthracis. PCR analysis using primers that detect the vrrA gene variable region on the B. anthracis genome demonstrated that at least four of the five known strain categories defined by this region were present in the tissue samples: but only one category is found in a single B. anthracis strain. The conclusions are obvious, and chilling. (For a complete account, see Jackson et al., Proc Natl Acad Sci USA 1998, 95:1224-1229.)

Now a new word has joined the lamentable lexicon of human horrors: bioterrorism. The sight of white powder on envelopes is enough to send people racing to their doctors. Hordes of Americans are stockpiling an antibiotic they had never heard of (Cipro, the trade name for Bayer's ciprofloxacin hydrochloride, for the treatment of inhaled anthrax). B. anthracis, the causative agent of cutaneous, gastrointestinal and inhaled anthrax, is almost an ideal bioweapon. It is a spore former, so it can survive desiccated for months to years. It is very deadly in aerosolized form, killing about 90% of those who inhale it. Research on anthrax as a biological weapon began more than 80 years ago. Today, at least 17 nations are believed to have offensive biological weapons programs, although it is uncertain how many are working with anthrax; Iraq, for one, has publicly acknowledged producing it. The manufacture of a lethal anthrax aerosol is probably beyond the capacity of individuals or groups without access to advanced biotechnology; but autonomous groups with substantial funding and contacts with states that sponsor terrorism maybe able to acquire the required materials and expertise. One terrorist group, Aum Shinrikyo, responsible for the release of the nerve gas sarin in a subway station in Tokyo, Japan, in 1995, dispersed aerosols of anthrax and botulism throughout Tokyo on at least eight occasions. The attacks failed to produce any illness, which is comforting to know, but it is not comforting to know that the reasons for this failure are still unclear.

An anthrax aerosol would be odorless and invisible following release and would have the potential to travel many kilometers before disseminating. In 1970, a World Health Organization (WHO) expert committee estimated that casualties following the theoretical aircraft release of 50 kilograms of anthrax over a developed urban population of 5 million would be about 250,000, of whom 100,000 would probably die without treatment. A 1993 report by the US Congressional Office of Technology Assessment estimated that between 130,000 and 3 million deaths could follow the aerosolized release of 100 kilograms of anthrax spores upwind of Washington DC, a mortality comparable to that expected from a nuclear weapon. An economic model developed by the Centers for Disease Control and Prevention (CDC) suggested a cost of $26.2 billion per 100,000 persons exposed.

If all this is frightening... well, that is the objective of terrorism. But terror itself can harm much more than anything the terrorists can do. Terror can cause us to surrender our freedoms in pursuit of a false sense of security, and to make decisions based on our fears rather than on facts. Here are the facts, taken in large part from a report by the Working Group on Civilian Biodefense from the American Medical Association, published in the Association's Journal on May 12, 1999.

The name Bacillus anthracis derives from the Greek word for coal, anthrakis, because the disease causes black, coal-like skin lesions. B. anthracis is an aerobic, Gram-positive, spore-forming, nonmotile bacillus species. The nonflagellated vegetative cell is large (1-8 μm in length, 1-1.5 μm in breadth). Anthrax spores germinate when they enter an environment rich in amino acids, nucleosides, and glucose, such as that found in the blood or tissues of an animal or human host. Vegetative anthrax bacilli will form spores only after local nutrients are exhausted, as happens, for example, when anthrax-infected body fluids are exposed to ambient air. Full virulence requires the presence of both an antiphagocytic capsule and three toxin components: protective antigen, lethal factor, and edema factor. Vegetative bacteria have poor survival outside an animal or human host; colony counts decline to undetectable within 24 hours following inoculation into water. The spore can survive for decades. Inhalational anthrax follows deposition of spore-bearing particles of 1 to 5 μm into alveolar spaces. Macrophages ingest the spores, some of which undergo lysis and destruction. Surviving spores are transported via the lymphatic system to mediastinal lymph nodes, where germination may occur up to 60 days later. (The process responsible for the delayed transformation of spores to vegetative cells is poorly understood but well documented. In Sverdlovsk, cases occurred from 2 to 43 days after exposure.) Once germination occurs, disease follows rapidly. Replicating bacteria release toxins leading to hemorrhage, edema, and necrosis. In experimental animals, once toxin production has reached a critical threshold, death occurs even if sterility of the bloodstream is achieved with antibiotics. On the basis of primate data, it has been estimated that for humans the LD 50 (lethal dose sufficient to kill 50% of persons exposed to it) is 2,500 to 55,000 inhaled anthrax spores. Mortality rate is estimated at 90% after first symptoms appear.

But - and here's the crucial point - those mortality figures are derived from very old studies, long before there were very effective antibiotics available. And there is a superb one available now: Cipro, the first of the fluoroquinolone antibiotics. These compounds do not work in a penicillin-like fashion by disrupting cell-wall synthesis; they are DNA gyrase inhibitors, attacking an enzyme unique to bacterial replicative machinery. Fluoroquinolones are broad-spectrum and relatively free of side-effects. They are very effective against urinary tract infections, which are the leading bacterial infections in most developed countries. And they are very effective against B. anthracis, in part because, as far as is known, a resistant bioweapons-grade strain has not been developed.

But if people everywhere now start hoarding Cipro and taking it for every winter cold or flu symptom that comes along, or prophylactically, which is probably useless, we may not have this situation for long. Resistance arises from just such usage, and resistance travels throughout the bacterial world with great speed. The complete genome sequence of the bacterium Yersinia pestis, the causative agent of the bubonic plague, which was just reported (Parkhill et al., Nature 2001, 413:523-527), reveals that this little microbe, which in the fourteenth century killed about a third of the population of Europe, contains many genes that seem to have been acquired from other bacteria and viruses (including adhesins, secretion systems and insecticidal toxins). Pathogens are like that: they constantly acquire resistance genes and virulence factors. Indiscriminate use of antibiotics just plays into their hands.

Besides, anthrax isn't the only threat. Y. pestis has been tinkered with in germ warfare factories too. So have Clostridium botulinum, and the tetanus bacillus. Viral diseases, like Ebola, Marburg and smallpox, which are contagious, are potentially a greater hazard. And yet, individual acts of terrorism do not a widespread terrorist assault make. It is very difficult to make and deliver bioweapons on a wide scale, and they have the nasty habit of not respecting borders, or politics, or religions. Governments are unlikely to use them for that reason, and terrorist cells are probably unable to mount them as a large-scale threat. The danger, then, is in our overreaction. Vigilance is an appropriate response; terror is not.

Research is also an appropriate response. We need more microbiologists, and more work by pharmaceutical companies on microbial diseases, an area they largely abandoned thirty years ago. We need funding for innovative methods of rapid diagnosis, strain typing, and antimicrobial treatment. More microbial genome sequences, especially of different strains of pathogenic organisms, would also be very useful. And we need something else: condemnation, and swift justice, for those who create or deploy such weapons. Nations, like individuals, have the right to defend themselves. But bioweapons are different: because they do not respect borders or uniforms, they are not defensive weapons. Their only use is far from home, in an offensive strike. I believe that anyone who creates or helps to create such a weapon is a traitor to science and should be brought to trial in an international court of law for crimes against humanity.

Published: 23 October 2001

A piece of the action

Genome Biology 2001, 2:comment1014.1

We lost another one last week. A bright young assistant professor in his first few years as an independent faculty member at a university e-mailed me to say that he was leaving academic science. He wasn't leaving because he wanted a bigger salary, or because he hated his job - quite the contrary; this is a man who loved what he was doing passionately. He was leaving because he had been unable to get funding for his research. This happens, of course, to people with bad ideas, or no ideas, but I don't think he fits either of those cases. I've seen his research proposals and I think the ideas were imaginative, even exciting. But they were not particularly fashionable and they were not sparklingly written, and he was not working at a powerhouse research institution. So we have lost a promising scientist and we have also lost the work he might have done, at least until someone else comes up with the same ideas. And even then, given the conservatism and trend-worship of the funding agencies, who knows if that someone else will have better luck? All of us know of cases like this, and many of us harbor the belief that there are many excellent ideas that never see the light of day because they can't get funded.

At the same time, in the USA, Congressional supporters of biomedical research are hoping to improve on President Bush's proposed $2.8 billion increase in the budget of the National Institutes of Health (NIH), the major supporter of such research. They are seeking a 16.5%, or $3.4 billion, increase, which would bring the total NIH budget to $23.4 billion in fiscal year 2002. This would continue the ongoing effort to double the NIH budget over the period 1999 to 2003. Officials of NIH, awash in new funding, are actively seeking ideas for how to spend this largess. Afraid that they will have too little in the way of spectacular results to show for such spectacular funding increases, they are throwing money at genome-wide projects designed to accumulate reams of data, while not increasing the number of individual investigator-initiated projects that are funded, at least not at anything like the same rate.

So on the one hand we have an embarrassment of riches, while on the other we have people who leave science for want of a small amount of initial funding. To complicate the picture further, genomics is changing the scale of funding that investigators need. Driven by genomic discoveries and the cultural change they are creating, biology is becoming Big Science. To do front-line biology research increasingly requires access to expensive technology such as cDNA microarray facilities, mass spectrometry, mouse genetics and so on. New investigators at small universities, whose start-up packages barely cover setting up a modest lab and paying a technician or postdoctoral fellow for a year or two, are having increasing trouble getting their programs off the ground, let alone competing in this climate.

I have an idea that may help address these problems. It offers a radical and, I think, creative use for some - not even all that much, actually - of that additional funding. It helps level the playing field between large institutions that can give generous start-up packages and small ones that can't. And it gives beginning investigators at all institutions a chance to try out their most innovative ideas without the burden of first having to acquire preliminary data, even when their ideas are completely out of fashion.

The idea is this. Last year NIH awarded research grants to principal investigators at 485 degree-granting institutions in the USA. Since some of these were educational grants to non-research universities, let's say there are 400 PhD-awarding institutions in the biomedical sciences (the exact number doesn't really matter for this discussion). I propose that three starting faculty from each of these institutions, each year, be designated NIH Biomedical Beginning Investigators. Every beginning investigator will then be given a research grant of $175,000 each year for the first three years of his or her career. No proposal is needed and no review will be undertaken. Small and large schools will be treated alike. If an institution doesn't have three starting faculty members in one year, they may carry over those slots until they are filled, but no institution may have more than nine such investigators at a time. Thus, at steady state, the program will be funding up to nine people each year at 400 institutions at $175,000 per year, for a total outlay of $630 million. That is only 3% of the total NIH budget, and it is less than 20% of the requested increase in that budget for this coming year. Each year, 1,200 investigators will leave the program and up to 1,200 more will enter it.

A few more important rules must be noted. The money may not be used to pay any portion of the investigator's salary. Not a penny of institutional overhead (affectionately known as 'indirect costs' in the US) maybe taken out of the grant. Apart from these two restrictions, the money can be used for any research-related purpose. If the investigator wishes to save the money for the first two years in an interest-bearing account and then buy a big piece of equipment at the start of year three, that is fine. No yearly accounting will be required. At the end of the third year the investigator must submit a two-page summary of the work that was supported, including a list of any publications and funding that has been garnered because of the results. This information will be collected and summarized, but will never be used in any critique of the investigator by any funding agency.

To those who would charge that the program spends money foolishly, without regard for quality, I would answer that this is exactly the point. Quality judgements remain in research funding, in the regular research grants program, which would still account for more than 95% of the total budget. This proposal is meant to do something very different. It is meant to give the maverick, the geographically-restricted, the late bloomer, or the gremlin from left field, the opportunity to have something they do not have now: a piece of the action. We have long wondered whether, 'out there' somewhere, there may not be scores of great ideas that never see the light of day for want of initial funding. Now we can find out. It hedges our research bets, corrects for possible oversights that we may make in the peer-review system due to ignorance, laziness, rigidity and faddishness.

My proposal is directed at the largest US funding agency but there is no reason that a version of this program cannot be implemented at smaller agencies such as the US National Science Foundation, which funds non-biomedical research, and at equivalent agencies in other developed countries. If so large-scale a program is impossible elsewhere, even a smaller version of it will still help deal with the same problems, which are endemic everywhere that governments support scientific research. The exact number of investigators and institutions is not crucial and can be adjusted to fit the available resources.

If we do this, maybe there won't be so many e-mails like the one I just received. And to those who would charge that throwing money at large numbers of investigators just to see what will turn up is a betrayal of our tradition of peer-reviewed funding, I would answer that it betrays nothing. It merely seeks to remedy a few of the defects of that system. Besides, isn't just seeing what will turn up exactly what the current data-acquisition program triggered by genomics is all about?

Published: 22 November 2001

A Christmas Carol

Genome Biology 2001, 3:comment1001.1

No, this isn't another story about some selfish miserly person learning the value of kindness and generosity. Charles Dickens told that particular tale better than anyone before or since. But it is a story with a happy ending, and a moral that I believe is worth remembering. It's a story about the value of basic, hypothesis-driven research. I think the story is important because in the age of genomics such research is increasingly taken for granted, if not slighted. Discovery-driven research is so much flashier, so much easier to sell to funding agencies and government officials since it is, by definition, guaranteed to produce results. By discovery-driven research I mean research that seeks simply to collect data: the sequencing of the human genome is the obvious example. Another example would be any of the structural genomics or proteomics initiatives; these are, in essence, cataloging exercises. I don't mean to disparage such activity - in biology it has a long and honorable history. Charles Darwin's expedition on the Beagle was a cataloging exercise, and from it sprang the single most important tenet in the life sciences, the theory of evolution by means of natural selection. There is nothing at all wrong with cataloging, especially if someone with the genius of Darwin (or, to be fair, Alfred Russell Wallace) peruses the catalog.

Then there is targeted research, research that has a specific practical objective. The war on cancer (by the way, I haven't read the newspaper lately - who won?) and many other clinical research programs would fall into this category, as would the agricultural research that led to the Green Revolution of the mid-nineteenth century. This kind of research can be extremely important and often brings great benefits to mankind. Consequently, it is usually well-supported and easily justified to press and public. Carried to extremes, it produces work that has as its objective the completion of some clever stunt. Occasionally it results in technology that is useful to many other scientists, but more often it yields difficult, expensive, cumbersome technology that is useful only to its inventors. I've read many papers in this vein, and in the end they only leave me with an impression of the cleverness of their authors, which, I suppose, is precisely the impression they were meant to leave. Rarely have they taught me anything about how the world works, and I find it somewhat disheartening that such work is so widely publicized and so well rewarded these days. Our story isn't about targeted research, whether valuable or self-indulgent, nor about discovery-driven research. It's about the other kind, the kind that sometimes seems to be going out of style in biology under the onslaught of genomics.

Barnett Rosenberg wasn't trying to cure cancer. He wasn't working on cancer. He wasn't working on any disease-related problem. He wasn't even working with human cells. All he was trying to do was to test a hypothesis about what would happen when dividing bacteria were placed in a strong electric field. Yet he may have saved the lives of more cancer patients than most of the cancer researchers in the world put together. Our story begins one day in 1964 in his laboratory at Michigan State University. That day Barnett Rosenberg (Barney, to his friends) put a suspension of Escherichia coli cells between two platinum electrodes to see what would happen. He had no more practical goal than to satisfy his own curiosity about a hypothesis he had formulated. He was a microbiologist, and the behavior of bacteria was his research interest. He knew that when a bacterial cell divides the cell's DNA has to become organized, and he hypothesized that a strong electric field might interfere with the arrangement of the highly charged, precisely oriented chromosome. So he put a continuous culture of E. coli cells in buffered medium between two platinum electrodes and turned on the current.

What he saw surprised him. Cell division was inhibited, but in addition the bacteria, which are normally shaped like small rods, grew into long filaments, up to 300 times their normal length. Now our story actually has several morals, but a very important one is that in science there is no such thing as useless information. Barney Rosenberg happened to know that E. coli cells became filamentous under certain other conditions, including exposure to certain anti-tumor drugs. It didn't take long for him to establish that it wasn't the electric field itself that was producing the filamentous behavior. A chemical substance in the solution was responsible, but the effect required that group VIIIb metal electrodes be used to generate the electric field - no other electrodes would do - suggesting that the substance was being generated electrochemically from components in the media plus the platinum metal.

Many scientific journals today seem to function largely as press release vehicles, but Barney's 1965 Nature paper (205:698-699), in which he describes these studies, is an experimentalist's delight. Not only does he give enough information to enable anyone to repeat the work - the minimum standard of a scientific publication but one that is seldom met any more - he tells the story of the reasoning process he followed. After further studies he was able to isolate the active substance: he had accidentally synthesized Peyrone's salt: cis-dichlorodiammine-platinum(II), also known as cisplatin. A square planar platinum compound with two chlorines and two ammines coordinated to the metal ion, cisplatin was first described in the 1800s but had never been tested as an antibacterial or anti-tumor agent before; after all, everyone knew that transition metal complexes were poisonous. That had been the conventional wisdom for over a hundred years. But remember, Barney knew that some anti-tumor agents produced the same effects on bacterial cells that cisplatin seemed to, so in 1968 he made what he later called the "purely intuitive jump" to test this complex for anticancer activity in a mouse tumor model system. He needed help to carry out these tests because he had never done anything of the kind before. He got that help from Virginia Mansour, and on April 26 1969 they published in Nature (222:385-386) the astonishing result that cisplatin completely inhibited the development of the solid Sarcoma-180 tumor in mice.

Now, a lot of stories start out like that. If a hundred years of cancer research has taught us anything, it is that if you must get cancer, you want to be a mouse, because we can cure cancer in mice. Curing it in people is immensely harder, and most promising therapies fail at exactly the transition from mouse to man. So it took Barney some time to find clinicians who believed in his work enough to try cisplatin in human patients. But within two years, Harris and others had carried out preliminary clinical trials showing anticancer activity in several patients; and by 1973 it was clear from work by Wallace, Wiltshaw and Carr that cisplatin had a particularly high degree of activity against testicular and ovarian cancers, diseases considered terminal and unresponsive to the best prior therapies. Kidney toxicity hampered the deployment of the drug for a time, but Hayes and associates eventually found that the simple trick of hydrating the patient to wash the toxic material out of the kidneys markedly diminished this side effect.

Our story concludes in the Christmas season of 2001, thirty years after the first human trials of Barney's discovery. Cisplatin has become the best-selling cancer drug in the world. It is a complete cure for testicular cancer if the disease is detected early enough. It is one of the most effective drugs against melanoma and non-small-cell lung carcinoma, and in combination therapy it also shows considerable promise against ovarian cancers. Well, I promised you a happy ending. Now for the other moral. I have nothing against big, targeted or discovery-driven science programs per se (although I do object, strongly, to such programs being oversold to a trusting, anxious public). These endeavors have produced much useful information and keep many scientists off the unemployment rolls - both laudable achievements. And I can understand the political pressures that drive the US National Institutes of Health and its orthologs in other countries to nudge biological research towards working more with human cells, and with human proteins, and on human diseases. But I don't see how a 'War on Cancer' or targeted biomedical research, in any academic institution or pharmaceutical laboratory, ever gets you to cisplatin. This is not a compound that would ever be found in any combinatorial library or collection of natural products. There isn't a single atom of carbon in it. No medicinal chemist would ever have thought of it. No targeted research program would have investigated it. No discovery-driven program of chemical genomics would have included it. Cisplatin came from outside the box - in fact, so far outside that the box wasn't even visible; it came from a place no one would, at that time, have dreamt of looking in for an anticancer drug.

We can, and should, focus teams of well-trained researchers on specific goals such as unraveling the mechanisms of tumorgenesis. We can, and should, try to coordinate and plan our disease-fighting efforts so that our resources are spent efficiently. But we must never forget that Barney Rosenberg, with his bacterial cells and electrodes, and his curiosity, imagination and persistence, may have saved the lives of more people than most of the cancer researchers in the world put together. So, the next time some Scrooge bah-humbugs basic research, or asks you what investigator-initiated, hypothesis-driven science is good for, tell them Barney's story.

Published: 28 December 2001

If you can't take any more of this, please press two

Genome Biology 2002, 3:comment1002.1

The widely syndicated columnist George Will remarked that American football - a game characterized by brief bouts of mayhem interrupted by lengthy huddles among the players, or between players and their coaches - exemplifies the two worst features of modern life: violence and committee meetings. Lately I've been tempted to add a third feature to his list: those recorded telephone menus that, it would seem, nearly every organization now uses to avoid paying human beings to answer their phones. Companies argue that this system actually allows callers to be directed to the precise person who can respond to their needs, but I think that's disingenuous. The real purpose of these maddeningly patient, infinitely nested, incredibly stupid mechanical receptionists is clearly to produce so high a level of frustration in callers that they hang up in disgust before bothering anybody.

All of this would be only another annoyance in the catalog of daily irritations to which we are all subjected, were it not for the disturbing possibility that it is symptomatic of something serious: the increasing depersonalization, perhaps dehumanization, of our lives. It is now possible to go through much of life experiencing minimal contact with other human beings: one can rent videos of movies and watch them at home, by oneself, instead of having to deal with a collection of strangers at a movie theater. One can order food to be delivered, and not have to buy it in a crowded grocery store or sit in a room full of other people at a restaurant. And with telecommuting, one can work from home, alone, never meeting one's coworkers face to face.

Technology, and the basic science that produces it, usually gets the blame for all this, but I think that's a bad rap. My reading of history is that the dehumanization of man has usually been done for reasons of religion, or politics, or economics. Of these, economics is perhaps the most ruthless and cold-blooded. Religions, when they dehumanize man, do so either by making God too remote and man too small or by demonizing people whose beliefs are different. Horrible as the consequences can be, at least some sort of moral imperative (however misguided) is often behind such acts. Political systems dehumanize man by reducing the individual to a dispensable cog in some utopian vision or conflict aimed at preserving the welfare of the state. Again, despite the terrible deeds that have been done in the name of various political ideologies, at least there is sometimes an underlying attempt to craft a better society, even if that vision happens to be perverse. But economic dehumanization has no higher purpose than the creation of profit. And many of the assaults on the dignity of the individual that have been carried out in the name of religion or politics are actually intended to line the pockets of the perpetrators at the expense of the exploited. In a secular, democratic society the great danger to individual human freedom and dignity comes from the desire of people to make money regardless of the consequences, a desire that is justified by devotion not to a god or political creed but to the ideal of free-market capitalism. So, if it adds to a company's bottom line to replace people with tape recordings and speech-decoding devices, companies will do just that, and human interactions will become a little scarcer and our world will get a little colder, and all the while those responsible will wonder why things seem to be going to hell around them.

Of course, the genomics revolution is furnishing those who fear science and technology with plenty of fuel for the fire of their paranoia. Foremost is the fear that all human behavior will be shown to be genetically determined, reducing man to the status of servant of his DNA. Then comes fear of the loss of privacy, of having one's individual genetic information known to employers and insurance agencies and governments. Implicit in this second fear is the first, for both imply that a sequence of bases can tell someone else everything about who we are. It is that assumption, not science and technology, that is actually dehumanizing. Those who fear what biology can learn about our minds and our bodies have already reduced each individual to a gene-programmed automaton, whereas biology in general, and genomics in particular, is actually doing just the opposite. A real understanding of the findings of genomics should elevate our sense of what it means to be human. We have much the same genetic material as a zebrafish or a mouse, yet our behavior can be - and often is - governed by rational choice, not preprogrammed instinct. There is no obvious gene for heroism, or generosity, or honesty, or loyalty, and in many cases these behaviors seem to act against the interest of the individual - particularly the economic interest. We choose them because they allow us to serve something larger than ourselves, and we have learned to do so slowly, over millions of years. Human evolution occurs not just at the level of our chromosomes, but at the level of our civilization and philosophies.

Genomics should also help put to rest one of the most common grounds that politics, economics and religions use as a justification for human degradation: racial differences. The genomes of black and white, Asian and Hispanic, Native American and Aborigine, are more alike than are the genomes of two related species of chimpanzee. Nor can one justify religious persecution in the cold light of genomics: there is no gene that makes one person a Muslim, another a Hindu, a third a Christian and a fourth an atheist. At the level our genes, a Democrat differs not one whit from a Republican, all Tories look like Socialists, and Communists, Monarchists and Anarchists are indistinguishable. No one can ever again be considered biologically inferior - and therefore less than human - for their religion, or their politics, or the color of their skin. If we understand fully the lesson that the human genome sequencing effort has taught us, we can free ourselves from any danger that we can ever be dehumanized in the name of some god or political principle.

Which leaves only the danger of depersonalization for economic motives. I can see a danger that modern biology might unwittingly contribute to that, because there is a kind of Darwinian, survival-of-the-fittest character to much economic theory and practice. If we try to justify putting profits ahead of people as an expression of our basic biological nature, we ignore all of the progress we have made as a species in mastering our instinctive behavior with our power to think and our ability to choose. So, every time we pick up the telephone and a tedious, obtuse and impersonal recorded menu comes between us and the chance to deal with another person, however briefly, we would do well to remind ourselves that it is not science and technology, but greed and laziness, that are the real threats to our humanity.

Published: 28 January 2002

The father of us all

Genome Biology 2002, 3:comment1004.1

Contrary to the implication in some obituaries, Max Perutz, who died on February 6 2002 in Cambridge, England, just a few months before his 88th birthday, did not determine the first three-dimensional structure of a protein molecule. John Kendrew did that. Max did determine the structure of the hemoglobin molecule (Figure 1), but Kendrew's low-resolution myoglobin structure predated the 5.5 Ångstrom-resolution hemoglobin structure by more than a year, and when Max published his low-resolution work showing that hemoglobin had the same all-helical fold as myoglobin, Kendrew was publishing his interpretation of myoglobin at 2 Ångstroms resolution, in full atomic detail.

Max Perutz (Courtesy of the Medical Research Council, UK).

Nor, as many people have assumed, did Max invent the method used to determine those two structures, and thousands that have come after them. The method was invented years earlier for small organic molecules by J. M. Robertson of Glasgow University, in a series of brilliant crystallographic studies. Robertson had even suggested at the time that the so-called isomorphous replacement method might be used to solve the structures of very small proteins like insulin. But no one believed it could work for a protein the size of myoglobin, much less hemoglobin, which is four times larger - no one except Max Perutz.

Against the prevailing opinion of nearly every physicist, Max did the experiment. He did it because he had realized that, while the scattering from the thousands of atoms in a protein crystal was weak because the structure was spread out over a large volume, the scattering from a single heavy atom such as mercury, bound to the protein in a specific place, would be strong enough to produce measurable changes in the intensities of the protein X-ray reflections. When Max Perutz showed that these changes not only could be measured reproducibly but also could be interpreted to determine the so-called phases of the protein reflections in the same way Robertson had done, Kendrew was able to use the method to solve myoglobin. It was as much for that pioneering development of the method as it was for the hemoglobin structure that Max Perutz shared the Nobel Prize in Chemistry in 1962 with John Kendrew, who by the way had been Max's first doctoral student many years before.

Since then, anyone who has determined a protein structure by X-ray crystallography has followed in Max's footsteps, but his legacy is much larger than that. I don't even intend to mention his founding of the famous Laboratory for Molecular Biology in Cambridge, which has been home to ten Nobel Prize winners since the late 1950s. For me, his greatness - and his relevance to all of us in the age of genomics - rests on two other pillars. "I wanted to solve an important problem in biology," Max once said when asked what had motivated him to undertake to solve the structure of hemoglobin when most people believed that it was impossible to determine the exact position in space of all of the atoms in anything so large as a protein molecule. He wasn't referring to doing the first protein crystal structure either. The problem Max wanted to solve was a problem in biology, not physics. He wanted to figure out how hemoglobin works. Everything he did, including working out the method to crack the phase problem in protein crystallography, was a means to that end.

Max needed to see what hemoglobin looked like because he knew it was impossible to understand how it functions without that information. For him, structure was always in the service of the biological question. Nothing proves that more than the fact that, once the structure was solved, he didn't do what most other crystallographers have done since: go on to the next new protein structure. He kept working on hemoglobin. He kept working on it because that first structure alone didn't answer all of the biological questions. So Max studied mutant hemoglobins with abnormal oxygenation properties from people with genetic diseases, and he worked on hemoglobins from animals with unusual physiology, and he looked that the protein at different pH values and with allosteric regulators bound, and so on, until the very last years of his life. It was only in the past few years that he began work on another problem, that of the structural and functional consequences of repeating sequences such as those found in the protein involved in Huntington's disease. He had just sent off a set of papers on this subject before he died, and as always, his structural studies were driven by the underlying biological problem. In an era when data-gathering for its own sake is much in vogue, including the gathering of reams of protein structure data, Max's scientific life reminds us that the best science is usually driven by a passion to find the answer to a fundamental and important question.

The other great thing Max did was to embark, in his 70s, on a second career: as a writer of popular essays on science and scientists. Over the past two decades he penned numerous articles in places like The New Yorker and The New York Review of Books and the Times Literary Supplement. Some of the best of the early ones have been collected in the book Is Science Necessary?: Essays on Science and Scientists, published in 1991 by Oxford University Press. Not a sparingly elegant stylist - he never met a polysyllabic word he didn't like, and his sentence structure tended towards the convoluted - his writing nonetheless passes the supreme test of being not only readable but rereadable. Not bad for someone who, like Conrad, was not a native-born English speaker. My favorite of Max's pieces is Enemy Alien, a delightful account of his internment in Canada in the early months of World War II (because of his Austrian origin), followed by his service in a bizarre undertaking to build giant warships out of icebergs. In these writings he not only defends, brilliantly, the importance of science and scientists, he also puts a human face on what we do, and explains it so that the lay public can be both enlightened and entertained.

The great Soviet neuropsychologist A.R. Luria believed that scientists are obliged to produce two kinds of writings: the dry technical reports of their work, and stories told for everyone to understand. He did both wonderfully (if you don't know his work, I recommend The Man With a Shattered World (New York: Basic Books; 1972), his moving account of a soldier with a terrible brain wound), and established a tradition that has been carried on magnificently by Oliver Sacks, whose latest book, Uncle Tungsten (New York: Alfred A. Knopf; 2001), is as good as his classic The Man Who Mistook His Wife for a Hat (London: Gerald Duckworth; 1985). It is hard to think of anything more important than helping the public - who after all put us in the laboratory and trust us to work for their ultimate benefit - to develop a sense of familiarity with what we do and an understanding of what it might mean for them. Genomics is rapidly producing all sorts of discoveries that make lay people profoundly - and perhaps justifiably - uneasy. Max showed us that our obligation does not end with our best efforts in the laboratory. We can't all write the way he did, but we can all find ways to reach out to nonscientists with the same affection, clarity, and lack of condescension.

Max Perutz had two children who bore his name, but his work and his ideas produced thousands of progeny. No other form of scientific immortality seems to me more worthwhile.

Published: 22 February 2002

What's in a name?

Genome Biology 2002, 3:comment1005.1

Perform a literature search for articles concerning ARF, a small GTP-binding protein that is involved in vesicular transport, and you will find to your surprise that it is also a tumor suppressor gene product that binds to p53-DNA complexes. Except that it isn't. There are two completely different proteins with the same name. One ARF is ADP-ribosylation factor, the small GTPase. The other is derived from the name of a genetic locus, INK4a-ARF. I would like to believe that the cancer researchers who named their protein ARF in the mid-1990s were not aware that the name had already been used for over a decade for another important eukaryotic gene product; that they didn't deliberately try to appropriate the name for their own discovery and thus muddy the waters of protein annotation. Nothing, however, seems to engender more passion and provoke more quarrels than the matter of assigning names to things. Scientists defend their choices with the tenacity of a mother tiger protecting her cubs, with the result that the scientific literature is awash with names that range from the cute to the stupid. Duplications abound, and the information content of most gene names is nil. This was tolerable when the number of genes and proteins one had to worry about was manageably small, but in the era of genomics something has to be done about it. And whatever is done, it is clear to me that we cannot cede responsibility to the cell biologists.

When it comes to naming things, cell biologists seem to have about as much imagination as the American actor/screenplay writer/director Sylvester Stallone, who came up with Rocky; Rocky II; Rocky III; Rocky IV; ... and then Rambo; Rambo II; Rambo III. (By the way, have you ever noticed that, with a few exceptions, the quality of a movie is usually inversely proportional to the number of jobs the star has in addition to acting?) Examples of the cell biologists' jaunty wit and evocative command of language include CD1, CD2, CD3, CD4 and so on - names that, at a glance, tell one everything about what the proteins do, don't they? - and my personal favorite, p53. I mean, what can you learn about function from a name like p53, except that the person who thought it up obviously didn't have a clue what the function was at the time? It isn't even a good uninformative name; didn't it occur to this person that there might just be a few other proteins around with a molecular weight of about 53,000? What are the cell biologists going to do when they encounter those - call them p53 II, p53 III and so on?

My personal preference - indicative, no doubt, of middle-aged nostalgia - is for the old style of naming things, where the name actually told you something about the function of the protein. Haemoglobin has a haem in it. The HIV protease is a protease from the human immunodeficiency virus. Triosephosphate isomerase isomerizes triosephosphates. These names were assigned by biochemists and enzymologists, who didn't feel they had the right to name something until they had some idea what it did. Another, perhaps more whimsical, alternative is to assign names arbitrarily from human names, just as is done for hurricanes and typhoons. In such a scheme, we would just name the INK4a-ARF gene product "Fred". p53 could be "Mary" or perhaps "Fatima" (we don't want to restrict ourselves to Anglo-Saxon names). There's precedence for this approach, actually. Jack Peisach, a biophysicist at Albert Einstein College of Medicine in New York, named the copper-containing electron-transfer protein he discovered in 1967 stellacyanin after his wife, thereby causing generations of biochemists to be grateful that he hadn't married someone named Gertrude. But the whole business is too important to be left to my preferences, sensible and imaginative though they may be.

What's clearly needed is a new, international commission on gene-product naming. This commission must not, under any circumstance, be connected with any International Union of Pure and Applied Anything, for those are the cretins who force-fed us the SI units. If you are my age - which, from the way my students treat me, means that you have personal recollection of the Middle Ages and used to go on double dates with Charlemagne - you probably spend much of your time in fond yearning for the Ångstrom, the atmosphere, the kilocalorie, and other units that actually suggest something. The Ångstrom is a wonderful unit for subcellular distances because the length of a carbon-hydrogen bond is almost exactly 1 Ångstrom, so when someone says that the thickness of the hydrophobic portion of a lipid bilayer is about 30 Ångstroms it immediately refers that thickness to something of the same size range that one can visualize. The atmosphere is a great unit for pressure, because if somebody says a pressure of 1000 atmospheres it immediately refers that pressure to something with which we are all familiar. The kilocalorie is a great unit for energy, because the amount of kinetic energy available at ordinary temperatures is about 1 kilocalorie, and the energy of most weakly-polar, noncovalent interactions in biology is also about 1 kilocalorie. But thanks to the SI gang, a group of mostly European nobodies who sit around all day with nothing better to do than to think of ways to make science even more jargon-laden and obscure than it already is, the Ångstrom has been replaced by 0.1 nanometers, the atmosphere by the easy-to-remember 101,325 Pascals, and the kilocalorie by 4.184 kilojoules, all of which are units that have no simple frame of reference whatsoever. (By the way, all of them were originally invented in France and two of them were named after Frenchmen; come to think of it, SI stands for Systeme International, which is French, so is this in fact some kind of linguistic revenge for English having given the French terms like le traffic jam and le weekend?) Not because of xenophobia, but simply as a way of resisting any further nomenclature hegemony, the SI crowd, who enforce the use of their system with great fervor, must not be allowed to get their hooks into the gene-naming game. A new and independent commission is essential.

This commission must have absolute authority to revoke stupid names - p53 ought to be the first to go, with H-Ras not far behind - and assign clever new ones that suggest what the protein actually does while being, if possible, entertaining as well. Thus p53 could be renamed, for example, Guardian, as it has been characterized as the "guardian of the genome". Some of these names might get quite long - I imagine H-Ras could end up as something like Ubiquitous Eukaryotic Protein that Binds and Hydrolyzes Guanine Nucleotides and Signals to Everything - but is that so bad? Many Spanish men have five or six names, and that doesn't seem to get in their way. To function as intended, the commission must be constituted very carefully. It can, and should, have advisory bodies of scientists, but no scientist should be allowed to sit on the commission except for whoever thought up the protein class 'chaperone' and a Drosophila geneticist (any community that can come up with gene names like Son of Sevenless and Sonic Hedgehog has shown it can be trusted). The remainder of the commission should be constituted as follows. One stand-up comedian. An advertising copy writer; it's true that we all hate them, but they do this for a living and they're good at it. Film writer and director George Lucas, because there has never been a better name for a villain than Darth Vader - clearly this man has the right stuff for the job. And finally my mother. I know this last suggestion smacks of rank nepotism, but I like the name Gregory, she chose it, and when you write your own column you can suggest your mother. I believe these people would take the job suitably seriously and would provide us with an improved working vocabulary for post-genomic biology.

Published: 26 March 2002

Grain of truth

Genome Biology 2002, 3:comment1007.1

Three billion people depend on rice for the greater part of their daily caloric intake. With the possible exception of wheat, which has been the cause of several major wars including, in all probability, the Trojan War (it was wheat, not Helen's face, that really launched those thousand ships), no other foodstuff has played a comparable role in human survival. In some countries the cultivation of rice has taken on almost a religious - or at least a patriotic - significance, and rice farmers enjoy political influence vastly out of proportion to their numbers. Little wonder, then, that the announcement in early April that two groups - one publicly funded and one a private company - had completed draft genome sequences of two closely related subspecies of rice made the front pages of newspapers worldwide. But I think the significance of this achievement lies not only in the scientific and agricultural consequence of knowing the first genome sequence of a cereal. There are also profound - some would say disturbing - consequences for the sociology of science in the post-genomic world.

Over a billion years ago, the eukaryotic kingdom diverged into plants, fungi and animals. Some time after that - the best guess is about 200 million years ago - the flowering plants diverged into dicotyledonous plants like Arabidopsis thaliana and monocotyledonous plants; the monocot cereals sorghum, rice, wheat, corn and barley diverged from their common ancestor about 60 million years ago. The monocots became the great staples of the human diet, but because of their differences in appearances most people don't appreciate how closely related they are. Gene-mapping experiments have shown that not only are most genes from any one cereal very similar in sequence to the corresponding genes from any of the others, but in most cases gene order is conserved as well. This observation was very exciting to agricultural scientists, because it suggested that beneficial properties in any one cereal - whether found naturally in subspecies or engineered - might be easy to transfer to one or more of the others.

Rice was the first of the great grains to have its genome sequenced, not because of its importance - sequencing efforts for corn, in particular, are well-established - but simply because it has the smallest genome. Its 430 million base pairs code for about the same number of genes (around 50,000) as are estimated to be in the corn and wheat genomes, which are 3 billion and 16 billion base pairs in size, respectively. For reasons that are unclear, rice is more compact by far.

It has escaped no one's attention that the number of genes in these higher plants is comparable to - and very probably exceeds - the number in the human genome. Perhaps our language needs revision: to refer to someone as being as dumb as a plant should no longer be considered a disparaging remark. Still, if the early history of genomics has taught us anything, it should be that genome size and number of genes is a poor indicator of the real complexity of an organism. In the absence of precise data concerning alternative splicing in higher plants we cannot be sure that the rice genome will give rise to as large a set of gene products as the human genome clearly does. Nevertheless, there are a lot of genes in rice. About 50% of them have homologs in Arabidopsis, whereas 80% of Arabidopsis genes have rice homologs. If this discrepancy is real, and not an artifact of annotation, it suggests that dicot genes are essentially a subset of the genes in rice (and indeed in all monocot cereals, since 98% of proteins examined in other grains have a related protein in rice). More than 50% of rice genes code for proteins whose function is unknown, so trying to find reasons for the large number of genes may be premature, but the most common explanation proffered by commentators is that plants are immobile, cannot evade predators, and so need to synthesize a host of toxic substances as defensive measures.

This seems sensible, and is probably true for many plants, but I'm not sure it's true for rice and the other cereals. (These are, after all, edible.) I think a more likely explanation is that since plants are immobile they cannot forage for food or move to a better environment if the conditions around them deteriorate, so they need a large complement of genes that allow them to scavenge nutrients, shift their metabolism, respond to various stresses, and go into quiescence until, for example, water becomes available again. I would not be surprised to find, when more functions of rice genes become known, that these activities are much expanded in higher plants.

More than most genome sequences, that of rice has immediate relevance to the quality of life in much of the world. Possible applications include enhancing nutritional content, improving crop yield, and adding resistance to diseases and pests. These have been discussed at length in the various commentaries, in the popular press as well as in the scientific literature, that have accompanied the announcements of the completed draft sequences. What I want to consider here are the political and sociological implications of what happened.

Two groups released draft rice genome sequences at the same time (Science 2002, 296:79-92 and 92-100). In an editorial, Donald Kennedy, the Editor-in-Chief of Science, remarks that this reflects a spirit of cooperation "too often absent in an enterprise in which competition sometimes dominates collegiality". The sequence of the japonica subspecies produced by the private company Syngenta (Torrey Mesa Research Institute, San Diego, USA) is proprietary and was not deposited in GenBank at the time of publication, as is normally required for all published genome sequences. An exception was made in view of the importance of the sequence and the authors' promise to make the data available to the scientific community over the worldwide web. The other sequence, of the indica subspecies, was done by a public effort centered in China and has been fully deposited in GenBank.

The decision by Kennedy and Science to publish the Syngenta results has been criticized by many scientists who argue that it constitutes a slippery slope for accepted standards (although the slide, if there is one, began earlier, when Science made the same exception for Celera's 'private' human genome sequence). Kennedy defends his decision on the grounds that the good of having the information outweighs this potential hazard, but I think there's an even stronger argument that he was right. I think the accepted standards need to be reconsidered.

Private sequencing efforts are often faster and more cost-efficient than public ones. If a suitable business model can be found for sequence-oriented companies - and this is far from certain - there are likely to be as many sequences of important genomes coming from the private sector as there are from the public sector. Lest genomics become a house of secrets, some mechanism must be found to get that information out into the community at large.

Allowing the results to be published, but with the proviso that they be made available by some convenient mechanism, even if that mechanism is not deposition in a public database, is one way to encourage such distribution. For-profit users of the data could be required to pay a license fee to access the data, while academic users would be granted free access. It would be easy to add a requirement for GenBank deposition as well, after some waiting period (six months, perhaps, or a year) that would allow the companies in question to retain some small measure of control over the results of their efforts. This is not much different philosophically from allowing companies to patent discoveries and inventions: it is easy to forget that patenting has a dual purpose, to allow the world to use the fruits of creativity and research as well as to provide exclusivity of profit for the originators. Without patent protection, companies would keep discoveries such as PCR a secret, to allow them to retain advantages over their competitors, and we would all be losers. Like all compromises, Kennedy's decision displeased many people, but even though his rice policy goes against the grain, it contains a kernel of the wisdom we need to deal with the complex and changing world that genomics has given us.

Published: 25 April 2002

Our own petards

Genome Biology 2002, 3:comment1009.1

My father, who worked for the US government, told me that he once received a memo from the Pentagon stating that too many trivial documents were being classified TOP SECRET and that the practice must stop. The memo was labeled TOP SECRET. He told me this story, he said, for two reasons: to remind me that a sense of irony is not commonly found in the military, and to persuade me never to work for the government. I depend on federal grants to support most of my research, so I suppose one could say that I never really learned the second lesson, but the first one sunk in. If it hadn't, though, a recent report by Debora MacKenzie in New Scientist 174(23442):4-5, 11 May 2002, would probably do the trick. Headlined "US Non-Lethal Weapon Reports Suppressed", the article describes a set of projects, most of them funded by the Pentagon's Joint Non-Lethal Weapons Program (JNLWP), designed to develop chemical and biological weapons that would do everything short of killing people to incapacitate soldiers and civilians and cripple infrastructure. The projects she mentions include engineering microorganisms to corrode roads and runways; to eat paint - especially the stealth anti-radar kind used on aircraft - and rubber; and to attack lubricants, fuels, and protective material like the Kevlar used in body armor. Other educational activities include establishing odor response profiles according to ethnic, racial and cultural influences; developing "harassing, annoying and 'bad-guy' identifying chemicals"; formulating lubricant and grease additives for immobilizing machinery; and designing "loaded speed bumps" (to which one who is constantly intimidated by those signs that threaten "severe tire damage" if one backs up can only ask, "Loaded with what?").

Now some of these sound silly and some sound impossible, but one should never underestimate what can be done if enough money is thrown at it - and no one has as much money to throw as the military, even in most democracies. If the sun were a weapon, we would have had widespread civilian use of solar power fifty years ago. Genomics is likely to help some of these projects to happen. The complete genome sequences of dozens of different microorganisms, with a wide range of metabolic characteristics, are now available. So the chances are pretty good that at least a few of these things will actually get developed over the next decade or two. What's wrong with that, you may well ask - especially in the light of the events of September 11, 2001, and the continuing threat from terrorist organizations and the 'rogue states' that shelter them.

Well, I think there are two things very wrong with that. The first, as pointed out by MacKenzie, is that many, if not most, of these research projects are probably illegal. Several international treaties on chemical and biological weapons expressly prohibit the development, production, stockpiling or acquisition of such weapons, regardless of whether they are lethal or non-lethal. One US law, introduced last year, specifically bans the possession of microbes designed to attack materials. The illegality of these activities may be why the US National Academy of Sciences, which collected information about 147 such projects for a report on research funded by the JNLWP, has thus far refused to release the documents, even though the information is supposed to be a matter of public record. The Academy's suppression of the data is the focus of MacKenzie's article.

But the second problem is something that MacKenzie doesn't point out. It's something my father would understand, because to see it requires that sense of irony that he believed was missing from so much of what governments do. The second problem is that all too often, the weapons we invent end up being used against us. One could argue, I suppose, that the Soviet Union would eventually have developed its atomic bomb without the aid of Klaus Fuchs and the other atom spies. But the fact is, it didn't. The hydrogen bomb, too, was our own creation. The nuclear weapons of mass destruction that have menaced us, and all mankind, for so many years were designed by us for our own protection. The anthrax strain that killed in Florida and elsewhere and terrified the US for months was our own weapons-grade strain, developed at home by our own scientists. All too often, when our troops go into battle, they are attacked, as they were in the Gulf War, by weapons we ourselves conceived and manufactured. The poison gas sarin that Aum Shinrikyo released in the Tokyo subway was invented in Europe. The botulism toxin that they tried to spread over Tokyo before that was developed as a bioweapon by the US and Russia.

Nothing can be kept secret forever, as the National Academy will soon learn, and anything we create our enemies can make, buy or steal. The world is filled with things we wish we could un-invent. Why haven't we learned from that? Why do we, in the name of security, fill the world with dangerous objects? And are we so arrogant, and so stupid, as to think that we can control a biological organism once it is released? Do we really believe that we can keep it from falling into the hands of our enemies - something that has never been achieved with any weapon in human history? Or that it won't expand into the nearest available ecological niche, to plague us in ways we never foresaw? The archive of folly is replete with stories of that blunder: the introduction of starlings into North America, and of rabbits - and then cane toads - into Australia; the obliteration of native flora and fauna in many countries by exogenous species, many brought in for decorative or commercial purposes. The list is long and sorrowful.

Shakespeare, who has a metaphor for almost everything, has a marvelous one for such hubris: "The engineer hoist with his own petar[d]" (Hamlet, Act III Scene iv, line 206). The words are even more apt when one realizes that a petard is not, as one might think, some kind of construction crane, but rather a bell-shaped case containing an explosive, used to break down a door or gate or breach a wall. In other words, Shakespeare has given us a phrase that describes a non-lethal weapon being turned against its inventor. MacKenzie's article warns us that there are still people out there making petards, heedless of the fact that they, and we, may eventually be hoist - blown up - by these very ones. Continue to develop engineered organisms of the type referred to, and the odds are that some day it will be our own roads that will be corroded, our own fuel that will be degraded, and our own rubber, plastics and paint that will be attacked.

The development of all bioweapons, worldwide, should cease immediately. The United Nations should make it a war crime, punishable by trial before the the newly established International Criminal Court, to develop, produce, stockpile or acquire such weapons. Enforcement will not be easy, but a good signal would be for the US to stop the biological and chemical activities of its own JNLWP. As long as such research goes on in the US, US condemnation of other countries' bioweapons programs will be ignored for the hypocrisy that it is. And those who might consider developing biological weapons, whether lethal or non, would do well to remember the words of Walt Kelly's wise cartoon possum Pogo: "We have met the enemy, and he is us."

Published: 29 May 2002

No place like Ome

Genome Biology 2002, 3:comment1010.1

"The goal which all the Vedas declare, which all austerities aim at, and which men desire when they lead the life of continence, I will tell you briefly: it is OM. This syllable OM is indeed Brahman. This syllable is the Highest. Whosoever knows this syllable obtains all that he desires."

- Katha Upanishad I, ii, 15-16

It was just sitting there on the table with the other free copies of miscellaneous journals, made available for attendees at the Miami Nature Biotechnology Winter Symposium. "OMICS," its title shouted, in huge white letters, and underneath: "A Journal of Integrative Biology." On the inside, on the contents page, in smaller print, it was revealed that this journal used to go by the name Microbial and Comparative Genomics. In an accompanying editorial (Omics 2002, 6:1), the Editor-in-Chief explains that "this field is rapidly expanding and the science is growing well beyond genomics into other 'OMICS-es [sic]'." He goes on to state that the renamed journal "will span all the OMICS-es to date, including genomics (the quantitative study of genes, regulatory and non-coding sequences), transcriptomics (RNA and gene expression), proteomics (protein expression), and metabolomics (metabolites and metabolic networks)." As if this were not enough, he then adds: "Additionally it will cover all the future OMICS-es that will emerge in the era of post-genomic biology and medicine, including pharmacogenomics (the quantitative study on how genetics affects hosts' responses to drugs), physiomics (physiological dynamics and functions of whole organisms), etc."

Whew. I hope there's plenty of room on the shelf of anyone who subscribes to this journal, because future issues are clearly going to be as thick as the London telephone directory. Of course, now that I think about it, there probably will be enough room on everybody's shelves, because why would anyone need to subscribe to any other journal? We finally have a solution to the problem of journal proliferation: one journal that covers everything.

And yet, one can't help thinking that all this is much less than it sounds. Leaving aside the creation of the new word OMICS, a word that I for one never wanted and, now that I've got it, want even less - and the even stranger-looking and less euphonious OMICS-es, which sounds like something Tolkien's Gollum would say - the repositioning of this journal has the distinct air of bandwagon-hopping. Which begs the question: is this particular bandwagon worth hopping on?

As far as I can tell, the word 'genomics' was introduced 24 years ago by Victor McKusick and Frank Ruddle (who may, about now, be wishing they had never thought of it) for the new journal of that name they had just founded. The word 'genome' is an amalgam of the word 'gene' and the syllable 'ome'. It was coined in 1920 by the botanist Hans Winkler. In their delightful essay, "'Ome Sweet 'Omics - A Genealogical Treasury of Words" (The Scientist, 15(7):8, 2 April 2001) Joshua Lederberg and Alexa T. McCray point out that, as a botanist, Winkler "must have been familiar with a host of -ome words like biome, rhizome, phyllome, thallome, tracheome - all of which predated 1920. They share in common the concept of -ome signifying the collectivity of the units in the stem. Thus rhizome is the entire root system, or modifications thereof. Any zoologist would have known coelome, or system of cavities. Hence, genome would be understood to be the collectivity - dare we say the genre - of the genes."

Of the two components of the word genome, 'ome' is the more interesting. It subtly suggests the evocative 'home'. Its sound is deep, resonant and powerful. It is a homonym for the great "Om!", the sound by which, it is said, Brahman breathed the heavens and earth into existence - in the Hindu version of the Big Bang Theory. According to the Mandukya Upanishad, which deals with the understanding and symbolism of Om, the past, present and the future are all included in this one sound and all that exists beyond these three forms of time is also implied in it. So maybe that not only don't we need any other journals now besides OMICS, we don't need any back issues of other journals either.

But while it's easy to poke fun at attempts at being all-encompassing, and at the creation of words like metabolomics that cause one to nearly swallow one's tongue as one tries to say them, these are merely symptoms of the horse that is driving the bandwagon: the desire to cash in, literally and figuratively, on the buzz that genomics has produced in the scientific and lay communities. Attaching the '-omics' label to one's discipline increases visibility, opens avenues for new funding, and indicates a willingness to consider problems at the level of the whole cell, or whole organism. Apart from mangling the language a bit, you may ask, what's wrong with that?

Maybe nothing, but maybe something significant. Words have great power, and what one calls something can get confused with the true nature of that thing. Abraham Lincoln once asked a man how many legs a dog would have if you called its tail a leg. When the man replied five, Lincoln said, "No, calling a tail a leg doesn't make it a leg." Yet we often unconsciously accept the name of something as an accurate reflection of its essence. And when that happens, the consequences can be negative.

What, after all, is 'structural genomics' really? It is nothing but high-throughput structure determination. There is no insight claimed or realized at the level of the whole cell or organism. Determining the structures of all of the gene products in a cell doesn't automatically explain the workings of the cell. And if we give 'doing high-throughput structure determination' a name that makes it seem more glamorous than it is and possessed of a higher intellectual content than it has, don't we mislead students, funding agencies, the lay public, and maybe even ourselves? Or take metabolomics. Isn't that just a new-fangled word for a field that's been around for a couple of hundred years, namely physiology? Physiology became unfashionable sometime in the mid-to-late twentieth century, with the result that there are very few physiologists around to help us interpret genomic information in the context of the whole pathway, or the whole organelle, or the whole organism. It could be argued that inventing a new, glamorous term in place of the old name will attract new people to the field, but I think that misses the point. What they would be attracted to isn't the old field, it's something ill-defined. We don't need a new field here, we need the old one back, and calling physiology metabolomics will never lead to an increase in people who are trained the way we need them to be trained, in traditional physiology.

One could make similar arguments about proteomics - a field that mass spectroscopists have largely hijacked. The intellectual content of a list of expressed proteins is minimal. Useful, certainly, but minimal. What's needed, I would argue, are not proteomicists (and I wince just to write that word) but biochemists and enzymologists. Just about every one of the new '-omics' fields lacks the substance of the core disciplines. And if we create new fields willy-nilly, without consideration for their substance and the effect they will have on how young scientists are trained, we run the risk of replacing solid science with fuzzy science.

Every time someone someone comes up with a new name for what's supposed to be a new field, we owe it to ourselves to ask if they aren't just calling a tail a leg - because calling a tail a leg doesn't make it a leg, and ultimately it's silly to pretend that it does. There should be nothing at all wrong with being called a name that describes what you really are.

Published: 26 June 2002

Summer reading

Genome Biology 2002, 3:comment1011.1

It isn't a thriller, or a romance, or an historical novel. It's not a biography, or a tell-all memoir. Nor is it a self-help manual or a new diet. The 23rd-most frequently ordered book on the sales list at Amazon.com at the time of writing is a hardcover book that's 1,197 pages long. It has approximate dimensions (in inches) of 2.5 × 10 × 8, so it's not exactly the sort of thing that fits comfortably on your lap on the beach, or while you're sitting on an airplane seat, or in the bathroom. Your laptop computer is probably smaller and lighter. And it isn't published by Knopf, or Random House, or Chapman and Hall, or any other publisher you've ever heard of. The book (ISBN 1579550088), published on 14 May, 2002, is A New Kind of Science by Stephen Wolfram. It has its own website, http://www.wolframscience.com, where you can read sample sections, glowing reviews, and comments from admirers. You can also read a summary of the book, which begins like this:

"This long-awaited work from one of the world's most respected scientists presents a series of dramatic discoveries never before made public. Starting from a collection of simple computer experiments - illustrated in the book by striking computer graphics -Stephen Wolfram shows how their unexpected results force a whole new way of looking at the operation of our universe.

Wolfram uses his approach to tackle a remarkable array of fundamental problems in science, from the origins of apparent randomness in physical systems, to the development of complexity in biology, the ultimate scope and limitations of mathematics, the possibility of a truly fundamental theory of physics, the interplay between free will and determinism, and the character of intelligence in the universe. Written with exceptional clarity, and illustrated by nearly a thousand original pictures, this seminal book allows scientists and nonscientists alike to participate in what promises to be a major intellectual revolution."

All of which sounds terrific until you realize that the publisher is Wolfram Media, Inc., so that the modest claims of being "long-awaited and written (with exceptional clarity) by one of the world's most respected scientists", and so on, are ... well... written by someone employed by the author, if not by the author himself.

And yet, this isn't some crank claiming perpetual motion. Stephen Wolfram actually is a highly respected scientist. He was born in London and educated at Eton, Oxford, and Caltech. He received his PhD in theoretical physics in 1979 at the age of 20, on the basis of significant work in physics and cosmology. He received one of the first MacArthur 'genius' awards. He's also been successful in business: in 1986 he founded Wolfram Research, Inc. and began the creation of Mathematica, now the world's leading software system for technical computing and symbolic programming (which explains where the money to start Wolfram Media, Inc. came from). Whatever he is, he's no crank. This is a man who's been highly successful at everything he's tried to do.

Which may be the problem. Early success is wonderful, I'm sure - one seems to be favored by the gods - but it creates the heavy burden of perpetual high expectations. Wolfram, by his own account, has spent the last ten years of his life on the science in this book. (He estimates that while writing it, he typed 100 million keystrokes and moved his computer mouse more than 100 miles.) Now 53 years old, he may feel under tremendous pressure to have another huge success - after all, that's all he's ever known. Working alone, self-funded, doing all his 'experiments' on a computer, he has been insulated from the real world of controls and peer review, from the need to be practical, from criticism of any kind. That may well be the ideal environment for producing a truly novel idea, but it isn't the ideal environment for any sort of reality check. The best scientists tend to be their own toughest referees.

What has Wolfram done, actually? I can save you the trouble of trying to read all of it - I'm sorry, I don't think it's written with "exceptional clarity"; I find it repetitive, self-indulgent (how could it be anything but?) and tedious. But having said that, I think a lot of people ought to read at least some of it, because while I don't believe that Wolfram has created a new kind of science, I do think he has created a very powerful tool that may have some if its best applications in genome-driven biology. The book focuses on the use of cellular automata - a type of computer algorithm that Wolfram popularized in the 1980s - to simulate the behavior of a host of natural phenomena. Cellular automata are, in the simplest sense, rules that specify how the colors of each row of squares depend on the colors of the previous row. Suppose one has a grid consisting of a set of squares arranged like a chessboard. One such cellular automaton might go like this. Start with a single black square in the middle of the first row. Then a square in the next row should only be black if one or the other, but not both, of its neighbors on the previous row were black. Such a rule produces a pattern of nested triangles. Since the output of cellular automata depend not only on the rule being used to generate the color pattern but also on the initial conditions - the arrangement of colors in the first row - chaotic patterns as well as regular patterns can be produced by them. In fact, some of the most dramatic examples Wolfram uses generate patterns that are regular in parts and seemingly chaotic in others, on the same diagram. He is able to model an impressive number of natural phenomena using these very simple concepts, with no use of equations. He does not, however, model general relativity, or predict the Higgs boson. If his method really is able to reproduce everything in the universe, he doesn't demonstrate it.

Part of the problem with his claim that he can reproduce everything is, of course, that the whole book might be based on a gigantic fallacy: Wolfram assumes that because complex behavior is widespread in nature and because it can be modeled by cellular automata, all complex behavior must be produced by cellular automata. There's no real evidence for that assumption. But while this difficulty makes it likely that his self-glorifying claim to have explained nearly everything in the universe is, to say the least, a trifle overblown, it does not mean that he hasn't done something important.

Genomics is driving all of biology back to the level of the whole cell, and the whole organism. Understanding such enormous complexity demands that the results of reductionist approaches such as biochemistry, cell biology and structural biology ultimately be combined into models that predict morphology and behavior. Consider the discovery that the gradient of a single chemical substance controls body pattern in the developing fly or zebrafish embryo: it used to be assumed that adequate descriptions of the progression from simple phenomena to such complex systems would require complex mathematical expressions. That assumption has probably retarded the development of systems biology, because most biologists tend to shy away from higher mathematics - that's often the reason they were drawn to biology rather than to, say, physics, in the first place. Wolfram has shown that very complex patterns can arise from extremely simple rules. Although he seems to think that concept is novel, it isn't; nearly every biologist I know of has always believed that, and genomics has only reinforced that belief. Genome sequences show that free-living organisms can be created from less than 1,000 genes, and even the most complex organisms, such as humans, seem to require far fewer than 100,000 genes. At heart, biology is simple; Wolfram is telling us nothing new when he asserts that. But the problem has always been how to generate complexity from that simplicity. Wolfram may or may not have found the way that complex systems arise - my bet is that he has for some things, but not all of them - but regardless, what he may well have done is to take biocomplexity out of the hands of the mathematicians and give it back to the biologists. The tool he has developed - computer simulations with cellular automata - can be carried out by anybody. Cellular automata may or may not be what Nature uses, but if they provide a rapid and accurate way of modeling what happens, they will help to drive understanding forward. Developmental biologists in particular should find them thought-provoking, but so should those genome scientists who are beginning to try to model signal transduction networks and the rest of the parallel, interconnected, highly redundant circuitry of the cell.

Downloadable programs for generating cellular automata are available online at http://www.wolframscience.com/nks/programs/; they are simple enough to allow anyone to try these ideas out. Have a go: it's fun, and you can decide for yourself if Wolfram has indeed come up with something that will make a real contribution to our ability to understand how complex systems work. But as for it being a new kind of science ... well, as far as that goes, some of the best advice I ever received was this: if someone says they have something that's better than sliced bread, you should probably invest immediately - in sliced bread.

Published: 29 July 2002

Fish tale

Genome Biology 2002, 3:comment1012.1

OK, I promise to try to keep the fish jokes to a minimum, but it won't be easy. The draft sequence of the genome of the Japanese pufferfish, Fugu rubripes, has just been announced (Aparicio et al., Science, 25 July 2002; 10.1126/science.1072104) and the temptation to humor is great. Fugu displaces the nematode worm as the most intrinsically humorous organism to have had its genome sequenced, the Caenorhabditis elegans folks having finally wriggled out of that embarrassing situation. It used to be thought that pufferfish had little to offer beyond a good dinner and an opportunity for sudden death, but now the scales, so to speak, have fallen from our eyes. Genetically speaking, Fugu is full of riches, right up to the gills, as it were.

The pufferfish gets its name from its habit of puffing itself up into a spiky ball three times its normal size when attacked. If this rather impressive display fails, it still has another strategy for survival. Inside its liver and ovaries lives a symbiotic bacterium, Pseudoalteromonas haloplanktis tetraodonis, that produces tetrodotoxin, a deadly neurotoxin that blocks voltage-gated ion channels. Most predators leave the pufferfish alone as a consequence. Despite this, Fugu is one of the great delicacies of Japanese cuisine, and every once in a while someone preparing it at home will die a quite unpleasant death.

I vividly remember my first encounter with Fugu sashimi. I was dining with some collaborators and former postdocs in a little restaurant in a back alley in Kyoto that specializes in serving the white, almost translucent slices of raw pufferfish with a variety of accompaniments. The flesh of Fugu has a delicate, very slightly sweet flavor with no fishy odor at all; its texture is semi-firm, somewhat like spaghetti al dente. It was delicious. My dinner companions assured me that there was no risk involved: by law, Fugu chefs must undergo thorough training in removing the poison-containing organs and have to be licensed by the state. I had just relaxed completely when one of my friends suddenly gasped, clutched his throat with both hands, and slumped over the table. I jumped up shouting for someone to call 911 - which of course isn't 911 in Japan - only to see him suddenly sit upright with a big grin on his face, while the rest of the party burst out laughing. Apparently, this is a fairly standard initiation rite for first-time Fugu consumers.

Ugly and toxic it may be, but to the genomicist Fugu is a thing of beauty. Its inflationary tendency does not extend to its genome. Fugu has the smallest known genome size of any vertebrate organism, about one eighth the size of the human genome. Yet the number of genes in its 365 megabases of DNA is 35,000-40,000, about the same as in the human or mouse genomes. It would seem that, as far as gene number is concerned, an animal is an animal is an animal. One reason for the compact genome size of Fugu is that dispersed repetitive DNA accounts for less than one sixth of the sequence, compared with 40% in humans; another is that the genes have fewer, shorter introns and coding regions occupy over a third of the genome. Thus it is much easier to identify genes, and their controlling regions, in the Fugu genome than it is in mammalian ones. Even though the pufferfish and man are separated by about 450 million years of evolution from their common vertebrate ancestor, it seemed likely to fellow Genome Biology columnist Sydney Brenner, who with his colleagues Sam Aparicio, Greg Elgar and Byrappa Venkatesh initiated the Fugu genome sequencing project in 1989, that knowledge of the fish genes would aid in identifying homologs in the human genome sequence, where genes are much harder to find because they represent only a small proportion of the total DNA. And since transgenic experiments in mice and Xenopus had already shown that mammalian and amphibian trans-activating factors are able to interact with Fugu cis elements to mediate cell- and tissue-specific gene expression, he also thought that Fugu genomic clones would be useful in dissecting locus control regions in mammalian and other cell lines and transgenic model systems. In short, Fugu and human genes get along swimmingly, to coin a phrase.

As usual, Sydney was right. Preliminary analysis of the 22 pairs of chromosomes in the Fugu genome (the project team is expected to complete the sequence and analysis by early to mid 2003) indicates that at least 75% of known human genes have a strong homolog in pufferfish. The members of the Fugu consortium (about which more in a moment) have already used the easily located Fugu genes to find about 1,000 previously unrecognized genes in the draft human genome sequence. More such insights are sure to come.

Published reports about the Fugu genome sequence have stressed the fact that the pufferfish genome is free from the enormous quantity of junk DNA that bedevils the genomes of the mouse and Homo sapiens. I'm not so sure that this is the correct conclusion to draw. The common ancestor of Fugu and mammals was a fish, and over the millions of years since their lines diverged most other vertebrates have undergone enormous morphological changes. Consider human evolution alone: in less than 250,000 years Cro-Magnon man has evolved into, well, us. Fossils of pufferfish ancestors, on the other hand, look very much like the contemporary carcasses that decorate the windows of little Japanese restaurants. I think one reason Fugu has either shed its junk DNA or never acquired it in the first place is that Fugu stopped doing any sort of meaningful evolution, genetically speaking, a long time ago. From which I draw two conclusions: that junk DNA is no such thing - it may in fact be the clay from which evolution fashions morphogenetic changes - and that people looking for other compressed genomes to sequence might look in other living fossils, like crocodiles and coelacanths.

The other interesting thing about the Fugu genome sequence is how it came about. It was done fast - less than two years after the consortium was formed in November 2000 - and it was done cheap, for only US$10 million. The consortium consisted of the Institute of Molecular and Cell Biology in Singapore, which actually took up Fugu in the early 1990S following Sydney Brenner's urgings; the Joint Genome Institute of the Department of Energy in the USA; the UK Medical Research Council's Human Genome Mapping Resource Centre at the University of Cambridge; and the Institute for Systems Biology in Seattle in the USA. A whole-genome shotgun sequencing strategy was used, and, towards the end, the consortium made use of excess sequencing capacity at several private companies, including Celera Genomics of Rockville, Maryland, and Myriad Genetics of Salt Lake City, Utah. This paid use by public sequencing initiatives of technology at private sequencing companies would seem an excellent model for further large-scale genome sequencing efforts. The entire Fugu sequence is being deposited in the public domain. And the project would have languished without the initial interest and support from Singapore, proving that genomics has become a truly international science.

The success of the Fugu consortium must be frustrating for zebrafish devotees, who have the enormous advantage of genetics in their favorite organism. Perhaps the moral is that, if they want to obtain its genome sequence in a timely manner, they should cultivate a taste for zebrafish sushi.

(Note: Some of the locutions in this column maybe obscure to non-native English speakers: they don't know how lucky they are to be off the hook.)

Published: 27 August 2002

An Asilomar moment

Genome Biology 2002, 3:comment1014.1

"An Asilomar moment." That's what David Galas, who used to head the Human Genome Project in the US Department of Energy and is now Vice President of the Keck Graduate Institute in Claremont, California, called it. I believe the phrase has also been used by others, but I first heard it from him. I agree. As governments in the US and Europe contemplate legislation that would divert funding of some genomics-driven research to Offices of Homeland Security and the like, and that would restrict the freedom of biologists to publish and share some of their data, we of the scientific community are facing a crisis, brought on by fears of bioterrorism, that eerily mirrors the early days of recombinant DNA research.

The phrase refers to a meeting of molecular biologists that was held at the Asilomar Conference Center in Pacific Grove, California, in 1975. Asilomar - the name is a joining of two Spanish words meaning a 'refuge by the sea' - was designed by Julia Morgan, one of the first women architects in the US, who also designed the Fairmont Hotel in San Francisco, and San Simeon, the mansion of publisher William Randolph Hearst (the real-life model for Citizen Kane). Set amidst pine and redwood trees by the shore of the Pacific Ocean, the buildings of the Center were made of local stone and redwood, to integrate them with their surroundings. In addition, most of the buildings are low and horizontal, which connects them with the local landscape of sand dunes and horizon. They have projecting eaves and low-pitched roofs, porches, grouped casements, sloping foundations, and use local materials - split wood shingles, for example. This rustic setting has served as the site for many purely scientific symposia over the years, but the meeting in 1975 had a different purpose. It was convened by, as Robert Sinsheimer, one of the organizers, put it, "a bunch of academics - focused, idealistic, and often naive - trying to do good, struggling to reconcile our conflicts, our apprehensions, our scientific ambitions our careers, our sometimes murky sense of obligation and emerge with a practical resolution."

The resolution they were trying to reach was how to move forward safely with recombinant DNA technology. The earliest reports of techniques that allowed foreign genes to be expressed in bacteria had created a flurry of reports in the popular press, which in turn had raised a chorus of alarms, from both professional Luddites and concerned citizens. Some would-be recombinant-DNA researchers themselves were worried that they might, through ignorance, accidentally produce organisms that would turn out to be dangerous. No one was quite sure what could happen once the species barrier was breached in this way.

It was against this background that the Asilomar Conference was held. (For those who want to read more about it and the times that spawned it, I recommend Donald S. Fredrickson's excellent book, The Recombinant DNA Controversy: a Memoir, published by ASM Press, Washington, DC, 2001). It was attended by both scientists and members of the press. The press, as Ronald Atlas, President of the American Society for Microbiology, has pointed out, "represented the public and provided the link between science and society." During the three-and-a-half day meeting, the group of about 150, which included most of the leaders in the emerging field, debated the risks - known and unknown - of cloning and manipulating foreign genes and expressing them in bacteria. The meeting ended with a series of resolutions to the just-established NIH Recombinant DNA Advisory Committee (RAC) that set forth guidelines for the safe conduct of recombinant DNA experiments, and that endorsed the RAC as the instrument governing the implementation of the guidelines. The public participated in the formulation of these guidelines through open hearings, and the guidelines were given force by linking their compliance with obtaining federal funds for any such research. Sinsheimer says that this result was "A middle ground ... too restrictive for some, insufficiently restrictive for others ... but Asilomar surely helped in many ways to launch the complex world of biotechnology we know today."

Twenty-seven years later, the world is very different. One reason the Asilomar process may have worked, as Atlas has noted, is "the relative small size of the scientific body and the fact that the technology had yet to be widely deployed." Now nearly every biologist uses recombinant-DNA technology. Experiments that were originally mandated under safety precautions suitable for handling nuclear materials are now permitted in open laboratories, and can be done, legally and feasibly, in someone's basement. We now understand that Nature breaches the species barrier constantly through the shuffling of mobile genetic elements, transposons, plasmids, and other vehicles for recombination and integration. Lateral gene transfer is acknowledged as a standard evolutionary mechanism. Much of what we feared had in fact been going on for millions of years. Most of the original guidelines have been relaxed, and some have been eliminated altogether.

It is in this climate of freedom of inquiry that the specter of bioterrorism has arisen. The ease of recombinant DNA materials and techniques, plus the availability of genomic data, even on human pathogens and known biowarfare agents, has made the creation of new weapons of mass destruction more feasible than ever before. This in turn has caused jittery governments to contemplate - and in some cases to attempt to implement - tight controls over the funding, conduct and publication of biological research. In the US, proposals under deliberation include one that would transfer control of funding for much of microbiology research, including all biodefense research, from the National Institutes of Health and the National Science Foundation to the newly created Office of Homeland Security, a non-science organization. Other proposals would require government review of essentially all papers in genomics, genetics, cell biology and biochemistry that deal with pathogens, their genes, or their gene products. These publications could be embargoed or could have portions of their data removed and classified. In July, the British Parliament passed a law allowing the government to restrict access to information that could be used to build nuclear, biological or chemical weapons. The Export Control Act covers information transmitted verbally, electronically or in print for the first time. Scientists were able to push through a last-minute amendment requiring any controls on research communications to be "no more than is necessary", but the law might be used to bar publication of gene sequences that, in the judgement of the government, could be used to make bioweapons.

Those of us who lived through the Cold War era know what affronts to human rights and freedom can be committed in the name of 'national security'. Yet it cannot be denied that almost every week the newspapers and scientific journals report some new biological horror in prospect. Australian researchers are reported to have cloned an immune system gene into mouse pox virus, creating a strain of such virulence that it kills not only naturally resistant mice but vaccinated ones as well. Japanese scientists have discovered that deletion of a single gene in a chicken 'flu virus makes it infectious to humans. Biologists at the State University of New York at Stony Brook have synthesized the entire genome of the polio virus, demonstrating that small pathogen genomes such as those of Ebola virus are accessible - and can be manipulated - by widely available methods. In response to such threats, it is hard to dismiss government efforts to control the flow of biological information as either a paranoid overreaction or an attempt to exploit a potentially dangerous situation to seize additional power, even though they might well be both.

Scientists are responding to these threatened restrictions in a number of ways. One is, of course, the traditional ostrich approach: bury one's head in the sand and hope the problem goes away. A smaller group is calling for restrictions, whether voluntarily agreed-upon or governmentally imposed, on experiments and publications such as the polio virus synthesis. Others believe that broad accessibility to all forms of information is vital to preparing for and responding to bioterrorist actions. And many scientists are protesting that any barriers to free and open inquiry and exchange of information represent a dangerous precedent that cannot be allowed to happen.

No one is more wary of this slippery slope than I am. But it is interesting to note that the following experiments were prohibited under the Asilomar guidelines as first adopted: cloning of recombinant DNAs derived from the organisms in CDC biohazard classes; deliberate formulation of recombinant DNAs containing genes for the biosynthesis of toxins of very high toxicity (such as botulinum toxin); deliberate creation from plant pathogens of recombinant DNAs that are likely to increase virulence or host range; widespread or uncontrollable release into the environment of any organism containing a recombinant DNA molecule unless a series of controlled tests leave no reasonable doubt of safety; transfer of drug-resistant traits to organisms that are not known to acquire them naturally; and large-scale experiments (more than 10 liters of culture) with recombinant DNAs known to make harmful products. Many of these are precisely the sort of experiments we are worried about again today, not because we fear what might happen by accident, but because we now realize that evil or deluded people may attempt them deliberately. And the scientific community once accepted these restrictions, partly because they seemed prudent but partly because they had participated in drawing them up themselves.

I think the government is not the best object of our concern in this situation. In the free world, governments tend to be responsive to the wishes and fears of their people. The real danger here is that the age we live in, the age of genomics, is slowly terrifying the average person. Long before the anthrax-laced letters began arriving in the mail, the public was voicing concern about human cloning, designer babies, and genetically modified foods. Bioterrorism is just the latest demon to arise from what the public sees as the Pandora's Box of modern biology. Governments may use this fear as an excuse to control research and restrict the flow of information, but in doing so they are responding to a public that is increasingly nervous about what we are doing and why we are doing it. Without that public anxiety, efforts at excessive regulation will fail.

Our aim as a community therefore should be to respond to this public concern, just as we did in 1975. And I think the best way we can do that is by agreeing as a community on a set of limited guidelines and restrictions, just as we did in 1975. If we ourselves act now to protect the public, we reassure them that we place our concern for their interest ahead of our self-interests. We also take away from those in government who would control every aspect of what we do both the moral high ground and the initiative.

I'm not alone in calling for a gathering of scientists and representatives of the public to debate these issues and come up with a set of recommendations that would try, as the Asilomar Conference did, to find a middle ground: too restrictive for some, not restrictive enough for others. D.A. Henderson, director of the Center for Civilian Biodefense at Johns Hopkins University, is just one of a number of voices to have suggested something similar. I'll offer some suggestions for how those recommendations might be implemented and enforced in my next article, but for now let's agree that this gathering must be held. It should at a minimum include the heads of all major life science societies, funding agencies and academies; deans of major medical schools; prominent researchers in microbiology, pathogenesis, immunology and virology; biodefense experts, both civilian and governmental; and the press as representative of the general public. As for the time, I suggest as soon as possible. And for the place, why not Asilomar? It served us well once before.

Published: 25 September 2002

The guards themselves

Genome Biology 2002, 3:comment1015.1

If we agree that, in the present climate of fear of bioterrorism, some restrictions on the conduct and/or publication of certain types of biological research are likely, and if we further agree that, as I argued last month (see Genome Biology 2002 3(10):comment1014), it is to our advantage to preempt government action by devising for ourselves restrictions that we can live with, then the inevitable question becomes: how should these restrictions be administered?

There are many models for regulating behavior. For example, government agencies can run things directly; this model was largely followed in the conduct of research related to atomic energy in the decade or two after Hiroshima, and is largely responsible for the widespread public affection for nuclear power. Activities can be run privately but subject to regular inspection by the government; handling of radioactive and other hazardous materials is dealt with this way, with the result that all over the world people are eager to have toxic waste disposal sites located in their communities. Or things can be run privately but inspected - audited, if you will - by independent private contractors; around these parts this is often referred to as the Enron/Arthur Andersen model. And then there's self-regulation.

Self-regulation also has a somewhat checkered history. In the US, politicians generally vote on their own salary increases and watch over each other's ethics, with predictable results. Lawyers, as a rule, police one another through their Bar Associations - and the morals of lawyers have been standard material for humor since at least Shakespeare's time. Most police departments have 'Internal Affairs' divisions for investigating charges of police misconduct, and considering their opportunities for illegality the general honesty of the police is noteworthy; nevertheless, police corruption is the stuff of countless newspaper exposes, movies, novels and television shows. Physicians do better, but even there enough instances of serial medical malfeasance have slipped past medical boards to warrant sporadic efforts at outside control.

Yet compared to other forms of regulation, systems of self-regulation - when properly constituted - can work well. Their strength (as well as their potential for abuse) lies in their inherent circularity: because those doing the regulating are also the subjects of the regulation, there is a constant tension that pulls things back into balance when rules become either too loose or too strict. Furthermore, there is always the opportunity to take new information into account, since the regulators are the ones generating it. Perhaps the best example of a well-functioning self-policing system is provided by science.

Instances of scientific fraud are rare, in part because if a result is sufficiently noteworthy it will soon be checked by numerous other laboratories that were, or wish to become, competitors. Internal competition guarantees that no outrageous claim will go unchallenged, and the demand for reproducibility ensures that even most honest errors will be detected relatively quickly. Punishment for deceit is swift and permanent. Genuine mistakes do not doom scientists but do harm their careers enough to provide a strong incentive for one to check one's work carefully. This system of self-regulation is almost completely informal, but has been highly effective.

Yet when the specter of monsters generated by recombinant DNA research appeared in the 1970s, the scientific community realized that this informal system was not enough to reassure an increasingly frightened public. The result was the National Institutes of Health Recombinant DNA Advisory Committee (RAC), which, with the advice and endorsement of the 1975 Asilomar Conference on Recombinant DNA Research, set forth guidelines for the safe conduct of recombinant DNA experiments (see Genome Biology 2002 3(10):comment1014). The early, highly restrictive guidelines slowly evolved into more relaxed recommendations and regulations, as years of experience convinced both scientists and, more importantly, the general public that such research could be carried out safely with no disastrous consequences. But throughout this evolution the machinery for regulating the research has remained in place: a system of local Institutional Review Boards (IRBs) ultimately answerable to a national oversight committee. That system is also one of self-regulation, but it is a tiered process with accountability built in. I think it represents an excellent model for how the biology community might regulate research, particularly genomics-driven research on pathogens, that might conceivably be useful to would-be bioterrorists.

Don't misunderstand me here: I think that government is best that usually governs least, and I believe that nearly all forms of research should be unfettered and published openly and completely. I think it's naive to assume that we must keep things under wraps because our enemies would never think of them unless we put the ideas into their heads. The history of scientific research teaches us that most ideas are arrived at by a number of different people at about the same time, and, sadly, I see no reason why this principle should not apply to potentially evil ideas as well as to beneficial ones. We're better off in the long run, I think, making sure that all of us know what's possible so that we can bestir ourselves to doing something about it. But that doesn't mean that there might not be some experiments that we shouldn't do, or information that we might not want to have openly available. And if we're not sure about this, then I think in order to calm the fears of a public that is increasingly viewing us with suspicion and anxiety we need to accept some limitations.

But the point is that these limitations need to be self-imposed, and I think the IRB system represents an excellent way of going about it. Most US universities already have several institutional review boards: one for recombinant DNA research, another for research involving hazardous substances, a further one to oversee animal experiments and, in the case of medical schools, yet another for review of experiments involving human subjects. These boards are staffed by working scientists and are answerable, ultimately, not only to the administrations of their own institutions but also to the funding agencies that support research activities. The threat of even a temporary cut-off of grant support is enough to guarantee that the local boards will take their responsibilities seriously. But since local boards can't modify regulations as new evidence comes in, and because there should be a mechanism to appeal decisions that seem arbitrary or misinformed, someone is needed to watch over the IRBs and periodically review the regulations. In recombinant DNA research in the US, the RAC fulfills this function.

So one possible regulatory mechanism could look like this. Guidelines for safe conduct of research protocols involving, say, CDC category A, B, or C biohazard materials/agents and for adequate security regarding 'sensitive' materials and information will be developed by a Biohazard Advisory Committee (BAC) set up by the funding agencies. The composition of the BAC is a matter for community discussion, but I think it should have at least a majority of working scientists in the areas of microbiology, immunology, virology and genomics. Each institution receiving government support for such research must set up an IRB composed of knowledgeable internal scientists. (Privately funded research at these institutions would simply be subject to the same rules; research done in companies would be regulated by a different mechanism, providing an outlet for extremely sensitive projects for which the results might be unpublishable.) Thereafter, for any research specified in the guidelines as having a potential bioterrorism impact, the following procedure would be followed.

1. Research protocols and results must be submitted for local IRB review prior to submission of proposals for funding or of papers for publication

2. Following preliminary review, additional information may be requested prior to the IRB meeting

3. For clarification of regulatory questions, research protocols involving CDC category A, B, or C biohazard materials/agents may be submitted for BAC review prior to local IRB review and approval

4. Decisions of the IRBs may be appealed to the BAC for final adjudication

A number of variations are possible, but something like this would cause a minimum of disruption to research, would ensure that decisions are made by people who best understand the issues, and would create the least intrusive bureaucracy.

The fundamental problem with any regulatory system was pointed out by the Roman satirist Juvenal more than 19 centuries ago: Sed quis custodiet ipsos custodes?, or "But who will guard the guards themselves?" He gave no answer to this conundrum, and it may well be that there is no good one. But I think that, sometimes, if the ones being guarded become the guards themselves, the question can at least be rendered moot.

Published: 25 October 2002

Banana republic

Genome Biology 2002, 3:comment1016.1

What do you call a country in which the 13,000 richest families have as much income as the 20 million poorest families? One in which those same 13,000 richest families have incomes 300 times that of the average family? And in which the richest 1% of families receive 16% of the total pretax income in that country, a percentage as large as that received by the entire bottom 40% of the population? Some might call it a banana republic. I call it the United States of America.

The figures I just cited are taken from a recent article by the political/economic columnist Paul Krugman ("For Richer: How the permissive capitalism of the boom destroyed American equality." New York Times Magazine, October 20, 2002). His thesis is that during the past 20-30 years the gap in income between the rich and rest of the population in the U.S. has grown so large that economic policy now increasingly caters to the interests of the elite, while public services for the rest of the population - he focuses on public education but the point covers other services as well - are starved of resources. Anyone who has looked at, for example, the largest U.S. cities can appreciate his point. New York City has become basically a two-tiered society: the very rich and the poor. Middle class neighborhoods are disappearing from the urban center, as are middle class people themselves. The United States used to be largely a middle-class society, both in appearance and actuality. But income disparities have increased so much in recent decades that now both the economic and the political systems are driven not by the needs of the middle class but by those of the wealthy. Krugman warns that the U.S. "may become a country in which the big rewards are reserved for the people with the right connections; in which ordinary people see little hope of advancement; in which political involvement seems pointless, because in the end the interests of the elite always get served." In short, a banana republic.

'Banana republic' is a pejorative with a hundred-year old history. Thomas H. Holloway, Professor of Latin American History at Cornell University in Ithaca, New York, traces it back to O. Henry (1862-1910), the famous American short story writer. O. Henry, whose real name was William Sydney Porter, began his working life as a financier. Unfortunately his financial activities strayed over the border of legality - behavior unknown to the financial officers and accountants of our day, of course - and he ended up serving time in prison for bank fraud. Incarceration has a bad reputation as a mechanism for rehabilitation, but it seems to have worked for 0. Henry: while in prison he began his writing career. But before being jailed he hid out for a time in Central America, on the north coast of Honduras. He used his experiences there as fodder for his book Cabbages and Kings, a loosely connected set of vignettes recounting the misadventures of various gringos in the mythical Latin American republic of 'Anchuria', which is Spanish for 'widths' ('Honduras' is Spanish for 'depths'). Professor Holloway notes that the material was apparently first copyrighted in 1904; in any case, on page 328 of the 1912 edition (Doubleday and Page, Garden City, USA) he found the earliest reference to the term in an explanation from a gringo character as to why he chose to emigrate swiftly to such a benighted tropical venue: "At that time we had a treaty with about every foreign country except Belgium and that banana republic, Anchuria."

My Collins dictionary defines banana republic as "A small country, esp. in Central America, that is politically unstable and has its economy dominated by foreign interest, usually dependent on one export, such as bananas." Now, I love my Collins but I disagree with this definition. I don't think the domination of the economy by foreign interest has to be there (although I concede that typically it is) and I think political instability isn't a requirement either. 'Republic' here is a euphemism for dictatorship, and as any Iraqi can tell you, dictatorships can be more stable than one might wish. The dictatorship implied in this case is rule by a small, wealthy (usually corrupt) clique. A banana republic, in other words, is a country where a very small percentage of the population has a very large share of the wealth and power.

We can argue about whether Krugman's concern that the United States is headed in that direction is justified, and if so what can be done about it. But it's becoming less and less easy to argue that the term doesn't apply to biological research, and one of the biggest reasons is genomics. The trend has been evident for some time. I think it started in the U.S. in the 1970s, when a small number of clinical research labs in medical schools grew to enormous size, necessitating equally huge research grants. It became institutionalized in the 1980s, when the Howard Hughes Medical Institutes poured large sums of money into select subjects, guaranteeing chosen investigators lavish support for many years, thereby freeing them from the insecurity of the federal funding process. (Although Hughes Investigators were almost entirely U.S.-based, a small number of foreign scientists benefited from this largess as well.) It was no coincidence that, in its early years, the Hughes program was restricted to researchers in medical schools, and thus tended to accelerate the distinction between the level of support enjoyed by some investigators there and their brethren on main campuses. When the program expanded in the 1990s to include scientists not affiliated with medical schools, a class structure was created in American science. The upper class consisted of Hughes investigators. Blessed with the best equipment money could buy plus long-term support more easily renewable than federal grants, they could - and did - embark on high-risk/high-return projects and projects requiring long incubation periods. A small number of favored lab leaders at a few privately endowed research institutes also belonged in this category. The middle class comprised those academic scientists fortunate enough to have a number of large federal grants, perhaps augmented with support from non-governmental foundations. They could do front-line research provided it didn't require lavish instrumentation and large numbers of personnel. Everyone else made up the underclass.

Some other countries had a similar class structure long before. In Germany, for example, directors of Max Planck Institutes enjoyed a research life-style much like that of Hughes Investigators. Some professors in Britain were similarly blessed (I recall a famous report in the late 1980s, I believe, showing that a very few senior organic chemists in the U.K. commanded a disproportionately large share of the total research funds in that field). My description isn't meant to be critical; admission to the upper class, in the U.S. and elsewhere, was usually based on merit. Nor was it an accident that so many of the breakthroughs in biology came from the upper-class labs: the ability to take both risks and a long-term view was as important to these advances as superior infrastructure. I don't think science as a whole was too ill-served by this system, despite the jealousy and envy it created. Even though a small percentage of scientists were significantly better off than those in the next tier, for the most part the middle class were not shut out from any broad area of biological research, although some specific problems were beyond their available resources.

But I think something has happened in the past 5-10 years that may be widening the gap between the classes to the point where entire fields of biology may become closed to those below the top. In other words, I think that in some areas there will cease to be a scientific middle class. And the area that strikes me as the most likely to become a banana republic is genomics. I'm not referring to genome sequencing; it's more a technology than a field, intellectually speaking. Structural genomics is similar. By genomics, here, I mean an integrated approach to biology that is genome-driven. It focuses on pathways and processes involving the functions and interactions of many gene products. It makes heavy use of genome-wide technologies such as microarrays and high-throughput mass spectrometry as well as expensive genetic methods like knockout mice. Heavy reliance on expensive, large-scale instrumentation is only one reason that this new science is difficult for all but the largest, best-funded labs. The need to employ many very different techniques - and disparate modes of thinking as well - is another barrier to entry.

Now none of this would matter much if we were talking only about a sub-discipline. But genomics and biology are fast becoming one thing. The transformation of the life sciences from a purely reductionist discipline to one in which the cell, organ and organism are the real objects of study is not just a trend. I see it as an inevitable progression that marks the maturing of biology, and it would be a pity - and would retard that maturation - if the field balkanized into a small number of labs that think and work at that level and a large number of labs that can't.

So I think there's a message here for those who set science policy at all levels, from the heads of funding agencies to deans, department chairs and center directors. If the middle class of scientists is to benefit fully from, and participate fully in, the age of genomics, then creative approaches to the funding and conduct of research are needed. I think that more attention must be paid to providing shared instrumentation resources available at low cost. Collaborations are one way in which individual small labs can acquire the techniques and breadth of expertise that otherwise might require a large, interdisciplinary group or center, but funding mechanisms that facilitate such multi-lab programs are spotty and underfinanced. The length of the average government research grant, 3-4 years, is too short for the kinds of problems that collaborations like these are meant to tackle. Junior investigators are often discouraged from participating in such program projects because independence is a frequent criterion for promotion. Only their senior colleagues can change a culture that penalizes those who wish to build communities while rewarding the selfish.

The choice seems to me to be clear: we can share equipment, projects, students and ideas, and provide the individual investigator with financial support that encourages such sharing, or we can sit back while a small group of biologists with access to specialized resources and dependable support wield ever more influence and carry out ever more of the important, trend-setting experiments. That wouldn't spell doom for genomics, but it would mean that this new field, and thus perhaps modern biology, would be dominated by a small, elite group that controls most of the wealth and power. And you know what kind of republic that is.

Published: 26 November 2002

Everything I need to know about genomics, I learned from Yogi Berra

Genome Biology 2002, 4:102

"I really didn't say everything I said."

Lawrence Peter (Yogi) Berra

As 2002 draws to a close, I find myself contemplating the future of biology with hope, but also with uncertainty and some apprehension. Will biology continue to be the richest source of discoveries and ideas in all the sciences? Will it become just another Big Science, like nuclear physics, in which the many slave for the enrichment of the few and powerful? Will it bog down in its own arrogance? Will it lose the trust of the public as bioterrorism fears grow and genetically modified organisms try to pervade the marketplace? Or will it become the savior of mankind, ridding the world of disease and famine? And will I be able to get in on any of this?

When I find myself in such a spiritual quandary, I usually turn to a guide - a guru if you will - someone whose wisdom and penetrating insight has served me well in the past. Someone whose wit is equaled only by his clarity of thought. Whose international renown is exceeded only by his stature in the sheltered world of philosophy. I am referring, of course, to Yogi Berra.

Yogi (born Lawrence Peter in 1925 in St. Louis, Missouri) Berra was for many years a baseball catcher (the rough equivalent of wicket-keeper for those of you who play the equally obscure game of cricket) for the New York Yankees, which were, not coincidentally, during his tenure the top team in their sport. Despite his stocky stature he was a great athlete - he was named to the All-Star team fifteen years in a row and three times won the award as the Most Valuable Player in his league - and he was, like his predecessors Siddhartha and Gandhi, a man of simple means and modest needs. He was not given to ostentation or excessive worry about the future - on one occasion his wife, Carmen, asked him: "Yogi, you are from St. Louis, we live in New Jersey, and you played ball in New York. If you die before I do, where would you like me to have you buried?", and he replied: "Surprise me." Mr Berra displayed in all things the demeanor of the true teacher/philosopher. A man of deep introspection - he is said to have remarked, on seeing a film featuring the late actor Steve McQueen: "He must have made that before he died." - Mr. Berra has given us in his spoken statements (it is not clear whether he can write) a set of observations so clear, so pointedly addressed to the needs of the life sciences today, that we would be fools not to consider them with the reverence they deserve.

True, some Yogi scholars have claimed to find obscurity and bewilderment in these straightforward utterances, but that is doubtless either because they are so used to the deliberate cloudiness of everything in the social sciences and humanities or because they have been laboring under the mistaken assumption that his aphorisms were actually about mundane things such as baseball or life. Once we realize that Yogi, in essentially every comment he has ever offered, is actually talking about biology in the age of genomics, then the mists clear and it becomes apparent that these are the sayings of a sage - perhaps the quintessential sage of our time. As my holiday gift to my readers, I offer this small anthology of just some of his words of wisdom.

"It ain't over 'til it's over"

This is perhaps Mr Berra's most famous aphorism. Although some scholars have speculated that it means a baseball game is not played to any time limit, and therefore the game is not over until the last inning has been completed, clearly a deeper significance is intended here. Yogi is obviously referring to those people who think that genomics is a passing fancy, and that biology will revert to individual-investigator-driven science very soon.

"You can observe a lot by watching"

Mr Berra intends to remind us that computer analysis of reams of data may be fine for the myopic, scientifically speaking, but there is much to be learned from simply looking at the primary results ourselves.

"When you come to a fork in the road, take it"

Scholars have puzzled over this one for decades (some have been driven mad by it, so such scrutiny is now frowned on), but once one realizes that all of Yogi's dictums refer to genomics the meaning becomes clear. Biology is at a fork in the road - it can either go down the path of big science or try to maintain its 'small is beautiful' character as much as possible. Mr. Berra's preference is obvious.

"Nobody goes there anymore, it's too crowded"

In a profound comment on the herd mentality so prevalent in biology today, Yogi is reminding us that the road less traveled often contains the most interesting possibilities. He warns us that creative minds eschew the crowd.

"This is like deja vu all over again"

By this Yogi clearly means that the current fad for all things genomic (for example, cDNA microarray analysis of everything under the sun) is in many respects a recapitulation of earlier fads for site-directed mutagenesis, protein structure determination by X-ray crystallography, signal transduction, and so on. All these 'new sciences' eventually became more-or-less routine laboratory techniques. It can happen to any new discipline, and it probably always will.

"In theory there is no difference between theory and practice. In practice there is."

Can one imagine a more important observation in the age of genomics? As we rush to draw conclusions - general ones, at that - from genome sequences and microarrays and protein structure databases, Yogi reminds us that there is no substitute for careful experimentation. Because Nature has a nasty habit of surprising us just when we think we have Her figured out.

"A nickel ain't worth a dime anymore"

Mr Berra is obviously commenting on the enormous cost of genome-driven biology, and urges the funding agencies to increase the average award size immediately. His words are directly addressed to the program officer who administers my grants.

"The future ain't what it used to be"

To which one can only say: How true.

"You've got to be very careful if you don't know where you are going because you might not get there," and "If you don't know where you are going, you might wind up someplace else"

Phil Rizzuto (a teammate) said "Hey Yogi I think we're lost." Yogi Berra replied "Ya, but we're making great time!" Clearly this is a recurring theme in Mr Berra's work: the journey; the voyage through life that we all undertake. He wishes us to understand that biology, too, is on a journey, and its ultimate destination - or even the route it is following - is unclear. As scientists we tend to shun planning for the future of our discipline, preferring to go with flow, so to speak, and be carried along towards whatever shore the current is tending. In this cluster of sayings, we see that such insouciance sometimes has a price - namely shipwreck. Yogi would have us sometimes pause, and consider where we would like to end up, and adjust our course accordingly.

"It was impossible to get a conversation going, everybody was talking too much"

This is the one saying of Yogi's that does not explicitly refer to genomics. I believe he is commenting here on academic committee meetings, but some scholars differ in interpretation.

"There are some people who, if they don't already know, you can't tell 'em"

And most of them, for some reason, now seem to work in the general area of analysis of large genomics-driven databases.

"If you can't imitate him, don't copy him"

What words to live by. Yogi reminds us here that copying is easy, but to be as good as the person imitated is not. As we all scramble to reinvent ourselves, and retool our experiments and our ways of thinking to match those of the genomicists who are receiving so much publicity and funding these days, it is well to keep in mind that sometimes we do best by just being ourselves. As Mr Berra might have said (but didn't - although with him one can never be sure): You are what you are.

"You should always go to other people's funerals; otherwise, they won't come to yours"

I don't have the slightest idea what Yogi really meant by this statement. And I'm willing to bet that he doesn't either.

Editor's note: interested readers can learn more about Yogi Berra at his official website, http://www.yogi-berra.com/

Published: 31 December 2002

Funky, not junky

Genome Biology 2003, 4:104

As I write this, the holiday season is upon us again. It tends to arrive, in my case anyway, with the suddenness - and sometimes the consequences - of a train wreck. But amid the carnage there are moments of relative calm (by which I mean periods when one's relatives are calm and one can slip off to get some work done or just relax), and this year I've been using such moments to catch up on my reading.

I've been perusing 'Of Mice and Men'. No, not the sad, brilliant, haunting short novel by John Steinbeck, nor the delightful, insightful poem by Robert Burns that contains the phrase Steinbeck borrowed for his title. The particular Of Mice and Men I've been engrossed in is much more recent, and a lot longer. It came out last month and it has about 2.5 billion words. I had thought I could skip anywhere from 95 to 99% of it, since advance reviews had predicted that all but about 30,000 paragraphs would be unimportant. But now it looks as though I may have to plow through the whole damn thing. I had thought, in other words, that the draft sequence of the mouse genome would be like one of those paperback potboilers - something by, say, Harold Robbins or Jacqueline Susann - that one can just skim without missing much. Instead, it seems to be more like Proust's Remembrance of Things Past.

We live, as I'm fond of pointing out in these pages, in the age of genomics, and these days it seems as though every week brings us the complete genome sequence of yet another important eukaryotic organism. Yeast is followed by worm followed by fly followed by human, Arabidopsis, Fugu - the news comes so thick and fast that it's easy to get blase. But even in these jaded times, the draft sequence of the mouse genome was front-page news. That's a lot of fuss, considering that as a result we can now take pride that our closest relative in terms of complete sequence information is a creature best known as a coward and a household pest. But I think all the publicity was justified. I would go even farther: I think the mouse genome sequence is more important, short-term, than the human genome sequence.

Most published commentaries on the mouse genome sequence, which was published on 5 December (Nature 2002, 420:520-562), have stressed the insights that will come from comparing it with that of Homo sapiens. That comparison has already started. For one thing, the mouse genome sequence validates the estimate of about 30,000 genes in the human genome, because Mus musculus appears to have about that number, and 99% of mouse genes have a human counterpart and vice versa. Even though the mouse genome contains 14% fewer base pairs (2.5 billion compared to 2.9 billion), over 90% of the two genomes can be partitioned into corresponding regions of conserved synteny (segments in which the gene identity and order in the most recent common ancestor has been conserved in both species). It is perhaps unsurprising that it is not the presence of unique set of genes that makes us human, but rather the way that a generic mammalian gene set is regulated.

At the nucleotide level, almost half of the human genome can be aligned to that of mouse, and the proportion of small (around 100 base-pair) segments in both mammalian genomes that is under selection can be estimated at about 5%, a number much higher than can be accounted for by protein-coding sequences alone. The implication is that in both mice and humans, the genome contains many 'non-coding' regions that are under selection pressure, and therefore that have important functions.

In many respects, the most intriguing part of the mouse genome sequence is what it has told us about these so-called 'junk' DNA sequences. In a mammalian genome, much of it originates from retrotransposons, which accumulate by being copied over and over into new locations. Given that retrotransposons reproduce via an RNA intermediate, they require reverse transcriptase to make the DNA copy that hops back into the genome. About 40% of the mouse genome seems to have derived from retrotransposons - about the same proportion as in the human genome. But in our genome the activity of these genetic parasites seems to be low, with only about 100 still active. In mouse, by contrast, about 3,000 are actively jumping around. They come in three flavors: long interspersed elements (thousands of base pairs; 20% of the mouse genome) and long terminal repeats (10%), both of which produce their own reverse transcriptases, and short interspersed elements (about 300 base pairs; only about 8%), which do not.

What do these elements do? It appears they can do a number of things. When they jump into a host gene, they can disrupt its function completely or alter it subtly. They may be an important part of the clay that Nature uses to generate new functions as higher organisms evolve. Mart Speek has shown that long interspersed elements can alter the expression of neighboring host genes (see, for example, Mol Cell Biol 2001, 21:1973-1985), indicating that they may be co-opted into becoming part of the machinery used to regulate transcription. John Moran and Jef Boeke have also shown that, in cultured human cells, they can cause deletion of large blocks of DNA (see Cell 1996, 87:917-927). And Dixie Mager has suggested that regions of the genome free from accumulated retrotransposon sequences may be hallmarks of functional importance (Genome Res 2002, 12:1483-1495), like the Hox genes that specify body plan.

How much of the 'junk' DNA will actually turn out to be useful for the cell is anyone's guess at present, but it seems clear that the term is outmoded. Calling something junk just because we don't understand what it does strikes me as narrow-minded. I suggest replacing this designation with 'funk' - functionally unknown DNA. I would prefer to think of our genome as funky rather than junky.

Mouse knockouts will certainly be important as disease models, and along with work in other model organisms mouse genetics and cell biology will be very useful in establishing what many mammalian genes are doing. And there's a school of thought that says that even though it's expensive to run a mouse lab, many biologists will now switch to doing mouse experiments because of how similar the mouse genome is to the human. But I'm not sure that the really interesting aspect of the mouse genome sequence will be what it can tell us about the location and likely functions of genes in the human genome. What has always fascinated me about the mouse is how easy is it to cure disease in mice and how frequently those cures fail to work in humans. Far be it from me to tell anyone what to do - OK, maybe not very far - but I think that the really interesting thing to figure out would be why, for example, so many treatments kill tumors in mice and don't do so in people. If I were the funding agencies, I'd be thinking about encouraging research that looks into the differences between mice and men, not just work that focuses on their similarities. The real excitement about the genome sequence of the model organism of the moment might just be the opportunity it affords to learn why a great model for understanding disease is so often a poor model for doing anything about it.

While we're waiting for the research directions to sort themselves out, we can keep busy trying to figure out what those couple of billion funky base pairs in the mouse, and human, genomes are doing, a process that will probably take decades. I suspect few of its founders would have thought, when they started the human genome project, that one of its consequences would be that thousands of scientists would spend their careers working on what used to be called junk. But then, the best laid schemes...

Published: 29 January 2003

Still no flying cars

Genome Biology 2003, 4:106

Hobbes: A new decade is coming up.

Calvin: Yeah, big deal! Hmph. Where are the flying cars? Where are the moon colonies? Where are the personal robots and the zero gravity boot, uh? You call this a new decade?! You call this the future?? HA! Where are the rocket packs? Where are the disintegration rays? Where are the floating cities?

Hobbes: Frankly, I'm not sure people have the brains to manage the technology they've got.

Calvin: I mean, look at this! We still have the weather?! Give me a break!

Calvin, the feckless creation of the cartoonist genius Bill Watterson, is a six-year old boy with an overactive imagination, and Hobbes is his constant companion. To everyone else, Hobbes is a stuffed tiger; to Calvin, he appears as a real tiger, with a philosophical bent that matches his namesake. Calvin's complaint, voiced in a comic strip more than ten years ago, was echoed a number of years later by several pundits when the millennium turned. Reporter Cindy Gierhart, in an article entitled "Where are the flying cars?: The future that didn't come true", cited a 1967 Wall Street Journal book, Here Comes Tomorrow!, that predicted a variety of new technologies for the dawn of the twenty-first century, including trains that moved through air-cushioned tubes at up to 600 miles per hour, a manned Mars landing, and of course, the inevitable flying cars. Yet here we are, in 2003, still commuting to work on outmoded rail systems (misnamed rapid transit), or via 'sport-utility vehicles' so unaerodynamic that they couldn't fly if they had a rocket engine strapped to their rear bumpers.

Futurologists are always being taken to task for their overly optimistic predictions, but the authors of Here Comes Tomorrow! didn't do so badly on some counts. One of their predictions was for a worldwide communications system that would transmit vast amounts of information at enormous speeds - this in 1967, when the Internet was not even a gleam in anybody's eye. And they predicted that parents would be able to choose the sex of their child through artificial insemination, although they missed the magnitude of the ethical dilemmas that reproductive technology brought with it. Yet Calvin's complaint lingers. Why, after less than two centuries of almost incomprehensible technological progress - remember that until the mid-nineteenth century no human had ever traveled faster on land than a horse, and no one had ever traveled through the air or under the water at all - has progress in so many areas seemed to slow almost to a halt. We don't travel any faster now than we did in the mid-twentieth century; in fact, if you live in a major metropolitan area, the odds are that most of the time, thanks to traffic, you travel slower than you could have done fifty years ago. After a series of costly failures, we are probably further from sending a manned expedition to Mars than we appeared to be in the late 1960s. We're certainly further from moon colonies: the costs have ballooned beyond expectation. Personal robots exist, but as no more than expensive, largely useless toys. And there are no flying cars. In nearly all the science fiction novels of the mid-twentieth century, and most of the science fiction films, the skies of the twenty-first century were filled with flying cars. Where are the flying cars?

It's actually pretty easy to account for some of the seeming lapses of technological progress. Space exploration became too costly, in men and materials, to justify expeditions that could be done more safely and cheaply by unmanned craft. Public transportation in many developed countries became a poor stepsister to automobiles, although there are signs that this trend, which was driven in part by human laziness and desire for independence and in part by aggressive lobbying by the oil and automotive industries, may be ripe for change. As for the absence of flying cars, well, I think that's the easiest of all to explain. Like all urbanites everywhere in the world I am firmly convinced that my city has the worst drivers on the planet, and if they were given access to flying cars it would be raining automobile parts. I suspect that we have actually had the technology to produce flying cars for twenty years but that it's been suppressed for reasons of public safety, and as a Boston driver all I can say is, it's a good thing.

And yet, for me Calvin's rant resonates in another technology-driven sector, that of publicly funded scientific research. What he was saying, after all, is that he was disappointed that scientific progress hadn't lived up to its promises. He was wrong, of course, because what he was really complaining about was the absence of things largely forecast by science fiction, not science, and science fiction has the habit of making exaggerated promises about the future. But in recent years, biology has also started making big promises about the future in order to justify big increases in public funding, and there are signs that this habit is having serious negative consequences.

It all started, I think, with the War on Cancer, proclaimed by U.S. president Richard Nixon in the early 1970s. I don't think increasing public funding for cancer research was itself a bad idea, but I hated the way it was done (see Genome Biology 2001, 2:comment1007.1-1007.2 for more on this issue). First of all, the title of the campaign conveyed the misleading impression that "cancer" was one disease, and therefore that there should be one cure, a fallacy that the scientific establishment did too little to refute. Second, the whole notion that all we needed to do to solve any major health problem was to throw buckets of money at it ignored the reality that different fields are at very different stages of development, and benefit in very different ways - and sometimes not at all - from injections of funding. Finally, I thought at the time that a cancer war would give the public an overly optimistic idea not only about what publicly supported science could accomplish but also about how rapidly it would accomplish it. Of course, thirty years later, the 'war' has not been won - indeed as described then it never could have been - and no one speaks of it now. Some very important breakthroughs have been made in understanding cancer in general and in treating a small number of cancers, in particular, but perhaps an equally significant outcome was a rise in the number, and influence, of disease activists, who have contributed, among much good, to a proliferation of disease-oriented 'directed' research initiatives, which are slowly siphoning resources from basic, individual-investigator-initiated, curiosity-driven science. And although there is abundant evidence that basic research has significant long-term payoffs, I have never seen an independent study of how effective government-funded applied research is in the biomedical sciences, an issue of particular significance given that at least some of it supports efforts that are amateur versions of the privately-funded research already being carried out by biotechnology and pharmaceutical companies.

I remember the rush of promises made when the gene for cystic fibrosis was identified. More than ten years later, it is not clear that knowing about this gene has contributed significantly to the life expectancy of a single patient. Now I am one of those who believe that some day it will, but history suggests that, unfortunately, some day is probably going to be a long way off. And there were few voices saying that when the gene was discovered. Gene therapy in general is an area where promises of miracles around the corner have been trumpeted. I remember being at a meeting where a respected scientist predicted - his flying cars as it turned out - that by the early years of the present century the drug of choice for most diseases would be a gene, and pharmaceuticals as we knew them would be on the way out. Several patient deaths later, most biotech companies, including several genomics companies, are scrambling to learn how to develop not gene therapies but those outmoded pharmaceuticals. Yet still it seems that every new 'breakthrough' is heralded as taking us to the brink of a cure for this or the way to prevent that.

Genomics hasn't helped counter this trend. The Human Genome Initiative showed that a big, targeted research project could garner huge governmental support, in no small part because it had a well-defined goal that was easy to explain to public officials. And so the effort to sequence the human genome has spawned programs to define the human proteome, and to determine the three-dimensional structures of all of the gene products in various organisms, and several other imitators. The rationale behind some of these initiatives seems to me as thin as the following: if the genome-sequencing people got theirs, then why can't I have mine? Bad enough that data gathering for its own sake - which I in no way condemn per se, I merely wish it to be in its proper place - threatens to become more highly valued than hypothesis-driven research. But more dangerous still is the hype that is used to sell such projects to the public and to public officials.

When the US National Institutes of Health was considering starting the Structural Genomics Initiative about five years ago, it convened several meetings to see what members of the scientific community thought about the idea. At one of them a well-known structural biologist stated that in his opinion the project couldn't possibly be oversold. He was old enough to remember the War on Cancer, but evidently he didn't, or didn't think the same risks applied to this project, from which he stood to benefit. And in due course the project was approved, and millions of dollars were poured into a number of consortia that each promised to deliver hundreds of protein crystal structures per year, with the goal of rapidly filling out the catalog of known protein folds and providing functional information via these structures for many of the genes of unknown function that were turning up in the genome-sequencing projects.

The first round of funding for these consortia is now being reviewed, and I suspect that many, if not all, of the consortia are now trying to find other justifications for their efforts. Not one is yet close to the kind of high-throughput that was promised originally. The low-hanging fruit, in terms of protein folds, seem to have been picked pretty thoroughly already, and the number of structures that have to be determined to find a novel fold is increasing, making the completion of the catalog subject to the law of diminishing returns. And the deduction of function from structure is turning out to be about as hard as the deduction of function from sequence, because the coupling between fold and function is not all that tight for many protein folds. I personally think there are sound scientific reasons to fund the Structural Genomics Initiative, but they are very different from those used to 'sell' it. I think a systematic effort to obtain a huge number of protein structures rapidly will lead to big advances in structure-determining technology, will provide an ensemble of structures of great utility for drug design, and will provide valuable information about how protein structure and function change during evolution. Those ought to be reasons enough, but instead the project was, I believe, oversold, and now there is a danger that the funding agencies and their constituencies may lose faith in it.

Much of the process of hyping new initiatives stems from a belief on the part of scientists that the lay public, and their elected officials, do not understand the value of research and need to be persuaded to support it by a steady diet of good news and promises. I think this attitude sells the public short: they're sophisticated enough to appreciate that basic research is a sound long-term investment. After the dotcom bubble, I don't believe that such an investment needs to be camouflaged with exaggerated promises of big short-term returns. "Underpromise but overdeliver", my mother used to tell me. I think that's good advice in many aspects of life, but especially nowadays in science. If we don't want those who support us to sound like Calvin, we'd better either start following that advice, or hope that the general public heeds the title words of a song by the rap group Public Enemy: "Don't Believe the Hype."

Published: 27 February 2003

Judgement call

Genome Biology 2003, 4:108

It was Hiawatha Bray, a columnist for The Boston Globe who writes about information technology, who broke the story, at least in my town. In a column on 3 February this year, he recounted what happened to the Litchfield brothers, a pair of British computer security experts whose company, Next Generation Software, specializes in developing programs to help businesses and governments defend against computer viruses and hackers. Mark and David Litchfield are experts at finding weaknesses in widely used software, and last year they found a bug in Microsoft's SQL Server database software. To establish that the bug could be used to cripple computer networks, David Litchfield wrote an exploit program, a kind of dummy virus. The existence of the bug, a buffer overflow problem, was then communicated to Microsoft, which published a fix in July. Other security experts had already been asking for copies of the exploit program so they could test their own systems and become familiar with this new potential method of attacking networks, and David Litchfield eventually released his code, but only after the patch to fix the program had been published. He thought, quite reasonably, that once the fix was available, SQL Server users would no longer be vulnerable.

He was wrong. On the last weekend in January, the Slammer worm struck. Millions of computers were attacked, and the entire worldwide web was crippled for some time. Businesses are estimated to have lost tens of billions of dollars. It seems that many corporations and individuals hadn't yet bothered to install the patch. And David Litchfield discovered, to his horror, that his code was used as the template for the worm. To be sure, any good programmer could have worked out the code without help, but because of the Litchfields' well-meaning publication of their exploit program, that hadn't been necessary. Now Mark and David Litchfield must decide whether they will ever again publish or distribute their exploit programs. They have received hundreds of e-mails from colleagues begging them to continue releasing such code, because many in the computer business believe that the best way to deal with such weaknesses in widely disseminated programs is to publicize them and make examples widely available. But these colleagues don't have to live with the feelings of responsibility that the Litchfields now have. So from now on, every bug they discover - and they've already found others, in Microsoft's Windows XP and 2000 operating systems - will call for their judgement.

A similar judgement call was made a few weeks ago by the editors of a number of life-science journals, who released a statement of a new policy regarding the publication of reports of scientific research in areas such as microbiology and genomics that could potentially be of use to bioterrorists. The policy, which has received widespread attention, permits the journals to request that experimental details be omitted from papers if, in the view of the editors or a panel of experts (depending on the journal), the information could be misused. In some cases, publication of the work could be embargoed altogether.

The policy has been sharply criticized. The arguments against it would be familiar to the Litchfields: that any form of censorship runs contrary to the spirit of science; that it creates a slippery slope leading to government control; that free exchange of ideas and data represents the best way to anticipate possible misuses of science and technology and to generate the methods to counter them.

The demand for freedom of inquiry and the open exchange of information always wars with the demand for security. While recognizing that absolute security is impossible, governments have a legitimate right - and a duty - to take reasonable steps to protect the lives of their citizens. In a repressive society, such steps are merely part of the general curtailing of liberty. But in a free society the trick is to strike a balance between protection and oppression. There is always a danger, as the witch-hunting excesses of the Cold War remind us, that one can destroy a free society in the name of saving it.

I am completely in agreement with those who worry that this danger is near. The US government has recently shown disturbing tendencies to ignore the fundamental freedoms of its citizens for the sake of what many of us believe is a false sense of security. Other governments are unlikely to resist the temptation at least to control the public's access to information, a goal that many in power have secretly harbored for years.

But I am not in favor of doing nothing. At the heart of many of the objections to the policy of the journal editors, I believe, is a basic sense that the corruption of biology for evil purposes is unlikely. I recognize, and share, the concerns of my colleagues that even self-censorship, as a concept, sets a dangerous precedent. But I wonder if many scientists - who after all tend to have a mostly positive view of human nature as a result of largely associating with other scientists, a class of humanity not known for crimes or acts of violence - have a realistic perspective on the existence of evil.

I once taught a course in the social history of the detective story to a class of extremely bright, well-read college freshmen. As part of the discussion one afternoon, I asked them if they thought that evil existed. Almost to a person, they argued that real evil was a literary abstraction. Historical examples I offered were dismissed as illustrating madness, not evil. The notion that someone could be technically sane yet delight in human suffering and death was something they were neither prepared nor willing to accept. I suspect that many scientists may feel the same way.

Professional writers, whose careers depend on understanding the human condition, tend to be less starry-eyed. Two noted science-fiction authors have explored this subject in stories that are eerily similar. The older story, 'The Supreme Moment', was unpublished during the lifetime of its author, Robert E. Howard, best known for his fantasy tales of Conan the Barbarian. It was eventually published in 1984 in Crypt of Cthulhu magazine #25 and reprinted in The New Howard Reader #1, edited by Joseph W. Marek. The story concerns five wealthy, powerful men who are trying to convince a crippled scientist to save the human race from a fungus that is spreading across the earth, destroying all vegetation. The scientist, Zan Uller, knows how to make a fungicide but refuses to reveal the formula. As a justification, he explains that he had a tormented childhood and a career bedeviled by sabotage from rival scientists, persecution by religious fanatics, and ridicule for his discoveries. His five visitors threaten to force him to reveal the formula by torture, believing it justified to save the planet. Before they can act, to forestall them and to take his vengeance on a world that has given him nothing but misery, Uller commits suicide.

'Judgement Day', by L. Sprague de Camp (who, interestingly, was chosen to complete Howard's unfinished Conan stories after the latter's early death), was published in the August 1955 issue of Astounding Science Fiction magazine and later reprinted by Ballantine Books in The Best of L. Sprague de Camp. A physicist, Wade Ormont, has developed a formula for a nuclear reaction using iron, a cheap, widely available material. If he publishes the details of his discovery, he realizes that the probability is high that someone will eventually use it to destroy the world. Although he doubts that the US government would do that he is convinced that if he turns over his information to them it will eventually become more widely known: as the theft of the atom-bomb secrets proved, nothing can be kept hidden forever. In thoughts that chillingly echo our concerns about rogue states and terrorist organizations with weapons of mass destruction, Ormont decides that sooner or later some 'crackpot' head of state will use this capability to wreak havoc on a planet-wide scale. He then reflects on his own life history. Like Uller in The Supreme Moment, he had a childhood filled with physical and verbal abuse. His marriage failed and most of his other human contacts have been brief and hostile. An attempt at therapy quickly ended when he resented the psychiatrist's description of his personality as schizoid. Now in his mid-50s, enfeebled by a heart condition and with little will to live, he has become thoroughly misanthropic. He guesses that even if he publishes his formula in an obscure place, it would be discovered and used by a madman within a decade or two, and it is unlikely that he would live to see the end of the world. Finally, he reaches a decision: "There is one way I can be happy during my remaining years, and that is by the knowledge that all these bastards will get theirs someday... I hate everybody... I shall write my report."

Both Howard and de Camp recognize that there can be people who are capable of great acts of malice and vindictiveness. It used to be argued that no one would be likely to use a chemical, biological or nuclear weapon since to do so would lead to far too great a risk of the user's own destruction, either through retaliation or the failure to control the damage from one's own use. The advent of suicide bombers and eschatological cults like Aum Shinrikyo should dispel that notion. There are people who would not blanch at the end of the world, or at least the destruction of large parts of it, and who hold their own lives (or, more commonly, the lives of their followers) very cheaply. Some of them are neither so insane as to be incapable of cunning nor so technically inept as to be unable to adapt 'peaceful' discoveries to their own ends. It is true that most of their activities up to now have been of the low-tech kind, and they probably will continue to be for the near future, but it is indisputable that at least some of them have tried to obtain or develop biological weapons, and it seems certain that such attempts will continue.

"We often forget that our actions...can have very real consequences in real life," David Litchfield wrote shortly after the Slammer incident. I think the biological community has to face the fact that software experts - and physicists and chemists - are no longer alone in their nightmares over the possible misuse of their discoveries. Until human evolution, ethically speaking, catches up with technological evolution, we will all have to live with this possibility. The policy adopted by the journal editors seems to me a wise attempt to seize the initiative from those in government who would use the public's increasing fear of biology as a license for repressive control of scientific research and publication. As a community, I think we should adhere to this policy for the time being while continuing to debate its merits and considering alternatives. During these discussions, we will no doubt also be asking ourselves how we would feel, and what the consequences to our profession would be, if one of our publications were to form the blueprint for a terrorist act. If we have trouble imagining the answers, Mark and David Litchfield do not.

Published: 28 March 2003

War and peace

Genome Biology 2003, 4:110

The shadow of war - certainly the longest and darkest of all shadows - has cast a pall on the celebrations taking place this month to mark the fiftieth anniversary of the publication of Watson and Crick's paper describing the double-helical structure of DNA. It's hard to be cheerful when the products of scientific research are being used to kill other human beings in the nominal quest for weapons of mass destruction that are, likewise, the products of scientific research. Regardless of one's feeling about the validity, morally or legally, of the war in Iraq, I would guess that most civilized people (with the possible exception of some government officials in certain members of the Coalition of the Willing) would agree that anytime war breaks out it represents a failure of our collective efforts as a species to overcome our instincts for violence, to evolve into something we can be proud of.

Man isn't the only species that wages war, of course. Ants, for one, campaign ruthlessly and with great skill, and make slaves of their defeated enemies. But man is certainly the only species that wages war while agonizing about whether it's right to do so. The concept of the just war is largely Judaeo-Christian. It is most completely set out in two treatises many hundred of years old: The City of God, by Augustine of Hippo, and the Summa Theologica of Thomas Aquinas. Just war theory says that war can only be waged legitimately if the following conditions are met. First, it is the last resort. Second, it is waged by a legitimate authority. Third, it is undertaken with a reasonable chance of success. Fourth, its aim is to re-establish peace. Fifth, the suffering caused, or thought likely to be caused, by the war must be less than the suffering caused by leaving in place whatever evil you are trying to correct - such as a despot on the throne (so, it is waged only in proportion to the injury suffered). And sixth, it must discriminate between combatants and non-combatants. The Bush doctrine of preemptive war argues that expansion of this theory is necessary because, as it has been put by Chuck Colson (older readers may remember him from the good old days of Watergate - well, he's back) "waiting for the other side to shoot first is tantamount to committing national suicide." That might be worth arguing about, but it's way too general. It implies that, for example, the US would be morally justified in waging preemptive war against anybody who has even the capacity to shoot first, regardless of how likely it is that they actually ever would (look out, England).

My personal opinion is that the war in Iraq has big problems with the first and second conditions, at least, but in any case it seems clear to me that nearly all wars in human history would have trouble satisfying these conditions. Perhaps the outstanding exception is the Second World War (if we put aside the Allied firebombing of Dresden and Tokyo, and the atom-bombing of Hiroshima and Nagasaki, where the sixth condition was blatantly ignored). World War II is of more than passing interest here, because this 'just war' gave rise to the modern system of publicly supported scientific research. Prior to 1945 nearly all scientists were doing either largely applied research funded by industry or the military or basic research funded chiefly out of their own pockets. Basic research well into the twentieth century was the province of the independently wealthy, like Robert Louis Stevenson's Dr Jeckyl. Government got into the business of funding fundamental research in a big way after World War II for two reasons: one is that Vanevar Bush, a science advisor to the US President after the war, argued successfully that science was, as he put it, "an endless frontier" that would lead to a brighter future for all mankind. But we should never forget that the other reason is that physicists (and to some extent chemists) had shown dramatically during the war that scientific research would also lead to bigger and better weapons of mass destruction.

The end of the Cold War shook the physicists' grip on the reins of science policy. With the nuclear threat diminished it was harder for them to argue for the huge chunks of money that nuclear physics, in particular, requires, and their counsel became less essential as well. Now biology is king, for a day anyway. Again, there are two reasons: one is because biologists have argued successfully that basic biological research will lead to a brighter future in terms of human health. But the other reason is that biologists have also shown that they too can make weapons of mass destruction.

Yet if the fiftieth anniversary of the double helix teaches us anything it ought to be that great scientific discoveries are almost never made in time of war or directly for the purpose of war. Governments at war aren't really interested in basic research. The Manhattan Project, which produced the atomic bomb, was the development side of 'R&D'; the research part was mostly done prior to 1940, for no purpose other than to address fundamental questions about the nature of matter. Watson and Crick would have had neither the time nor the resources to inquire into the structure of DNA if England had still been at war; in fact, Crick was soured on physics and turned towards biology in part by his military work during World War II. Great science is the product of peace. It is a luxury that well-defended but fundamentally peaceful peoples allow themselves. It is not clear to me that it can flourish in, for example, a society that adopts a doctrine of preemptive warfare.

As is apparent from the reminiscences in Watson's 1968 book 'The Double Helix', Watson and Crick didn't only walk into a pub and announce their discovery; they also published their model for the structure of DNA because they believed it was important that everyone know all about it. "The secret of life", as Francis Crick called it with characteristic modesty, was met with a resounding yawn. (A similar chorus of yawns greeted the announcement on April 14 that the draft sequence of the human genome had now been converted into a finished sequence with less than 0.01% error rate. Why couldn't the public genome project leaders have waited a few days and timed their announcement for the exact fiftieth anniversary of the Watson and Crick paper on April 25? They then would have received the front-page coverage their achievement - completion ahead of schedule and under budget - surely deserves.) Almost no one referenced the classic 1953 Nature paper for a considerable time. It was ten years before Watson and Crick were awarded the Nobel Prize (many discoveries of lesser importance have been so rewarded in five). Yet eventually the structure of DNA did what they knew it must do - transform biology into a molecular science - because it was out there for anyone to look at and think about. And so the direction of biology changed forever for the right reason, because all of a sudden we understood something we had never understood before.

Fear of bioterrorism is already threatening to erode our faith in the free and open exchange of scientific information. Massive increases in research funds for previously financially moribund fields such as microbiology and vaccine development, given in the name of biodefense, are likely to shift the direction of biological research for decades to come, but it will not be because we understand something new but because we are greedy and afraid. Some good things will emerge from all this, no doubt, but it's hard for me to be very sanguine about the future at a time when war is almost becoming respectable again. Well, happy anniversary anyway.

Published: 28 April 2003

Ira

Genome Biology 2003, 4:112

Like one of the Brazilian soccer stars, Pele or Ronaldo, he was often referred to by one name only. When he died, on April 28 this year from pancreatic cancer - one of the cancers you don't want to get - at the tragically young age of 56, it left a hole in the fields of genetics and genomics the size of the Grand Canyon. Many other fine scientists have the same first name, but for a quarter of a century in genetics if you said Ira the chances were you meant Ira Herskowitz.

I think the genuine sense of loss that accompanied his untimely death - his obituaries literally spanned the country, from the San Francisco Chronicle and Los Angeles Times to the New York Times and Boston Globe - was a reflection on more than the quality of his work, outstanding though that was. He was the geneticists' geneticist, a man whose work on the simple single-celled fungus Saccharomyces cerevisiae, budding yeast (also known as brewer's or baker's yeast), had important implications for understanding the behavior of all eukaryotic cells. He himself was living testimony to the power of genes: his father, Irwin Herskowitz, was a famous fly geneticist at Indiana University. He was also living testimony to the limitations of that power: he had an identical twin, Joel Herskowitz, who went not into genetics but into pediatric neurology and is free of the disease that killed his brother.

Ira started off fast: his graduate work on 'phage lambda, a virus that infects bacteria, was classic. But like most of the 'phage people who shaped the early days of molecular biology, he moved on to the study of a free-living organism. As a young faculty member at the University of Oregon he switched to yeast genetics because he felt, as did several others at that time, that the cell biology of 'higher' eukaryotes such as Homo sapiens could best be illuminated through an understanding of this model organism. Yet he never felt that was its only value: he genuinely loved the organism he studied, and he celebrated its beauty and surprising complexity in every conversation he had, every seminar he gave, and every paper he wrote.

His best-known work concerned yeast mating. Yeast cells come in two sexes, denoted a and α. Interestingly, like some types of frog, yeast cells are able to change sex under certain conditions: type a can switch to α or vice versa. Ira showed how the yeast cells could flip from one mating type to another by reshuffling their DNA, a process involving the endonucleolytic excision of segments he termed 'cassettes', which could then recombine elsewhere. This finding was one of the earliest demonstrations of how differentiation could occur, and it had important consequences for developmental biology as well as for the field of gene regulation. Yeast mating-type switching is a complicated business, and the story could easily have been relegated to the archives of obscure behavior by atypical organisms. But one of Ira's great gifts was to see - and to be able to explain - complex things in straightforward language. He was what Aristotle admired most in a creative person: a master of metaphor. His friend and colleague Gerry Fink, of Massachusetts Institute of Technology, said that he could "look at a large set of confusing and contradictory data and come up with a metaphor that put it all together in a magnificent way." This talent allowed Ira's findings to have an influence beyond the confines of yeast genetics.

In the 1980s he and a colleague developed a method for producing foreign proteins in yeast. This patented expression system is used to produce human insulin for diabetics, among other things. Over the years Ira donated half his patent income for fellowships for students in his laboratory. In recent years he became interested in pharmacogenomics, including the question of why different cancer patients respond differently to antitumor drugs such as cisplatin. His last two papers, on the distribution of transporter genes in people from different ethnic groups, were published in the Proceedings of the National Academy of Sciences of the USA on the day he died.

So Ira's was clearly a magnificent career, and worthy of note. But as I said, I don't think that's the real reason for the huge sense of loss that those of us who knew and liked and admired this man feel. What made Ira Herskowitz special was his style. Harold Varmus, Nobel Laureate and former Director of the US National Institutes of Health, called him a romantic. Jim Watson, of double helix fame, referred to him as an idealist. I spent a wonderful sabbatical year in Ira's lab, from 1995 to 1996, and I agree with them. The great thing about Ira was that he was always just as enthusiastic about other people's ideas and results as about his own. Talking with him was a tonic. The last time I saw him, about a week before he died (figure 1), he was obviously in pain and very tired, yet the first thing he said to me was, "After we catch up on some things I want you to tell me all about your latest results."

Greg Petsko presenting the 2003 Lewis S Rosenstiel Award for Distinguished Work in Basic Medical Research to Ira Herskowitz, April 2003.

In addition, he was one of the least stuffy people in science. It is said that Ira was responsible for the Cold Spring Harbor meetings becoming jacketless and tieless, and I believe it. He loved playing his guitar at meetings, and in addition to singing folk and blues songs, he also wrote scientific song parodies, such as the immortal "I've Been Working on the Genome". He was especially fond of performing a song written by his twin Joel called "Double Talking Helix Blues". He never gave the impression that he cared about being Ira Herskowitz, famous geneticist. One of my friends met him for the first time when she was a young bacterial geneticist. She sat next to him at lunch at a meeting and when he asked her what she worked on, she proceeded to give one of the world's great geneticists a 20 minute explanation of bacterial genetics. He never interrupted her, except to ask questions or to share her excitement with her ideas. It was only later at the meeting that someone else told her who he was.

Yeast genetics has the reputation of being open and welcoming to newcomers, of being characterized by sharing of ideas and data, of being just plain fun. That reputation owes everything to the great scientists who founded the field, Ira among them. Do giants emerge because they work in fast-moving and important areas, or do areas become fast-moving and important because they are lucky enough to have giants working in them? I don't know the answer, but I am fairly sure that the atmosphere, the character - the gestalt?, if you will - of a field comes from the top down. Some fields are stiff, insular and mean-spirited, hyper-competitive and ill-using of their young people, while others are relaxed, friendly, and nurturing. Genomics is too new to have fully developed its culture yet, although what I see so far is encouraging. I think part of the great sadness of Ira Herskowitz's death is that he would have brought to genomics - a field he was only beginning to work in - that same attitude that he brought to yeast genetics.

What kind of field will genomics become? Will it welcome new blood from other subjects and will it rejoice in, and foster, the success of its young people? Will the big names in it share data and reagents and behave with generosity instead of suspicion and selfishness? Will those who practice it poke fun at themselves and not take things too seriously? Will people in the field write and sing silly songs and take their ties off and not put on airs? Ira's life reminds us that the kind of field we get is the one we make for ourselves.

Published: 19 May 2003

A new recruit for the army of the men of death

Genome Biology 2003, 4:113

The message was dated Tuesday, 2 June 2003. "From the Executive Committee, XIX International Congress of Biochemistry & Molecular Biology: After careful consideration, the 2003 Congress Executive and Steering Committees have concluded that it is in the best interest of all delegates, exhibitors, sponsors and partners that the IUBMB Congress scheduled for Toronto this July 20-24 be cancelled. On April 29 we issued a worldwide message informing you that the first outbreak of SARS and the travel alert issued by the Center for Disease Control and travel advisory issued by the World Health Organization were being monitored and, at that time, we thought the worst was over and the Congress could proceed as planned. With the most recent outbreak of SARS being reported so close to the Congress we have heard from many individuals concerned that if they were to attend the meeting in Toronto and be exposed to SARS they could potentially spread the disease to others in their health-care system including colleagues and patients. The number of participants and speakers has dropped to the point that it is no longer possible to hold a successful congress."

Ironically, the day of that message, news stories were circulating all over the world that the epidemic of SARS (severe acute respiratory syndrome) had peaked and was starting to taper off. SARS, which appears to be caused by a new strain of coronavirus, kills around 10% of those infected; interestingly, mortality seems to arise from the severity of the victim's own immune response rather than from any toxic effect of the virus per se. The outbreaks in Vietnam and Canada have largely been confined to health-care workers and patients in hospitals; in Hong Kong and China, the disease spread beyond that. Although ten times as many people die each day from malaria than have died in toto from SARS, this new infectious disease has crippled the economies of cities and countries, caused some places to institute draconian quarantine measures reminiscent of the days of the Black Death, and generally scared the living daylights out of most of Asia and a good chunk of the rest of the world. So now the army of the men of death, in John Bunyan's memorable phrase, has a new recruit, and fear has a new face: a face wearing a surgical mask.

I think one reason for the extreme fear is that SARS is passed from person to person. There is something in human nature that makes us more afraid of other people than, for example, of insects, even though insect-borne diseases have killed, and continue to kill, far more than any human-transmitted illness. Added to that is our fear of the new and unknown: we live with influenza, a much more dangerous disease, because we are used to it. Consequently, SARS has caused much more economic damage than its prevalence warrants.

SARS has brought home the importance of being able to trust your government. One of the reasons it spread as it did in some countries is that people did not believe what they were told, and fled from or to the cities, taking the disease with them. It has also reemphasized the folly of commingling humans and livestock as we do. Farming practices that raise chickens and wild birds - both notorious reservoirs of viruses - in the same pens as pigs, whose immune system resembles ours sufficiently that an avian virus that learns to adapt to swine can often jump to humans, must be stopped. Controls also need to be instituted on open-air markets where a huge variety of live wild animals, many of uncertain provenance, are often held in close proximity to one another and to throngs of people.

SARS has also demonstrated that the immediate impact of genomics on human health is not in the over-hyped realm of finding cures to all manner of complex conditions such as cancer and heart disease. It is in the development of technologies that will revolutionize public health. The complete genome sequence of the SARS-associated coronavirus was obtained less than two months after the disease was first identified, which is surely a record. It was obtained by the whole-genome shotgun sequencing method that was developed for much larger microbial and mammalian genomes. And even before that, DeRisi and associates at the University of California San Francisco used one of the great tools of genomics, the cDNA microarray, to identify the SARS virus as a coronavirus. It took them only about 24 hours after receiving their first tissue sample, with the aid of a microarray containing gene fragments from 1,000 different viruses, to type SARS as a new strain of coronavirus, suggesting that this technology could be invaluable in the first days of, for example, a biowarfare incident.

Yet the story of SARS to date has also highlighted our ignorance. We have the complete genome sequence of the virus, yet we cannot state with certainty how many genes it contains, which are expressed under what conditions, or which are essential for human infectivity and virulence. Clearly, our ability to gather information about genes has outstripped our ability to interpret that information, and much work will be needed to understand what even a simple genome sequence implies.

Just as the SARS epidemic seems to be coming under control - this year, anyway; it remains to be seen if it will become endemic anywhere - other candidates are queuing at the recruiting station. Since the mid-1970s, about 30 new infectious diseases have cropped up, ranging from AIDS (for which 45 million new infections are predicted between now and 2010) to Ebola virus, a new outbreak of which is still raging in Africa as I write this. The Netherlands has been wrestling with a new strain of avian influenza that has devastated its poultry farms - about 20% of the country's chickens have had to be slaughtered - and infected 80 humans, one of whom has died. Twelve confirmed cases of monkeypox, a disease related to smallpox but previously unknown in the Western Hemisphere, have just been reported in Wisconsin and several other midwestern US states; another 50 or so unconfirmed cases are under investigation. Prairie dogs, cute little rodents that have recently become popular as pets, appear to be the immediate source of human infection; they, in turn, were probably infected by a West African rat kept at the same pet supplier. Monkeypox is much less lethal than smallpox, causing fatalities in only a small proportion of cases (for smallpox it can be 30% or more), and even that figure comes from developing countries where those infected are less healthy overall and available medical care is less sophisticated, so there is probably no reason to be concerned yet. Still, this incident is yet another example of how vulnerable even the developed world can be to diseases that were formerly considered Someone Else's Problem. And West Nile virus, another developing world disease that has now become endemic in the US, is about to pay its annual mosquito-borne visit as the summer commences.

In considering how we respond to these threats, I would contend that market forces are fine for controlling some things but disastrous for others. Left to themselves, pharmaceutical manufacturers phased out many of their infectious disease programs during the last few decades of the twentieth century because, thanks to antibiotics, there didn't seem to be a market for new antiinfectives in the West, or in the developed countries of the Far East. But now, along with the 'new' plagues, a number of 'old' diseases, such as tuberculosis (Bunyan's "Captain of all the men of death"), staphylococcus, enterococcus and streptococcus infections, are turning up in drug-resistant forms, and suddenly there is a scramble to resurrect these old research programs, and microbiology is becoming a fashionable discipline again.

No better argument for the importance of basic research programs at universities need be sought. If academic research followed fashion, and only did what was immediately believed to be relevant - or worse, only did what industry and government thought was needed - there might be no reservoir of expertise for situations such as the one we now face. The rise of infectious diseases emphasizes the importance of universities as guardians of old knowledge as well as discoverers of new. Funding agencies and academic administrators need to ensure that fields don't die out prematurely. None of us is smart enough to predict what will be important in the future.

Our generation has grown up not knowing what it was like when every wound was potentially life-threatening, when every cough could signal a deadly illness. But the line between our blithe present and the frightening past is finer than we like to think. For proof, all we have to do is look at what happens when the public health infrastructure is neglected, or worse, collapses altogether. Diphtheria is once again endemic in parts of the former Soviet Union. Cholera epidemics are occurring with disturbing frequency in parts of India, Bangladesh, and Africa. Over 100,000 people are believed to have died from infectious disease outbreaks in Iraq following the first Gulf War, and serious public health issues are developing in southern Iraq following the latest one.

Infectious diseases aren't making a comeback; they never left. SARS is merely the latest reminder that, no matter how clever we are, the men of death are always out there, waiting. And the men of death are always hungry.

Published: 27 June 2003

Galileo's stepchildren

Genome Biology 2003, 4:114

Inside the church of Santa Croce in Florence, just to the left of the main aisle as you enter, is the tomb of Galileo Galilei. Condemned by the Catholic Church as a heretic and forced to recant his scientific conclusion that the earth moved around the sun, he was excommunicated in 1633. With typical swiftness, the Church reinstated him in 1992, which I'm sure eased his mind considerably. Florentines still bring fresh flowers to his tomb.

Exactly opposite Galileo's tomb, on the right side of the aisle, is the tomb of Michelangelo Buonarroti, architect, painter and sculptor. His bust, which adorns the top of his sarcophagus in the fashion of the time, stares out across the aisle directly at the bust of Galileo. Michelangelo died in 1564, the year Galileo was born, so these giants of the Italian Renaissance, who helped drag mankind, kicking and screaming, out of the Dark Ages, never met. Yet they now lie only a few meters apart. One is tempted to introduce them: Michelangelo, meet Galileo; Galileo, this is Michelangelo.

Seeing the great scientist and great artist entombed facing one another, one cannot help but reflect that, throughout history, every enlightened society has held the view that science and the arts are not intrinsically incompatible. Which raises the question: what does that make us? If ever there was a society that seemed hell-bent on retreating from the idea of science and the arts as integral parts of the intellectual life of every well-brought-up person, it's ours. By 'ours' here I mean Western society in general and North American society in particular. In many universities it is possible to obtain a bachelor's degree from the College of Arts and Sciences without ever having taken a course in either the arts or the sciences. It is widely believed that the 'hard' sciences are incomprehensible to the average person and that, even if they could be comprehended, there is no need to do so. Another common belief is that knowledge of the arts is 'impractical' and therefore a waste of time compared with studies of business (a subject that, as we have seen, really needs to have a major in ethics as a prerequisite but obviously doesn't), law (clearly important because of the serious shortage of lawyers, especially in the US), and other professional qualifiers. And the idea that science and the arts should in any way be related is seldom considered.

It was C.P. Snow - whose mediocre ability as a writer was exceeded only by his less than mediocre ability as a sociologist - who introduced the notion of 'the two cultures', by which he meant science and everything else. His ideas were quite influential and did a lot of harm. They made it respectable to shun science on the one hand or focus on it almost exclusively on the other, and the intellectual climate they helped create is with us still. It has a lot of insidious, subtle consequences. One of them is that practicing scientists who try to communicate the excitement of their subject to the general public are often regarded with the sort of esteem usually reserved for political traitors and used-car salesman. Another is that professional intellectuals who know nothing about science can make pronouncements about science being 'just another belief system' like, say, Confucianism or vegetarianism or a belief in the magical power of crystals, without being recognized by the rest of the non-scientific community of professional intellectuals as the idiots they are. One can go further and speculate that at least some of our current preoccupation with, among other things, the oxymoron of alternative medicine; ideas that run counter to the theory of evolution; increasing belief in the existence - and power - of the spirit world; and the superiority of trusting 'feelings' over thinking (which, along with a distrust of technology in general, forms the philosophical underpinning of nearly every recent Michael Crichton novel or Steven Spielberg movie, and you know how popular those are) would not have become so widespread without at least some serious debate had the disconnect between science and the humanities not become respectable.

Ironically, I think that science and the arts have a lot more in common than almost any other pair of disciplines, not so much in subject matter (although it is gratifying to see so many contemporary artists taking inspiration from the staggering beauty and variety of forms in the natural world as revealed by science) as in flavor. Science and art are both subjects that are best practiced by people who see them as vocations rather than careers. In both cases one is trying to reveal truth, and often also attempting to uncover or create something beautiful ("That's beautiful!" is often the highest compliment one scientist can pay to another's work). Devotion to the purity of one's vision is ultimately valued in both fields above following fashion. Science is for most scientists a form of self-expression, just as art is, which probably accounts for the love that most scientists express for their work, except at grant-renewal time.

Which brings me to my summer reading recommendation: "A Short History of Nearly Everything" by Bill Bryson. Bryson, a superb travel writer and social commentator who combines humor with pointed observation, decided that he knew nothing about science - couldn't tell a proton from a protein, in his words - but that it was important and could be fascinating, so he set out to immerse himself in subjects ranging from physics to genetics over a period of three years. The result is an extraordinary book, one that tells the story of our universe, planet and species with wit and clarity. Never missing an opportunity for an amusing - and engrossing - anecdote, Bryson also gets the science right and tells it in a way that anyone, even practicing scientists, will find enlightening as well as enjoyable. If he - an avowed scienceophobic beforehand - can find in what we do great stories that are fun to read about, I see no reason why we can't convey that same mixture of information and excitement to non-scientists.

I am convinced that courses in one or more of the 'hard' sciences, but especially chemistry and biology, should be required of all university students regardless of their major field. And I'm equally convinced that courses in subjects like art history and literature should be required of all science and engineering majors. It's gratifying to know that the leading lights of the Renaissance would agree with me: Michelangelo immersed himself in engineering and anatomy; Galileo was both a practitioner and a patron of the arts. Speaking of patrons, enlightened rulers such as Lorenzo the Magnificent supported - and were afficionados of - both scientists and artists. So was John F. Kennedy, but this is probably too much to expect of George W. Bush. You will note that I haven't mentioned Leonardo da Vinci here, and I won't, because a true polymath like him, who puts the rest of us to shame in essentially every subject imaginable, comes along only once every several hundred years, thank goodness. Michelangelo and Galileo are usually the Renaissance men we have in mind when we aspire to be called one. Our educational system and popular culture conspire to make that seem unattainable. As scientists we need to reach out to the public to make the things we do not only understandable but enjoyable. One way to do that is to acknowledge, and celebrate, the arts-like nature of our profession. Nowhere is this more important than in genomics, which is increasingly seen by the lay public as threatening to create a brave new world of genetically engineered food, animals, microbes and people.

Galileo is a hero - a sort of spiritual father - to many scientists because he dared stand up to the anti-science culture of his day. Standing in the church of Santa Croce in Florence, one is tempted to feel a similar kinship to Michelangelo as well. Presumptuous, of course, but somehow I think they wouldn't mind.

Published: 24 July 2003

The road worrier

Genome Biology 2003, 4:116

This summer I've noticed the continuation of a trend that's been developing for the past ten years or so. Increasing numbers of my colleagues are opting to take their vacations at home, or in summer properties they've purchased or rented close to home. Since this behavior predates those events of the past two years that made many people reluctant to venture abroad, I think it's motivated by something other than fear. It comes, I believe, from a deep sense of weariness, not wariness. Scientists travel a lot on business, and for many of us that has led to the feeling that the last thing we want to do is travel for pleasure. In fact, many of us believe that the very concept of travel for pleasure has become an oxymoron, like military intelligence.

Sometime in the last 20 years travel ceased to become an adventure and became a drag. Personally, I look forward to most of my business trips with the same enthusiasm that Sir Walter Raleigh expressed in contemplating his imminent beheading. There are many reasons for this attitude: snooty hotel staff - a problem not unique to, but endemic in, many European countries ("Sacre bleu! A green American Express Card! Pierre, show Doctor Petsko to ze room we reserve for peasants."); waiters in overpriced restaurants who treat every request as though one were Oliver Twist asking for a second plate of gruel; hotel rooms with windows that cannot be opened - presumably because the aforementioned snooty staff is afraid that the guests, in a fit of travel-induced melancholia, might hurl themselves to their deaths, even when the room is on the first floor; taxi drivers who not only do not speak one's language but do not speak the language of the country they're in, or any other recognizable human tongue, and whose knowledge of the area is confined to the location of a few five star hotels and strip joints; hotel coffee shops in which a cup of coffee costs more than the gross national product of the country in which the beans were grown; world-famous attractions that are open year-round except on the only day one tries to see them; and crowds, crowds at the beaches, crowds at the airports and train stations, crowds on the highways and in museums and shops, crowds everywhere.

Yet I honestly believe that we could put up with all this were it not for that bête noire of travelers everywhere, the airlines. Air travel, which was once glamorous, now has all the charm of riding in a cattle car, except that at least the cattle are on their way to a mercifully quick end, whereas the airlines seem to delight in extending one's torment as long as possible.

I'm not sure exactly when it happened, but sometime in the past couple of decades nearly every major airline around the world seems to have been taken over by direct descendants of the Marquis de Sade. Take the small matter - the very small matter - of airline seats. Although study after study indicates that, on the whole, people in much of the world are getting taller and heavier, the airlines seem to believe exactly the opposite. Most seats now would offer generous amounts of legroom only to a Munchkin, and they have become so narrow that one is constantly performing The Armrest Elbow Dance with one's seatmates, in a desperate attempt to lay claim to a precious extra inch of width. Should the person in the seat in front of you decide - as the person in the seat in front of me always does - to spend the entire 12-hour flight to Tokyo with his seat-back down as far as possible, you will lose what little room in front of you there was, and if your tray table was down when this happened you will never be able to raise it again, quite probably for the rest of your life.

Carry-on baggage is another endless source of delight. One's fellow passengers seem to believe that the overhead bins are not only capable of holding rollaboard suitcases - inventions of the devil if ever there were any - large enough to contain a baby grand piano, but that they have the right to schlep all their worldly possessions on your flight - and some of them possess quite a lot. These are invariably the same people who, when everyone is nervously waiting to disembark, wait until the last possible moment to gather up their tons of luggage, thus holding up all the passengers behind them. One will no doubt encounter these Nostradamuses again at queues for tollbooths and grocery store checkout counters, where they will realize with a shock at the last possible moment that they will actually have to pay something and so finally, after all their car has come to complete stop or their groceries have all been bagged, they will begin their lengthy search for a means to do so.

And let us not forget - or rather, let us try to forget as soon as possible - the matter of airline food, another oxymoron that ranks right up there with compassionate conservatism or reasonable attorney's fees. Many airlines, as a cost-cutting measure, are actually discontinuing serving meals on flights - one of the few bright spots in the area of public health news in recent years. But this does make one wonder how far this trend of off-loading tasks that used to be done by airline personnel, such as checking oneself in, onto passengers will go ("Oh, Doctor Petsko, it's your turn to fly the plane now".).

So why, in this age of teleconferencing and e-mail, do we put up with all this? One reason is the Schimmel effect. Biologist Paul Schimmel has famously remarked that the amount of respect accorded to a scientist increases sharply with the distance from his or her home institution and goes through zero at the origin. It is certainly nice to be treated like minor royalty for a day or two somewhere, even if one has to be treated like dirt to get there. And having tried teleconferencing on several occasions, let me say that, for me anyway, it just doesn't work. I miss the dynamic of direct interaction, the freedom of not being tied to a camera location, and the chance to experience new faces and places. Our lives are already too bounded by computer screens to need more of them. And of course, for young scientists, travel is essential as a means of getting one's work and oneself known in the community at large.

Genomics, as it does for so many other things, is magnifying this necessity. The interdisciplinary nature of genome-driven biology requires that we become familiar with an ever-expanding array of techniques, disciplines, and colleagues. We all must collaborate more, build bigger networks of friends with expertise in a wider range of areas, attend more meetings on more different subjects, and present our work to an ever larger number of audiences.

We can hide from this demand for a time - say part of the summer - but our need to know and be known is relentless. So regardless of how tedious and dehumanizing it is, come September the skies above us will once again be filled with scientists, all undergoing the twenty-first century equivalent of The Death By A Thousand Cuts.

Robert Louis Stevenson said, "To travel hopefully is a better thing than to arrive." Robert Louis Stevenson was never stranded at O'Hare or Heathrow airports. These days, it's better to arrive.

Published: 28 August 2003

The usual suspects

Genome Biology 2003, 4:118

"Round up the usual suspects!" In the classic film Casablanca, that was the automatic response by Louie, the police inspector, whenever a crime was committed. I've seen that movie about a dozen times, and the line always gets a laugh, even from the most jaded audience.

I doubt that Thomas Butler would laugh, though. On 3 September, in federal court in Lubbock, Texas, Dr. Butler, a 62-year old professor of medicine who is chief of the division of infectious diseases at Texas Tech University, pleaded not guilty to a 69-count indictment on charges that included illegal transportation of plague bacteria from Tanzania into and within the United States; lying to the Federal Bureau of Investigation (FBI) by claiming that 30 vials of the bacterial samples had been stolen when in fact, according to the FBI, he had destroyed them; embezzlement; tax evasion; and mail fraud. The case is scheduled to go to trial in November. Meanwhile, Dr. Butler remains free on $100,000 bail. Although he cannot, by the terms of his release, visit his laboratory and files at Texas Tech, with the help of a colleague at Johns Hopkins he managed last week to submit a paper to The Lancet on the effectiveness of different antibiotics against the plague.

There is a Kafkaesque quality to this story, which has so concerned biologists in the US that last week the National Academy of Sciences' Committee on Human Rights wrote to scientists urging them to protest at Dr. Butler's treatment at the hands of his own government and urging them to donate money for his legal bills, which are said to approach half a million US dollars already. The president of the Academy, Bruce Alberts, and the president of the affiliated Institute of Medicine, Harvey Fineberg, wrote a letter to John Ashcroft, the US Attorney General, on 15 August, stating that the case against Butler was "troubling" and likely to have a negative "impact on other scientists who may be discouraged from embarking on or continuing crucial bioterrorism-related scientific research."

My information on the Butler case comes from a variety of sources, including Eileen Choffnes of the Policy and Global Affairs Division of the Academy and some excellent pieces by Scott Shane, a reporter for the Baltimore Sun, and Ceci Connolly of the Washington Post. To begin with, it is important to realize that Dr. Butler is a recognized authority on infectious diseases, widely respected in that community, and a particular expert on the plague. His troubles stem from a series of trips he made in 1994 and 2002 as part of his research into the most effective treatments for plague, a bacterial disease that may have killed as much as a third of Europe's total population during the Black Death in the Middle Ages. On these trips he carried with him a number of vials containing samples of Yersinia pestis, the plague-causing bacterium. One of the charges against him is that he failed to properly report that he was carrying such specimens - even though this method of transport, which is clearly safer than sending them through the post, is so common that there is even a nickname for it in the microbiological community: VIP ('vials in the pocket'). The government's outrage seems as disingenuous as Louie's ("I am shocked - SHOCKED! - to find that gambling has been going on here," he says to bar owner Rick, just before a croupier hands him his winnings in another classic scene from Casablanca). But this incident would never have caught the attention of the government except for what happened next. Last January, for reasons that are still unclear and probably will remain so until Dr. Butler testifies in his own defense at his trial, he reported to officials at his university that 30 vials of the bacteria were missing from his laboratory.

Fearing that the samples may have been stolen by terrorists, Texas Tech immediately called in the FBI, who in turn notified the newly-created Department of Homeland Security. Within days, more than 60 law-enforcement agents had descended onto the normally sleepy campus in the west Texas town of Lubbock, a city whose previous claim to fame was as the birthplace of the legendary rock-and-roller Buddy Holly. Butler, his supporters allege, was taken away in handcuffs and interrogated for ten hours straight through the night without having an attorney present. What happened next is unclear, but sources say that, at around 3 am, he finally signed a statement saying that the plague vials had been "accidentally destroyed earlier" and that his assertion that they were missing was "inaccurate". He claims that he signed the paper because the FBI agents told him it was necessary to end the investigation. Instead, in April, he was indicted on 15 felony counts. During the first week of September, these charges were expanded to include mail fraud and embezzlement in connection with research that he conducted for two pharmaceutical companies. The indictment states that he received almost a third of a million dollars in payment from the companies without reporting the income to his employer, the university. Butler's supporters allege that these new charges are an attempt to divert attention from the weakness of the original charges relating to the plague samples. They believe that the FBI, the Department of Justice, and the Department of Homeland Security need a "victory" in the war against terrorism to distract the public from the failure of their investigation into the anthrax-laced letters incident, and that Butler is being used as a scapegoat. Through his attorneys, he denies wrongdoing in connection with payments from his pharmaceutical company work. Meanwhile, the whereabouts of some 30 vials of deadly germs remain unknown: Dr. Butler asserts that the statement he signed under duress was false, and that he has no memory of actually destroying the vials.

Without drawing conclusions as to Dr. Butler's guilt or innocence, one can conclude on the basis of the evidence available so far that he has acted somewhat peculiarly, and possibly stupidly. But that doesn't make him a criminal, and it seems to me that the government's prosecution is far out of proportion to any offences he may have actually committed. This whole affair has the smell of a witch hunt about it, and it's pretty easy to guess why. Federal agents and the government officials who control them need to produce culprits from time to time to prove that they are doing their jobs. It's much easier to prosecute a hapless individual who can be induced to admit guilt to something than to do the difficult - sometimes, to be fair, impossible - work of finding out what really happened in a situation where imperfect memory, faulty record-keeping, and the general sloppiness common to many scientists make tracing samples a logistical nightmare.

But I don't entirely agree with the Academy's claim that Butler's prosecution - some would say persecution - will necessarily have a chilling effect on research into the genomics, biochemistry and physiology of pathogenic microbes. Scientists go where the money is, and right now, in the US at least, there is a lot of money for biodefense-related studies. Funding trumps fear. What will happen, I think, is that any scientist with more brains than a gerbil will think twice before reporting any discrepancy or possible theft of biohazardous material to either his or her institution or to the government. Why raise an alarm when the reaction is likely to be to shoot the messenger, or at least to try to send the messenger to jail for a long time? The unintended consequence of the Butler affair is likely to be that it will become more difficult for governments to fight bioterrorism, because their natural allies, their own scientists, will not trust those governments to treat them as allies. Why chase terrorists who are hard to find when you can bring to the dock people you already know? Don't all witch hunts concentrate, not on outsiders, but on those close to home?

Witch hunts make the hunters famous and powerful, at least for a time, which probably accounts for their recurring popularity throughout history as an instrument of policy. And witch hunts begin with rounding up the usual suspects. In the post-genomic world of bioterrorism, it would seem it is the biologists, not the terrorists, who are most likely to become the usual suspects. And although one would hope that governments and scientists would naturally work together against the misuse of science and technology, the Butler affair makes one fear that, unlike the case of Louie and Rick at the end of Casablanca, this will not be the beginning of a beautiful friendship.

Published: 22 September 2003

Sleeping dogs

Genome Biology 2003, 4:120

'Let sleeping dogs lie' is a common English-language expression. It means, of course, to let well enough alone; that it's advisable not to disturb someone - or something - that might bite you if you do. Like many old aphorisms, there is much wisdom in it, and there have been a number of times when I wish I had followed it.

As I write this, two dogs are sleeping on the sofa next to me. I won't wake them, not because they'd bite - they're the gentlest dogs in the world and wouldn't bite anyone - but because they look so cute and peaceful snuggled together. They have no idea that last week the juggernaut of comparative genomics rolled round to them. On 26 September 2003, a joint team from The Institute for Genome Research and The Center for the Advancement of Genomics, both in Rockville, USA, and headed by Claire Fraser and Craig Venter, respectively, announced a 1.5X whole-genome sequence of the domestic dog (specifically Shadow, Claire and Craig's pet male standard poodle; see Kirkness et al., Science 2003, 301:1898-1903).

The dog genome sequence represents a landmark in the genomics era for several reasons. As the sequence makes clear, the dog is the closest relative to man yet to have a mostly complete draft genome sequence determined. The attempt to do it on the cheap, with minimal coverage, turned out to be surprisingly successful, presaging a flood of quick-and-dirty mammalian genome sequences in the near future. Another reason is the enormous, well-cataloged phenotypic variation of the canine: in the more than 100 centuries since the first canids were domesticated, dogs have been bred to display, in over 400 well-defined genetic sub-types ('breeds'), a huge range of morphological and behavioral characteristics that can now, in principle, be linked to their genes.

The strategy used to obtain the 1.5X whole-genome dog sequence is likely to become a model for future draft sequencing efforts. It yielded contiguous sequences (contigs) too small to extend across chromosome-length distances without a physical or genetic map; happily, there was already a radiation hybrid map that could be used to anchor the sequences to their positions in the 40 dog chromosomes. Most of the coding sequences were fragmentary, but with the aid of the human and mouse genomes it was possible to determine that about 80% of human genes have identifiable homologs in the dog. As the database of complete, high-coverage mammalian genome sequences grows (the public genome project should have a 6.5X dog genome sequence in the future, and similar efforts for chimp and cow are far advanced), future low-coverage sequences will have even more reference genomes to aid in assembly, alignment and interpretation. While the present dog genome sequence makes it clear that high-coverage sequencing is essential for the important organisms, it also demonstrates that useful information for comparative genomics and organismal biology can be obtained relatively cheaply. Since there are about 5,000 different known species of mammal, we can also conclude that the sequencing programs are not likely to end any time soon!

Humans have a higher content of repetitive DNA in their genomes (46%) than either mice (38%) or dogs (31%). Yet, even though only 2% of the dog genome is believed to code for proteins, more than 4% of the intergenic sequences are conserved between dog and human. Whether these conserved regions are functional remains to be shown, but clearly one reason for sequencing a number of mammalian genomes is that any functional constraints should eventually be apparent, and we might finally figure out what some of that 'junk' DNA is really for. Another interesting piece of information to emerge from the 1.5X dog sequence is that the overall mutation rate of the dog genome appears to be about the same as it is for humans; mice seem to have a mutation rate that is twice as fast. Given this difference, it is not surprising that the overall sequence similarity between the dog and human genome is higher than that between mouse and human or mouse and dog. Of the 24,567 annotated human genes, the dog has clearly detectable orthologs for more than 18,000 (about 80%), and given the fragmentary nature of the dog genome sequence it seems certain that this number will eventually get much larger.

The recent dog genome paper presents data to support the view that the dog lineage was the first to diverge from the common carnivorous ancestor of dogs, mice and humans. Dogs, like mice, have a much larger number of olfactory receptor genes than humans, but surprisingly the mouse has the larger number, suggesting that those cute drug-sniffing dogs we see at airports should perhaps be replaced by mice on leashes.

Dogs are unlikely to become a major model organism: most of the tools of mammalian genetics are not yet available for the canine and most people, myself included, would rather see them as companions than research tools. But the dog genome sequence may nevertheless shed light on two areas of human biology: genetic diseases and behavior. Because of the huge veterinary literature about man's best friend, we know of at least 350 genetic diseases in the dog with human counterparts. Since a number of BAC sequences can already be found in the GenBank database from other breeds of dog, Fraser, Venter and colleagues were able to do a preliminary comparison with the standard poodle genes. Interestingly, they found examples of numerous sequences that differed only by the insertion of a short interspersed nuclear element (SINE). One SINE in particular, which apparently derives from a lysine tRNA sequence, represents 7% of the dog genome and has homologs in all carnivores. A single subfamily of this SINE with a consensus length of 189 bases has almost a quarter of a million copies in the dog genome. About 16,000 of these are estimated to be bimorphic, in contrast with fewer than 1,500 bimorphic SINES in the human population. If one of these mobile genetic elements becomes inserted in a gene, it can have significant consequences: the insertion of SINEs into the hypocretin/orexin-receptor-2 (Hcrtr2) gene in Labrador retrievers and other dogs causes narcolepsy, a chronic neurologic disorder characterized by excessive daytime sleepiness. (As one who lives with a Labrador retriever, I can only ask: how could they tell?)

But it is the possible value of the dog for understanding the genetic basis of behavior that has always intrigued biologists. The 400 breeds of dog display an enormous range of phenotypes, especially behavioral differences. The dog genome-sequence team speculates that this diversity may be largely due to the abundance of bimorphic mobile genetic elements. If so, it may be relatively easy to identify genes responsible for many different behaviors, and eventually to alter them at will. I can see such differences every day in the two dogs on my sofa. Mink, the 100-pound chocolate Labrador retriever, has qualities that anyone would want in a friend. He's brave, friendly, intelligent, calm and incredibly generous. He's also lazy. Clifford, the 20-pound mixed breed (half cocker spaniel, half poodle) sleeping next to him is not only physically very unlike his stepbrother but also completely different in character. He's selfish, greedy, fundamentally cowardly, not as bright, and generally rambunctious. It's tempting to believe that the world would be a better place if there were more people like Mink and fewer with the qualities of Clifford, but I don't think that's necessarily true. I love Clifford just as much as Mink, not in spite of his peccadilloes but because of them. The contrast between their two characters and temperaments is a constant source of delight. Without Clifford to prod and provoke him, Mink would be lazier and maybe even a bit boring. Without Mink to look after him and provide a contrast, Clifford would get in a lot more trouble and be less amusing.

Understanding the origins of behavior is apt to tempt some people to try to shape it to their own view of what is desirable. I'm not sure that we humans have the wisdom to do that. A world without selfishness may seem idyllic, but where does ambition end and selfishness begin? A world without ambition would be a world without accomplishments. Bravery is valuable, but is the absence of caution a good idea, and could we ever engineer one without the other? The world, I think, needs not the sameness of genetically determined 'goodness', whatever that is, but different kinds of people with contrasting characteristics, like Mink and Clifford. They provide the richness of life and are necessary for human progress. Maybe greed, selfishness, foolhardiness and other 'negative' characteristics are the price we have to pay as a species for the existence of determination, overachievement, courage, and a host of other traits we find desirable. Maybe, as some philosophers have suggested, good can't exist without evil. I don't know if these things are true, but how can we afford to take the chance? Manipulating behavior genetically seems to me the kind of thing that can wake up and bite you. I think this is one sleeping dog we would do well to let lie. Now, if you'll excuse me, it's time for them to take me on my afternoon walk.

Published: 23 October 2003

For the good of the state

Genome Biology 2003, 4:121

"It is by my order and for the good of the state that the bearer has done what has been done."

Cardinal Richelieu, in The Three Musketeers
by Alexandre Dumas

In the largely liberal circles in which I, and most other academic scientists, travel there is a perception that the present US government is slowly eroding - or at any rate would like to erode if it thought it could get away with it - many of our basic civil liberties. There is also the concern that, eventually, in the name of 'national security' or 'the war on terrorism', 'they' will be allowed to get away with it, because the public is afraid. Regardless of one's politics, we can probably all agree that people are more fearful than they were, say, ten years ago, but I don't think it's just terrorism that the public is afraid of. Another big component of this swelling fear is the rapidly accelerating pace of scientific and technological progress.

The unknown usually provokes anxiety, and the closer the unknown comes to touching us directly the greater the anxiety becomes. Recent advances in biology and medicine, from the sequence of the human genome to the cloning of mammals to the engineering of bacteria and viruses for biowarfare as well as for therapeutic purposes, have made many lay people profoundly uneasy about the future of humanity. In this climate of unease, the public seems willing to accept restrictions on many things, including science. President Bush's decision to limit the supply of stem cells available for medical research was one such restriction.

In an attempt to forestall more of them, on 9 October 2003 a panel convened by the National Research Council (NRC), a component of the US National Academy of Sciences, recommended voluntary prior review, at both the university and federal levels, of experiments in seven areas of genetics, biochemistry and microbiology. These areas were chosen because they represent types of research that could conceivably provide terrorists or hostile nations with information or material useful for the creation of biological weapons.

The proposal from the panel, which was headed by yeast geneticist Gerry Fink of the Whitehead Institute (Cambridge, USA), calls for self-regulation by scientists through a review process that would operate at several levels. The first is local: rather than the creation of a new machinery, it recommends using the existing system of institutional biosafety review committees, which already must approve any research that involves genetically engineered organisms or ones deemed hazardous, such as human pathogens. These local review boards are meant to ensure that experiments are conducted in a manner that protects the scientists involved and the community in which they work. In the Fink panel's proposal, these committees would also be given the additional job of issuing, or withholding, approval for projects whose results might conceivably be misused by terrorist organizations or rogue states.

As a second tier, the report proposed that rulings of the local committee could be appealed to the federal Recombinant DNA Advisory Committee (RAC), a body set up by the National Institutes of Health in the late 1970s as a result of public concern about the possible release into the environment of genetically modified organisms produced by recombinant DNA technology. The RAC would also serve as a resource for local committees that were unable to come to a decision. Perhaps the most important suggestion of the NRC panel was the creation of a final level of review, a new advisory committee for the Department of Health and Human Services - note, not the Department of Homeland Security - involving both biologists and security experts that would coordinate the scientific aspects of biodefense across many different federal agencies. This committee would help to ensure that scientific information was properly taken into account in any decisions involving the possible misuse of biological research.

A key element of the proposed system of self-regulation is that it would be entirely voluntary. The Fink panel, which consisted of lawyers, public policy experts and former high-ranking security officials as well as scientists, agreed that peer pressure and the humanity of most scientists would be enough to ensure compliance. Although the report focused on research carried out in universities and medical schools, the Fink panel also recommended that pharmaceutical and biotechnology companies submit voluntarily to such prior review as well.

What about research that was approved but whose findings might later be deemed by some to constitute a risk? Significantly, no specific restrictions on the publication of completed research results were proposed. I think this is a wise decision. Most biological research - with the exception of the seven areas specified in the report (which include, for example, experiments aimed at engineering microbes to avoid the human immune system) - has great potential benefits for human health as well as a small possibility of misuse. Given that, in biology especially, those who make a discovery are almost never those who eventually turn it into some practical application, widespread dissemination of research findings is essential for those benefits to be realized.

By these recommendations, life scientists have taken the lead in trying to prevent dangerous research from being carried out in the first place - a policy more sensible, and less erosive of liberty, than censorship of publication (which, as the panel notes, is unlikely to prevent others from learning about it anyway). The Fink panel's report attempted to strike a balance between the need to reassure a public that is increasingly anxious and suspicious about biological research and the desire of scientists to avoid excessive government intrusion into their freedom to conduct that research. The stem cell debacle is a good illustration of why scientists are right to believe that the present US government, in particular, may wish to restrict some research for purely political or religious reasons, and might try to use the public's fear of bioterrorism to aid in doing so.

Few forms of human endeavor depend as much on freedom - freedom of thought, inquiry, action and communication - as does basic scientific research. Unlike applied research, basic research is conducted largely to satisfy the curiosity of the individual investigator. Yet it is from just such research that nearly all breakthroughs emerge. The best-selling anti-cancer drug, cisplatin, was discovered serendipitously in a basic research project studying not cancer but bacteria (see Genome Biology 2001, 3:comment1001.1-1001.2), and the entire biotechnology industry is based on a series of discoveries by molecular biologists and biochemists who were studying bacterial processes that everyone, including themselves, thought had no practical significance. It is not a coincidence that those countries that lead in the advancement of knowledge and the creation of new industries from that knowledge are also the world's most free. Although the panel's recommendations will strike some scientists as starting biology out on the slippery slope to governmental control, and others as not going far enough to keep our discoveries out of the hands of would-be bioterrorists, I believe they are a measured and appropriate response to the twin threats of misuse of science and government interference.

In The Three Musketeers, Cardinal Richelieu gives one of his agents a letter that excuses any act of villainy, even murder, as being for the good of the state. In a fine piece of irony, this letter falls into the hands of D'Artagnan, who uses it to escape the Cardinal's vengeance for having helped to kill that same agent. Likewise, the umbrella of 'national security' or 'the war on terrorism' can, ironically, be used to shelter the very abuses that it is meant to protect us from: repression and tyranny. Thus are our swords, as Brutus says at the end of Shakespeare's Julius Caesar (another tale of patriotic impulses gone wrong) sometimes turned "into our own proper entrails."

Voluntary restrictions, when no longer needed, are usually easily lifted; but when a government takes freedoms away it is much harder to regain them. I believe that many of those who would impose censorship and restrict our liberties do so with the best intentions. But one of the things that history teaches is that some of the worst things imaginable have been done with the best intentions. It makes it even harder to bear, if one loves one's country, that such actions are carried out by other patriotic people for the good of the state.

Published: 27 November 2003

Live and let diet

Genome Biology 2003, 5:101

I wanted to lose a few pounds in anticipation of the holidays, a time of year that in the U.S. should more properly be referred to as the season of joy and gluttony. By the time you read this, many of you may want to shed your holiday pounds (and kilos). A number of sensible options were available to me: I could reduce the amount of food I ate at each meal, thereby decreasing my total caloric intake without making drastic changes to my eating habits. I could increase the amount of exercise I get each day (like most academicians, this usually consists predominantly of running from students disgruntled about their grades), thereby increasing the number of calories burned without making any changes to my eating habits. Or I could do the most sensible thing of all, namely eating a bit less and exercising more, thereby losing weight even faster while adopting a more healthy lifestyle. Being an American, I of course chose to go on a fad diet instead.

It used to be that one's generation could be defined simply by the war one fought in. Thankfully, we live in a time of relative peace, but since the middle of the last century, equally defining - and perhaps equally hazardous - are the diets that each generation has been swept up in. If you lived in the '40s, '50s and '60s, you were told that too many calories were bad for you, and that the best way to lose weight was to eat less, period. During the '70s, '80s and '90s, you were told that it wasn't the number of calories but the type of calories that made the difference. Fat was the big enemy. Eat less fat, and you would lose weight no matter (the unspoken assumption seemed to go) how many calories of protein and carbohydrate you ate. Today the average U.S. diet is approximately 15% protein, 51-53% carbohydrate and 32-34% fat; the National Academy of Sciences recommends a diet that is 10-35% protein, 45-65% carbohydrate and 20-35% fat - not very different. Yet Americans are getting fatter by the year. And now the latest diet craze is the Atkins diet (or its slightly less draconian variant, the South Beach Diet), in which you are told that the real enemy is not fat but carbohydrates, and if you want to lose weight you can eat as much fat and protein as you want, but you must consume almost no carbohydrates at all.

So I'm now doing Atkins. (One speaks of "doing Atkins"; it sounds so much more hip than "I'm on this godforsaken Atkins diet".) The Atkins diet (named after its creator, Robert C. Atkins, a New York City cardiologist who, in one of life's cruel ironies, supposedly lived a very healthy lifestyle only to die prematurely when he slipped on a patch of ice) is divided into three phases: the induction phase, in which carbohydrates are eliminated from the diet almost completely (this lasts a minimum of two weeks, usually longer); the second phase, during which complex carbohydrates are added gradually back to the diet but refined sugars and starches are still mostly eliminated; and the maintenance phase, which is an Atkins euphemism for "You'll be on this godforsaken diet for the rest of your life, which may be longer because you'll be eating healthier but will be no fun at all."

I'm still in the induction phase, and a carbohydrate hasn't so much as touched my tongue in weeks. I would kill for a piece of chocolate cake right now. According to Atkins, you can eat as much protein and fat as you want during this time, but there's a catch: just about the only foods that have protein and fat but no carbohydrates at all are eggs, meats, fish, butter and cheese. There are only so many ways you can combine these into meals before becoming very repetitious, and they are fairly bland foods as well, so there's a certain sameness of taste to every meal. Doing Atkins, I'm here to tell you, is boring.

It is also effective. Unlike many fad diets, this one makes some biochemical sense, which may be why so many scientists I know seem to be on it. The basic logic of the Atkins diet is that a high-carbohydrate diet provides more grams of carbohydrates than are necessary for immediate energy usage. Some carbohydrates are converted to glycogen and stored in the liver, but this represents only a small percentage. Most of the excess is converted into fat for storage in the body tissues. Thus, eating a high-carbohydrate diet - which is exactly what has happened in the West in the past twenty years, as our fear of fats has led to the consumption of more and more carbohydrate-rich foods that are low-fat - can result in big weight increases, especially in non-athletes. Further, when carbohydrate in the diet is high, the preferred fuel for most metabolic processes, especially the brain, is glucose and consequently the capacity to mobilize fat is limited. Foods high in carbohydrates also increase blood glucose, stimulating insulin release and all the metabolic sequelae of circulating insulin: fatty acid synthesis is activated and fat breakdown is profoundly inhibited by insulin even at very low concentrations of the hormone. After about 48 hours of low carbohydrates (less than about 25 grams per day), the glycogen stored in muscles is depleted, and the body begins to burn fat for fuel, causing relatively rapid weight loss.

The 'glycemic index', which is a measure of how quickly carbohydrates are converted into glucose, is different for different types of carbohydrate. So-called 'high impact carbs' raise blood sugar levels rapidly, causing insulin to spike. Using 100 as the reference, table sugar has a glycemic index of 65. White bread is 72 and baked potatoes have a glycemic index of 85. Corn flakes have a glycemic index of 84, while ice cream has a glycemic index of 50. The Atkins diet allows consumption of complex carbohydrates with very low glycemic indices after the induction phase, but suggests that one should limit one's consumption of high impact carbs forever. Foods with low glycemic index values include dairy products, green vegetables, beans, and pure fructose, which has a glycemic index of 20.

Remember also that the Atkins diet allows you to eat lots of fats and proteins. Fats, unlike carbohydrates, have a high satiety factor. Whereas carbohydrates make you hungry a couple of hours after eating, fats make you full, and the satiety lasts for hours, proponents claim. Thus, you tend to consume fewer calories on a high-fat diet than on a high-carbohydrate diet. Since insulin levels are low on this diet, the fat you eat cannot be stored. Yet your blood glucose does not drop too low, because your liver continues to convert some of the dietary protein into glucose. Any excess dietary fat is not stored but broken down by a process known as lipolysis (the opposite of dehydration synthesis) and excreted. This excretion requires a lot of water and so one needs to drink plenty of water on this diet. Metabolized fatty acids are broken down further into ketone bodies, which become the primary fuel of the brain in the absence of glucose. Any excess ketones are not stored but are excreted in the urine - again the need for lots of water. The production of ketones during fat metabolism is called ketosis and can be recognized by the characteristic, somewhat fetid breath of Atkins dieters, one of the diet's many charming features. Although ketoacidosis is dangerous, the effects of long-term, low-level ketosis such as that produced by low-carbohydrate diets are not established.

Genomics may turn out to be a boon for dieters, especially those on low-carbohydrate diets. Different people respond differently to such a diet: most lose weight fairly rapidly, but some are 'metabolically resistant' and do not. What this means exactly is still controversial but the claim is that, in general, high carbohydrate consumption can result in overproduction of insulin and eventually in people becoming less sensitive to it, which is thought to lead in some cases to diabetes. Presumably some percentage of dieters may have genetic profiles that make them naturally more resistant to insulin, and for such individuals a different dieting strategy may be needed. It should be relatively easy for the burgeoning science of pharmacogenomics to identify such individuals by simple comparative genome expression profiling, which leads me to speculate that services for doing just that are likely to be a growth industry - and probably one rife with charlatans - in the near future.

Low carbohydrate diets induce a milder version of many of the same biochemical changes as diabetes, or prolonged fasting. Lawrence McKeown, of West Belfast, Northern Ireland, holds the record for the longest period that any human has gone without food and lived to tell the tale: 70 days. He and his fellow Republican inmates in the H Blocks at Long Kesh (also known as Maze Prison) went on a hunger strike in 1981. Bobby Sands, their leader, died after 66 days. Nine other prisoners died as well. McKeown, a former footballer, was in superb condition at the start of his fast, which perhaps explains how he was able to escape the long-term disabilities, including kidney failure, optic-nerve damage, strokes and early heart attacks, that have plagued most of the other survivors. But there remains the tantalizing possibility that he, and his compatriot Raymond McCartney, who endured a 53-day fast without lasting damage, possess some unique genetic characteristics that protected them - a question that would not be difficult for genomics to address, given a suitable database of allelic variations in metabolic genes among 'normal' individuals as a basis for comparison. McKeown's description of the physical changes that took place during the early stages of his time without food are a magnified version of what occurs during the induction phase of Atkins. "What I remember most is the chill in my bones," he recalled during an interview with jouralist Bob Drury. His sense of smell was heightened, and his appetite diminished as he became ketotic. Muscle fatigue and exercise intolerance also occurred rapidly. I had a much milder version of all of these symptoms by the end of the first week of the induction phase of the Atkins diet, consistent with my glycogen stores becoming depleted after about four days, and a switch to ketone bodies as the primary source of fuel for the brain. My ability to tolerate exercise (I mean physically - psychologically I never have cared for it much) also dropped, although it recovered after a couple of weeks. Fasting for weight loss is apparently a rising fad in the developed world. No doctor I know would endorse it. Neither would McKeown, who says simply that fasting without a cause worth dying for is beyond his ken.

The Atkins diet, of course, is not a fast; in fact, one is allowed to eat as much fat and protein as one needs to maintain a feeling of satiety. However, there have been a number of reports lately that question the safety of a diet that is so high in fat and protein but low in fiber and vitamins (although the Atkins book explicitly advises that one should not undertake this diet without seeing a doctor first, and that one should take a vitamin and mineral supplement while on it, and drink copious amounts of water). Many doctors, and the American Heart Association (the same folks who endorsed the low-fat diet, remember) have warned that the increased urination in the first few days of the diet can cause a potentially dangerous reduction in calcium and potassium levels in the blood. This drop in electrolytes has been cited as a possible contributing factor in the deaths from cardiac arrhythmia of some people who were on the diet, and for heart damage to others. Paul Robinson, director of adolescent medicine at the University of Missouri hospital, has published a paper in the Southern Medical Journal advising against this diet for adolescents until more research is done. It's hard to know whether such concerns are valid, because when millions of people go on the same diet, there will always be a small number who have a previously existing, undiagnosed abnormality that makes such a diet contraindicated. Statistically, one also expects that a small number of people will develop some serious health problems whether they are on the diet or not, but in the litigious society we live in, nothing happens to anyone by chance. If anything bad occurs, it must be someone's fault, and therefore someone owes you money. In such a climate, even when the research needed to decide whether a diet is really safe has been done, it can be difficult to persuade people to believe the results.

Some cardiologists have claimed that the premise that carbohydrates make people fatter than other foods is questionable, and that the high-fat content of the Atkins diet could worsen heart disease by raising cholesterol (to be fair, the Atkins diet book warns against consuming much saturated fat). I've been careful to eat more protein than fat, have avoided saturated fats like the plague, drunk enough water to irrigate a small farm, and taken vitamin supplements religiously. So far everything seems fine, but I doubt that I'll stay on Atkins much longer anyway. Once the holidays are over, my plan is to go back to a more balanced diet, probably with a good bit less starch and sugar than before and certainly with smaller portions of everything. Besides, I have found that, for me anyway, the real problems with the Atkins diet are psychological, not physiological.

Psychologists are fond of saying that it's important to get in touch with your anger. No problem; I've found mine: it was hidden under all those carbohydrates. Atkins dieters, the book notes, may experience "some increase in irritability" during the induction phase. That's like saying that Scuba divers may experience some water. One consequence of a carbohydrate-free diet is a dramatic reduction in the level of serotonin. Serotonin is the neurotransmitter that helps us feel happy and prevents us from attacking one another at random. I don't have much serotonin now, so my interactions with people lately have been, shall we say, somewhat prickly. I have a cactus in my garden that's less prickly than I am at the moment.

Then there's the matter of concentration. Low-carbohydrate diets are claimed to improve your ability to concentrate. I can attest that this is true, but what that they don't tell you is that your concentration will be on chocolate cake. Many people have the problem of being obsessed with certain foods, or foods in general, some of the time. Doing Atkins, claims the diet book, will change all that. It does. I'm obsessed with food all the time now. Much of that obsession is with foods I can't have, like chocolate cake - and this does not improve my irritability (q.v.).

Once you've done Atkins, the book says, you'll be ready for a whole new life. I can confirm that: being on this diet has made me regret the day I was born. But soon it will be over. You'll know when that happens, because you'll probably be able to hear my cry of joy from whatever country you're in.

Published: 22 December 2003

Bad chemistry

Genome Biology 2004, 5:102

A few months ago I helped move my parents into an assisted living facility. Because they were going from a large house to a two-room apartment - one of the consequences of declining health is that your world suddenly becomes very small - we had the sad task of packing up, and in many instances disposing of, a lifetime of stuff (my father is a pack rat and has never thrown anything away voluntarily). Among the accumulated clutter in the basement I found a cardboard box labeled 'Greg 1965'. It contained, among other things, the complete set of notebooks from all of the classes I took as a junior in high school, back in Washington, DC. One of those classes was honors chemistry, a course designed to provide the same material as an introductory college course. Leafing through that notebook, I realized an extraordinary thing: I could use those notes to teach that same course at any university in the United States today, with no modification whatsoever. The order of topics, the level of treatment, even the examples used, were the same as you would find in nearly every first-year college chemistry textbook. General chemistry courses haven't changed significantly in forty years.

Your first reaction to this might be, "Why should they?" After all, the basics of the subject have been known for more than forty years, and those basics are essential prerequisites for any advanced, more 'modern' material. But I think if that was your first reaction, on reflection you will agree with me that this situation isn't just extraordinary, it's appalling. And it goes along way towards explaining something that's been bothering me for a long time: the flight of increasing numbers of good students away from chemistry.

In the United States, a course in general chemistry followed by a course in organic chemistry is a requirement for admission into medical school, regardless of what subject one concentrates on (we say "majors in") in college. Consequently, huge numbers of college students take introductory chemistry, usually in their first year, unless they have had a high school honors course like the one I took. At Brandeis, the small private university at which I work, there are about 800 new students admitted each year and over 200 of them take first-year chemistry; it is often the largest course on campus. More than half of them do so because they plan eventually to apply to medical school. At Ohio State University, the largest of the public universities in the US, there are about 13,000 new undergraduates per year and up to 3,000 of them might take introductory chemistry. These huge enrollments are both a curse and a blessing to chemistry departments at US universities: they impose a large teaching burden on the faculty, but also justify hiring large numbers of chemistry professors. And with medicine having become an increasingly popular career during the past five decades, the numbers of premedical students (we call them "premeds") have been rising steadily, with a few short periods of decrease, for that same period. Yet the number of students who go on to major in chemistry has actually declined since I was in high school, despite this bolus of prospective recruits who are exposed to the subject just as they enter college, usually before they have decided on a major field. Moreover, surveys of students consistently rate introductory chemistry courses among the most disliked, and feared, courses students ever take during their four years at university. Something is very wrong: instead of turning students on to chemistry, our low-level courses are turning them off, in droves.

Where do they go instead? Increasingly, the science-oriented among them gravitate toward biology. It is seen as a 'hotter', more welcoming, and just a more interesting subject. Which would be OK, I guess, except for two things: introductory chemistry and basic organic chemistry is then all of the chemistry many biologists are ever taught (I exclude biochemistry courses here, for reasons I'll discuss in a later column), and this shift away from chemistry is accelerating at precisely the time when, thanks to genomics and an increased focus on human health in the life sciences, biologists need to know much more chemistry.

Last year the US National Academy of Sciences released a report called 'BIO2010'. It was prepared by the Committee on Undergraduate Biology Education to Prepare Research Scientists for the 21st Century (or COUBETPRSFTTFC for short), which was set up by the National Research Council, the branch of the National Academy that conducts in-depth studies, because undergraduate programs that train biology researchers have remained much the same as they were before the fundamental changes brought on by genomics came on the scene. The report http://www.nap.edu/catalog/10497.html is intended to be a blueprint for "bringing undergraduate biology education up to the speed of today's research fast track". It includes recommendations for teaching the next generation of life science investigators, through: eliminating the administrative and financial barriers to cross-departmental collaboration; evaluating the impact of medical college admissions testing on undergraduate biology education; creating early opportunities for independent research; and designing meaningful laboratory experiences into the curriculum.

All of which sounds great, and who would disagree with it? But the report also includes one more recommendation, namely: building a strong interdisciplinary curriculum that includes physical science, information technology, and mathematics. I don't see how that can ever happen as long as college chemistry in general, and introductory chemistry and organic chemistry in particular, remain the way they are now. It isn't just that some of the so-called essential 'basic' material really isn't all that essential to most of the students, or to what other chemistry they will need to learn later. It's also that the examples used to motivate students to learn those topics that really are essential are dull, irrelevant, and archaic. In general chemistry courses today, just like 40 years ago, a week or more is spent teaching gas laws, but blood gases are almost never mentioned. Another week or more is often devoted to nuclear chemistry, but seldom in the context of the use of radioactivity in biology (radiocarbon dating is the favorite example these days). Electrochemistry is given several weeks of instruction, but not in the context of electrophysiology, which is the one place where it really will matter to most of the students in the class. Weeks are spent on molecular orbital theory. I have been a practicing biophysical chemist for thirty years and I can count on the fingers of one hand the number of times I have ever had to pay much attention to molecular orbital theory, which leads me to suspect that there aren't many physicians in the world who have ever found it all that essential in their work either. I could go on - and I could also make similar points about the course content, and emphasis, of introductory organic chemistry - but I think the message is clear: chemistry is not presented in such a way as to make it relevant, or even useful, much less exciting, to the would-be biologists and physicians who constitute the overwhelming majority of those being taught.

How did we get into this mess? Like a lot of other aspects of our current educational and scientific establishment, this goes back to the heady days post-Sputnik, when the West, in a paroxysm of self-flagellation, decided to reform its education programs to put increased emphasis on the physical sciences and mathematics. The economic slump in the next decade also made professional careers such as medicine increasingly attractive: not only were they lucrative, they were 'safe', offering guaranteed employment. These two circumstances, combined with the flood of students into higher education as the demographic bubble of the Baby Boom generation reached college age, led to large increases in enrollment in basic science courses, including chemistry, over a 20-year period. Someone had to teach these courses, and in the US that someone was usually a physical chemist. Positive feedback loops being what they are, the physical chemists realized that this continuing demand ensured that chemistry departments would keep hiring additional physical chemists. Once they got their clutches on introductory chemistry, they never let go, and as a result, the curriculum has remained mired in a 1950s physical-sciences mentality, and the teachers who should be getting biologists and premeds excited about chemistry - the biochemists - have largely been shut out.

I think it's important to understand this history because it helps explain why modernization of the subject has been so difficult. There is a group of faculty with a vested interest in keeping things the way they are: an entire generation of teachers who have taught general chemistry the same way for years, and consequently have little incentive, and no necessity, to do the work of updating and revising their notes that major changes would demand. And things have been this way for so long that there are other vested interests as well: textbook companies who are making big profits out of books that adhere to the same old curriculum, and, in the US at least, an American Chemical Society that promulgates a 'certified' chemistry curriculum that also hasn't changed much since I was a student.

Given these entrenched conservative forces, I think the prospects for bottom-up changes driven by students or faculty are still poor. It seems to me that the only way to break the inertia of the present system is to put a gun to the heads of the chemists (figuratively, of course) and mandate change from the top down. I don't see university administrations doing that, at least not without someone putting a gun to their heads (figuratively), but fortunately there is someone who can do just that. Because the overwhelming majority of students taking basic chemistry courses are premedical students, medical schools have enormous influence, and potential power, over the undergraduate institutions that serve those students. What is needed, I think, is for the deans and/or the admissions directors of leading medical schools, in the US and elsewhere, to get together and demand that colleges and universities devise a chemistry curriculum that prepares students for the challenges and excitement of medicine in the twenty-first century. Because medical education and graduate biology education have many points of congruence, this would also realize one of the goals of the BIO2010 report: to give biologists a grasp of chemistry that would assist them in doing interdisciplinary research in the age of genomics.

As an unreformed '60s radical, I like to think of myself as pretty far left of center on most issues. But my experiences in the antiwar movement back then taught me to value evolutionary change, often ahead of revolutionary change, because I've found that revolutions can hurt people and permanently damage human relations. Nevertheless, on this issue I'm as much of an anarchist as one can be. I think the best way to fix the problems of undergraduate chemistry education is for the medical schools to help us blow the whole thing up (figuratively) and start all over again to create something that works. Next month, I'll offer some suggestions for what that might be.

Follow-up

A few months ago, I wrote about the tribulations of Dr Thomas Butler, the Texas Tech scientist indicted by the US government on 69 criminal counts ranging from illegally importing and smuggling plague bacteria to lying to the FBI about the fate of 30 missing samples of plague bacteria to embezzlement (see The 'Usual Suspects': Genome Biology 2003, 4:118). On December 1, a jury found him not guilty on nearly all of the biohazard-related charges - they apparently believed his claim that he was manipulated by the FBI and has no idea where the missing plague cultures are. However, he was found guilty on 44 counts of theft, fraud and embezzlement (related to payments he received for work on clinical trials sponsored by the drug companies Pharmacia-Upjohn and Chiron) and three counts of unauthorized export and illegal transportation of hazardous materials. He faces up to 240 years in jail and millions of dollars in fines. His attorneys say he will appeal the verdict. Meanwhile, those 30 samples of Yersinia pestis are still unaccounted for. (For a superb piece of investigative reporting on the entire affair, see the account by Martin Enserink and David Malakoff in the December 19, 2003 issue of Science.)

Published: 2 February 2004

Good chemistry

Genome Biology 2004, 5:103

Last month (Genome Biol 2004, 5:102) I suggested that the teaching of basic chemistry courses in US colleges and universities was hopelessly out of date, as well as out of touch with the needs of students in the life sciences. Topics and examples in general chemistry haven't changed significantly in over four decades; and organic chemistry doesn't do much better. Both of these subjects are taught to large groups of students who will never become practicing chemists - chiefly, premedical students and life-science majors - and whose experience with chemistry neither endears them to the subject nor gives them much in the way of useful tools for their future professions. Because so many people, including textbook authors and publishers and the chemists who teach these courses, have vested interests in maintaining the status quo, I argued that reform from within the system was unlikely, if not impossible. And I proposed that the entire edifice be imploded and rebuilt from scratch, with the biggest consumers of chemistry students, the medical schools, taking the lead in forcing change from the top down.

I expected these deliberately inflammatory comments to provoke a storm of response, and they did. I received more e-mail about this column than I did even for the column on the dog genome, with its pictures of two cute puppies. But to my surprise, the response was one of unanimous - not just overwhelming, but unanimous - agreement. The consensus among readers seems to be that the system is indeed broken beyond what patchwork renovations can repair.

Given that my remarks appeared in a biology journal, I take this as a sign that chemistry is indeed failing to reach students in the life and medical sciences. (I expect that, had they been published in a chemistry journal, at least someone would have leapt to the defense of the subject; that no one did suggests that the failure is almost total.) Although it's always pleasant to be told one is right, I rather wish I had been wrong. Contrary to what one might have inferred from the commentary, I was trained as a chemist myself; I love the subject and am sick at heart to see what has happened to a once-glorious discipline.

Chemistry bills itself as 'The Central Science', implying that an understanding of chemistry is important for many, if not most other sciences. I agree with that sentiment, but I doubt many of today's students would. The image of chemistry is so poor that DuPont, the giant US-based chemical company, removed "Through Chemistry" from the tail end of its "Better Living" slogan. Basic chemistry courses do so poor a job of conveying the excitement and relevance of chemistry that the best and brightest students are more apt to go into biology, where they end up, ironically, often working on biochemical questions. But why should they stay with chemistry, when the subject matter in their chemistry courses reflects almost nothing of the issues that chemists are actually interested in today?

What is to be done, and, more important, how do we get it done? I originally imagined perhaps the deans and/or admissions officers of the leading medical schools might get together and issue a set of guidelines for reforming the system, but given the enormous inertia in chemistry departments that wouldn't necessarily force the matter. Of the many suggestions I received from readers, perhaps the most thoughtful - and the most practical - came from Hugh Auchincloss, a professor of surgery at Massachusetts General Hospital and Harvard Medical School. He suggested that the way to make the colleges and universities change what they teach is to change the content of the MCAT, the Medical College Admissions Test.

The MCAT is a standardized, multiple-choice examination designed to assess problem-solving, critical thinking, and writing skills, in addition to the examinee's knowledge of science concepts and principles deemed prerequisite to the study of medicine. (Deemed by whom? The answer is the Association of American Medical Colleges.) Scores are reported in each of the following areas: Verbal Reasoning, Physical Sciences, Writing Sample, and Biological Sciences. Almost all US medical schools require applicants to submit MCAT scores during the application process. Medical college admission committees consider MCAT scores as an important part of their admission decision process - in fact, the unofficial word is that many of the most selective medical schools use these scores to triage the flood of applications they receive.

The idea of using the MCAT as a club to force chemistry departments to change what they teach basic chemistry students is simple and, I think, would be very effective. It's already clear that colleges largely 'teach to the test' as it is. Box 1, for example, shows a small part of the list of chemistry topics that students who take the MCAT are expected to know.

Box 1

1. Absolute temperature, K scale

2. Pressure, simple mercury barometer

3. Molar volume at 0°C and 1 atm = 22.4 mol/L

4. Ideal gas

a. definition

b. ideal gas law PV=nRT

i. Boyle’s law

ii. Charles’ law

iii. Avogadro’s number

5. Kinetic molecular theory of gases

6. Deviation of real-gas behavior from ideal gas law

a. qualitative

b. quantitative (van der Waals’ equation)

7. Partial pressure, mole fraction

8. Dalton’s law of partial pressures

Most of these have little, if any, relevance, either to chemistry as it's practiced today or to chemical concepts that biologists and physicians need to understand. The same could be said for more than half of the other topics on the list, both in general and organic chemistry. What is covered on the test reflects the way chemistry is taught, and the way chemistry is taught reflects what is covered on the test, and the wheel goes 'round and we get nowhere.

So, the solution is for the medical college association to change the test, requiring that students learn those chemical concepts that matter for the life sciences, and that they learn to work with such material in the context of the medical and life sciences. 'Traditional' chemistry doesn't have to be short-changed by this transformation, since students wishing to become practicing chemists could always take a different track - in fact, in many colleges today, there are more rigorous general chemistry courses designed for the handful of true chemistry majors; these could be continued. But for the rest, there would finally be a curriculum that serves their interests and needs.

What might that look like? One possibility would be to replace the current, full-year, physical-chemistry-dominated introductory chemistry course with a two-semester course in which the first semester covers largely structure, bonding and reactivity, with almost all of the examples being drawn from bioorganic chemistry, and in which the second semester would basically be a revival of the old-time physiological chemistry course. In that course, concepts like pH, buffering, solubility of gases and solids, and kinetics would be taught based on examples from medicine, physiology and biochemistry. The second year would then offer first a continuation of organic chemistry, with a focus on the types of reactions important in metabolism and pharmaceutical chemistry, and then a one-semester biochemistry course in which metabolism could primarily be treated in terms of regulation, leaving room for more detailed study of biomolecular structure and function. I would then add a required cell biology course in year three for all life-science and premedical students; at present, premeds need only take a general course in biology.

This isn't the only possible curriculum, of course, and might not even be the best one - that's something that the medical schools should devise, ideally with input from some chemistry departments but, if necessary, without any. The point is to formulate a set of topics - and an MCAT reflecting them - that would leave chemistry departments no choice but to change their teaching.

I think it would even be in the chemistry department's best interests in the long term. If chemistry really is a central science, then it shouldn't allow itself to be marginalized, as physics has, by maintaining an insular, conservative, snobbish attitude toward building bridges to other sciences. Yet such marginalization is already underway, as 'true' chemistry begins to reflect an increasingly esoteric set of concerns - with barely concealed contempt for 'softer' applications in biology - and chemical education continues to present the field as if it hadn't changed in half a century. Chemistry is a wonderful subject, a magnificent intellectual edifice in its own right and a fabulous platform from which to view and tackle the life sciences. But you'd never know that from the way it's taught now.

Published: 26 February 2004

Doctor Dunsel

Genome Biology 2004, 5:104

"Dunsel ... is a term used by midshipmen at Starfleet Academy. It refers to a part which serves no useful purpose."

Mr Spock, in Star Trek, Episode 53: "The Ultimate Computer"

Paranoia began morphing into depression with the arrival of the 15 January 2004 issue of Nature. On page 247 was a paper by King et al. entitled 'Functional genomic hypothesis generation and experimentation by a robot scientist'. The paper describes an automated system that uses techniques from artificial intelligence to formulate hypotheses to explain observations. The system then devises experiments to test these hypotheses, and actually carries out the experiments using a simple laboratory robot. But that's not all. It then interprets the results so as to falsify any hypotheses not consistent with the data. Moreover, it can iterate this process, making it capable of developing and testing quite extensive models.

In the paper, the authors used this system to probe the genetic control of aromatic amino-acid biosynthesis in yeast, using various growth conditions and auxotrophic strains. The robot scientist took a series of systematic gene deletion strains and tried growing each in nutritional medium that lacked one of the intermediates in the pathway. If the deleted gene was required to make that intermediate, the strain would not grow and a component of the pathway would have been identified. The machine automatically examined the cultures to see how opaque they were, returned the results to the artificial intelligence package, and then received instructions for what experiments to perform to validate the hypotheses based on the results of the first round, and so on. The final result was the assembled pathway: the set of genes coding for the enzymes that control each step. The authors claim in the end that the automated system carried out the project just as efficiently - and more cost-effectively - than scientifically trained human volunteers.

Nature, perhaps feeling guilty about the hordes of scientists who might be losing sleep over the prospect of having to go out and actually work for a living, tried to soften the blow with an editorial comment called 'Don't fear the Robot Scientist' (page 181 of the same issue) that completely missed the point. "Contrary to first impressions," the commentator says cheerily, "an automated system that designs its own experiments will benefit young molecular geneticists. At first glance, it seems to render obsolete the armies of postgrads and postdocs employed in the world's molecular-genetics laboratories."

That wasn't what was worrying me at all. Replacing my graduate students and postdocs with machines that would work around the clock and never pester me for more disk space on the computer or a new set of pipetmen; that would never complain about the temperature in the lab and never forget to clear up after themselves - that didn't sound so bad. It was the thought that it might eventually replace me that was frightening. After all, this thing didn't just carry out the experiments, it designed them and formulated hypotheses based on them. I thought I was supposed to do that.

Nature continued, "The team behind the Robot Scientist argues that such automation 'frees scientists to make the high-level creative leaps at which they excel'". Well, the thing already plans, performs and interprets experiments. Just what leaps would those be, guys - designing the next generation of software for the robot? Still, I decided after an initial bad moment or ten, the robot was carrying out functional genomics. As we all know, genomics doesn't require real thought, just the semblance of it. Maybe I would have to surrender my genomics projects to some machine, but that only represented a part of my research effort. The rest of my work is structural biology, a branch of science of such technical sophistication and intellectual rigor that it could never be automated.

Then the 10 February 2004 issue of Proceedings of the National Academy of Sciences arrived. On page 1537 - right after a paper of my own, to add insult to injury - was an article by James Holton and Tom Alber (who was once my graduate student, to add injury to insult) entitled 'Automated protein crystal structure determination using ELVES'. It describes an expert system that can fully automatically determine the crystal structure of a protein from the primary X-ray data. True, individual steps in this process had been automated for some time, and the ELVES system had already been used to carry out such steps or even groups of steps, but always under the user's direction. This was different: there was no human intervention at all. The system was able to solve the structure of a 12,000 molecular weight coiled-coil protein from crystallographic data sets in two different crystal forms following a single command that launched the program and directed it to the location of the data files. The entire process, including interpretation of the resulting electron density map and refinement of the atomic model to convergence, took 9.5 hours on a multi-processor computer for one of the crystal forms, and 165 hours - the thing must have stopped for coffee or something - for the other form. The authors concluded that "high resolution structures with well-ordered metals can be determined automatically". To be fair, the protein structure, being all helical, did not present any real challenges in the model-building stage, and the authors are commendably candid about the limitations of the method: "ELVES is incapable of overcoming problems arising from poor data or inadequate phasing signal. Problems such as radiation damage, weak heavy atom signals, twinning, poor heavy atom models, low resolution, or crystal disorder that hinder crystallographic projects are not overcome by automation." Not yet, but just wait, I could hear them say sotto voce.

So, now I was about to be replaced as a crystallographer too. The year 2004 was sure turning out to be a terrific year. Well, strictly speaking I'm not paid just to do science anyway. Most of my salary comes from teaching undergraduates, and I consoled myself with the thought that I could always do more of that. Consoled myself, that is, until the arrival of last week's Boston Globe newspaper, with a story about a new effort at Massachusetts Institute of Technology (MIT) to revamp its undergraduate curriculum to take advantage of "innovations in educational methods". You know what that means - computer-based instruction. I could see it coming: once my lectures were all on the internet in interactive, self-test form, there would be no need for me to actually do any of the teaching myself anymore, or to be paid to do so - a fact I was sure would not be lost on any Brandeis administrator who might happen to read the article.

Feeling now very much like a horse might have felt about the time Henry Ford began turning out Model Ts, I tried to find something - anything - that I could do that a machine couldn't. Suddenly, it came to me: writing papers and grants. I probably spend half my non-teaching time writing things, things with highly technical content that also have to be comprehensible to people in my field who aren't involved in the work I'm doing or am proposing to do. In fact, if I want to get a grant from a foundation or publish a paper in a high-profile, general journal like Nature or Genome Biology, I have to try to make this highly technical material comprehensible to people who aren't in my field at all. Automate that, if you can.

Well, that may not be far off, actually. As Clive Thompson has pointed out (The New York Times Magazine, 14 December 2003), the music business is making strides towards doing something very like that. An artificial intelligence program called Hit Song Science from the Barcelona-based company Polyphonic HMI tries to determine whether a new song is going to be a hit. It uses a clustering algorithm to locate acoustic similarities between songs, similarities like common bits of rhythm, harmonies or keys. It compares these features of a new tune with all the Top 40 hits of the last 30 years; the closer the features of a new song are to a 'hit cluster', the more likely it is predicted, by the software, to be a hit. Thompson reports that the algorithm produces some strange groupings - the rock group U2 is similar to Beethoven, for example - yet it seems to work. A number of record companies are now using it to help pick which songs on a new album they will promote heavily. And, perhaps ominously, others are using it in the studio to tweak new songs as they are being recorded, changing various aspects of them to bring them closer to the hits in the nearest cluster. All well and good for the record companies, but it seems to me that this process is likely to take the spontaneity - and much of the novelty - right out of the music business. Hit songs tend to sound too much alike as it is, at least to this jaded listener; now they are going to be forced to sound even more alike. And clearly the same approach could be used, theoretically at least, to produce grants with a high probability of being funded, and scientific papers guaranteed to be accepted by top-rank journals. Hot Paper Science would cluster the titles, author names and affiliations, title words and key concepts that are shared by papers published in Cell, for example. One then only has to input one's own initial effort, 'The complete sequence of the gerbil genome' by Gregory A Petsko, et al., for example, and out would come 'Gerbil genome sequence: signal transduction pathways relevant to cancer, neurodegenerative diseases and apoptosis, with additional insights into systems biology and biodefense', plus a set of suggested coauthors that would help guarantee acceptance. The software would go on to write the paper, of course; submit it; and, if necessary, argue with the referees.

Well, that was it, I thought. Before long, even my writing functions would be taken over by machines. I was rapidly being made redundant, as they say in the UK - a twentieth-century equivalent of Captain Kirk in the Star Trek episode "The ultimate computer", his command capabilities handled more efficiently by a machine programmed to replace human beings in space exploration, his plaintive (and sexist) cry, "But there are some things men must do to remain men!" drowned out by the bootsteps of the relentless march of automation.

But then something happened to lift my gloom and restore my self-esteem. It was the arrival of an e-mail reminding me about the curriculum committee meeting scheduled for that afternoon. Of course! I wasn't useless after all. In fact, real human scientists are indispensable, and always will be. Computers may be better at solving crystal structures, and robots may be better at doing genome-enabled, hypothesis-driven experiments - may even be better at interpreting them - and eventually there will probably be software that writes better papers and grants, but we humans can still waste enormous amounts of time at interminable committee meetings. No machine will ever be stupid enough to do that.

Published: 29 March 2004

The Ascent of Man?

Genome Biology 2004, 5:106

Anyone who cares about the moral and social implications of genomics, genetic engineering and biotechnology should read Michael J. Sandel's article, 'The Case Against Perfection', in the April 2004 issue of The Atlantic Monthly. Sandel, the Anne T. and Robert M. Bass Professor of Government at Harvard University (where he teaches moral philosophy), is one of the deepest thinkers of this generation. He is a member of The President's Council on Bioethics, which George W. Bush established to make recommendations concerning stem-cell research, among other issues. In this essay, with characteristically clear and penetrating analysis, he argues that "the genomic revolution has induced a kind of moral vertigo", and that we are right to be troubled by such issues as human cloning and genetic engineering for improved human characteristics and performance. He dissects four examples of the use of our new-found power of biotechnology: muscle enhancement; memory enhancement; growth-hormone treatment; and reproductive technologies that allow parents to choose the sex and some genetic traits of their children. In each case, he concludes that such use is morally objectionable.

Strong words, but he defends them with tight logic and a thorough examination of the history and purpose of the technology. His grasp of the science is sound, and he manages for the most part to skirt the use of religious principles, which he acknowledges vary from religion to religion (and even within religions - consider the views of fundamentalist Christians versus those of more 'moderate' Protestants on the subject of abortion), relying instead on pitting what he terms "the ethic of willfulness and the biotechnological powers it has spawned" against "the ethic of giftedness". Sandel specializes in finding the inconsistency in moral and ethical arguments and positions - a tactic he uses here to dismiss such familiar grounds as fairness as a basis for prohibiting certain uses of biotechnology - and he makes instead a case that the drive to master nature, including human nature, and to perfect it through the use of technology undermines an appreciation of the gifted - and, therefore, imperfect - character of human powers and achievements, and prompts us to recognize that not everything in the world is open to whatever use we may desire or devise.

To give you a sense of the flavor of his argument and the elegance of his analysis, I'll quote two passages at length. Concerning muscle enhancement through the use of gene therapy, he writes: "It might be argued that a genetically enhanced athlete, like a drug-enhanced one, would have an unfair advantage over his unenhanced competitors. But the fairness argument against enhancement has a fatal flaw: it has always been the case that some athletes are better endowed genetically than others, and yet we do not consider this to undermine the fairness of competitive sports. From the standpoint of fairness, enhanced genetic differences would be no worse than natural ones, assuming they were safe and made available to all. If genetic enhancement in sports is morally objectionable, it must be for reasons other than fairness."

Later, discussing reproductive technologies, he states: "Some see a clear line between genetic enhancement and other ways that people seek improvement in their children and themselves. Genetic manipulation seems somehow worse - more intrusive, more sinister - than other ways of enhancing performance and seeking success. But, morally speaking, the difference is less significant than it seems. Bioengineering gives us reason to question the low-tech, high-pressure child-rearing practices we commonly accept. The hyperparenting familiar in our time represents an anxious excess of mastery and dominion that misses the sense of life as a gift. This draws it disturbingly close to eugenics... Was the old eugenics objectionable only insofar as it was coercive? Or is there something inherently wrong with the resolve to deliberately design our progeny's traits... But removing coercion does not vindicate eugenics. The problem with eugenics and genetic engineering is that they represent a one-sided triumph of willfulness over giftedness, of dominion over reverence, of molding over beholding."

All very closely reasoned, yet something in it makes me uneasy. Part of my uneasiness stems from the inherent subjectivity of any purely moral argument. Sandel doesn't just assume, though, that giftedness is a better ethic than willfulness, he tries to prove it by showing that willful transformation of human characteristics through biotechnology would erode three key features of our moral landscape: humility; a sense of being only partial responsible for our talents and performance; and solidarity. Yet I don't think the examples he gives succeed in establishing that these virtues are better than the alternatives (hubris, expectations of responsibility that cannot be met in practice, and selfishness). In the end, he takes it for granted that we will share his belief that they are. I happen to feel that way, so this leap of faith didn't really bother me that much. What did trouble me was a sense that something important was missing.

What that is can best be understood in light of Sandel's linking of genetic engineering with eugenics. Few ideas are apt to provoke as much moral outrage as efforts to improve humanity through selective breeding. But the history of eugenics is more complex than its treatment in this essay, which focuses on the coercive eugenics of the Nazi regime and the rising market for eggs and sperm from preselected donors. And that history is instructive. Eugenics, as defined by the American Bioethics Advisory Commission, is the study of methods to improve the human race by controlling reproduction. The word was coined in 1883 by Francis Galton, a cousin of Charles Darwin. Galton believed that social differences reflected differences in innate endowment, and that misguided charity encouraged the 'unfit' to bear more children, which upset the mechanism of natural selection - a mechanism that, left to operate properly, would lead to the continual improvement of the human race. He therefore sought to encourage the "most fit" - that is, members of the middle and, especially, upper classes - to bear more children, a process he likened to "artificial selection" and which he called "eugenics" (Greek for good birth). Galton's followers included George Bernard Shaw and Julian Huxley in England, and Ralph Waldo Emerson and President Theodore Roosevelt in the United States.

Eugenics for Galton was a positive process: nothing was to be done to stop the lower classes from procreating; rather, the birth rate of the upper classes was to be increased. As the idea spread, however, it became transformed. The eugenics movements in the United States, Germany, and Scandinavia soon favored 'negative eugenics', which advocated preventing the least able from breeding - in some cases through enforced sterilization. Lest anyone think that such notions have been permanently consigned to the garbage heap of history where they belong, in 1995 China passed a law that states, in part, "Physicians shall, after performing the premarital physical check-up, explain and give medical advice to both the male and the female who have been diagnosed with certain genetic disease of a serious nature which is considered to be inappropriate for child-bearing from a medical point of view; the two may be married only if both sides agree to take long-term contraceptive measures or to take ligation operation for sterility." A BBC survey in 1993 found that 91% of Chinese geneticists believed that couples who carried the same disease-causing genetic mutation should not be allowed to have children. More than three-quarters also believed that governments should require premarital tests to detect carriers of hereditary disease, and even supported the routine genetic testing of job applicants by employers. There was also strong backing for the genetic testing of children to see if they are susceptible to problems such as alcoholism.

So, Sandel may be right to raise the spectre of eugenics in the era of the genomics revolution. But for me, the most interesting thing about the history of eugenics is its connection with Darwinism. Not only were Galton and Darwin blood relatives, it was Darwin's theory of "natural selection" (not, it should be noted, "survival of the fittest" - that phrase, which Darwin never used, was coined later by psychologist Herbert Spencer) that led Galton to suggest that the high birth rate among the lower classes was interfering with the normal process of human evolution. Is it even possible to interfere with the normal evolutionary process? And if so, haven't we already done so? Evolution: that, I think, is what's missing from Sandel's argument. The most important single word in modern biology occurs exactly twice in the essay, in a discussion of a quote from biologist Robert Sinsheimer: "We can be the agent of transition to a whole new pitch of evolution." Sandel agrees that "it may even be the case that the lure of that vision played a part in summoning the genomic age into being... But that promise of mastery is flawed. It threatens to banish our appreciation of life as a gift, and to leave us with nothing to affirm or behold outside our own will." But he never challenges, or discusses at all, the assumption that we can now affect our own evolutionary changes, or asks whether there are scientific, as opposed to moral, reasons why we should or should not do so.

I think there are. At least two scientific arguments could be made in favor of the notion that we should consider intervening in our own evolution. One is that, because of technological progress, evolution has effectively stopped for Homo sapiens, and because that is a bad thing, biologically speaking, we must undertake to continue it ourselves. The other is that we have already been interfering with our own evolution, unwittingly, for at least a century, and in order to correct the damage we've done and avoid further damage, we need to intervene deliberately now. The first argument is an old one. It's based on the assumption that what governs much of the evolutionary process is the fitness of the individual for the environment - 'environment', in this case, meaning predominantly the climate and infectious diseases. According to this viewpoint, our technology now largely insulates us from the effects of climate, and antibiotics plus advances in public health have eliminated infectious disease as an agent of evolutionary change, at least in the developed world. Thus, human evolution, in a biological sense, has ceased. Since evolution is what keeps a species from stagnation and eventual decay, it is imperative that we now take charge of continuing the process artificially as best we can.

I'm not sure I buy the underlying assumptions. Global warming, for example, may represent a level of climate change to which our technology cannot make us immune. And infectious disease appears to be making a comeback all over the world, driven by a mobile, increased human population and the spread of resistance. Besides, I can think of many organisms that don't appear to have changed much in millions of years, and they seem to be doing just fine now - the crocodile and the mosquito, for example. But even if we grant all the assumptions, there is no objective evidence about the cessation of human evolution. Genomics, I think, is ideally poised to provide such evidence. DNA samples from Homo sapiens over the past two centuries can be gathered and analyzed. Comparative genomics and proteomics with our closest primate relatives should also be informative in this regard. How fast, genetically speaking, did the human race evolve over the past 10 million years or so, and has that rate changed? Definitive conclusions may be hard to come by, but any data will be better than what we have now, which is simply speculation.

The second argument, that modern medicine and changes in our social structures have already interfered with the normal course of evolution, is close to Galton's original hypothesis, which as far as I know has never been scientifically tested. It has several new flips now, though. For example, we could argue that improvements in human nutrition and economic prosperity have combined to increase not only the average height but also the average weight of the human population. Epidemic obesity is clearly bad for society, but what about the homogenization of other characteristics like height? We assume everyone getting taller is better, but how do we know? The same genome-driven scientific studies referred to earlier should shed light on these questions. Evolutionary biologists can contribute too, especially to a general discussion of just what hybrid vigor really means.

It's not obvious to me in any case, even if one of these two arguments turns out to have a factual basis, that it necessarily follows that we should manipulate our characteristics so as to restart, or restore, the process of evolution in Homo sapiens. Implicit in that conclusion is that we would know what we were doing, that any such deliberate tinkering would benefit our species in an evolutionary sense. I am not convinced that we understand the mechanisms and workings of evolution well enough to do that safely - but again, that is something about which only evolutionary biologists can speak with any authority. Sandel's thesis, for all its persuasiveness, does not let them speak.

Moral arguments are an important part of this whole discussion, of course, but sometimes they leave no place for scientists to weigh in as scientists, to offer evidence on what the facts are and whether those facts suggest certain courses of action to be desirable or undesirable. If the human race is indeed about to engage in a great debate about how - or in some cases whether at all - our new powers of biology are to be used on ourselves, then I think it is imperative that biologists provide a candid and objective assessment of what the available data tell us about human evolution. Ultimately, the decisions that follow from this debate must be made by humanity in general, and it may be that moral arguments will - and perhaps should - carry the day. Or perhaps the romantic vision of the quest for perfection, however unattainable, will prove to be irresistible. I don't know how all this will turn out in the end. But I do know that the discussion should not be undertaken in the absence of the information that only we can provide. Besides, our unique abilities as a species to integrate both objective and subjective factors into our course of action; to ask and try to answer questions that have both moral implications and factual issues; and to be skeptical and adventurous at the same time - aren't those gifts too?

Published: 26 April 2004

Pharmacogenomics arrives

Genome Biology 2004, 5:108

It happens all the time: a pharmaceutical or biotechnology company will spend ten years and hundreds of millions of dollars on a drug candidate that looks spectacular in animal models of a disease, only to see it fail during clinical trials, either because of unexpected adverse reactions in a small number of patients or a surprising lack of efficacy. For every drug that is approved, on average more than 6,000 new chemical substances are created. Only seven of these ever end up being tested in humans, and only three make it to Phase III clinical trials, the final step before a drug is approved by the Food and Drug Administration in the US. It takes over a decade and at least several hundred millions of dollars - sometimes close to $1 billion - to get that far, and even then, on average, only one of three candidates will emerge from Phase III and become a marketed drug.

This combination of colossal failure rate with astronomical cost - unique to the pharmaceutical industry - is the main reason new medicines are both expensive and hard to come by. Despite advances in synthetic chemistry, high-throughput screening, and structure-based drug discovery, the number of new drugs approved has remained relatively constant, at about 20-30 per year, for a quarter of a century. As human lifespan increases, the demand for medicines to treat more difficult diseases such as cancer, heart disease, autoimmune disorders and neurodegeneration is likely to cause this meager success rate to decline - which may already be happening, since many big drug firms currently have rather dry pipelines. Such a trend could spell disaster for some of the largest pharmaceutical companies, which have grown so big through mergers that they need historically high returns on investment just to survive. For many of them, only so-called 'blockbuster' drugs - those with projected annual sales in excess of $1 billion a year - are now seen as worth developing.

That would seem to leave much of the field clear to biotechnology, but the enormous cost of taking a drug all the way through Phase III clinical trials means that most small biotech pharmaceutical companies can't manage it without at some point partnering with one of the big firms. Industry experts saw all this coming years ago. In the absence of some transforming technology, it seemed to pose an unsolvable conundrum: how to satisfy an increasing public demand that the wave of exciting biological discoveries from academia and biotech be translated into a vast array of new, cheaper, better medicines, when the cost and time needed to do so was steadily getting worse.

No wonder the genomics revolution was viewed with such hope. Even before the genome of the first free-living organism was sequenced by Fraser, Venter and their associates (Smith et al., Science 1995, 269:538-540), one of the selling points of the human genome project was that it would lead eventually to a new era, the era of pharmacogenomics. The reason so many promising drugs failed so late in the development process - in human trials - it was argued, was that differences in individual human genome sequences led to different profiles of gene expression, especially of isozyme families such as the cytochrome P450 enzymes, which carry out much of the metabolism of foreign substances, like drugs, in the human body. Once these differences could be determined for each patient, it would be possible to predict who would be likely to suffer an adverse reaction to a particular drug. Such people could simply be excluded from clinical trials (and of course from later therapy), and consequently the success rate for drug development would increase markedly.

We've had the human genome sequence for a little while now, and it looks as though we're still some way off being able to exclude from most clinical trials those people who will probably suffer side effects. Toxicity is a complex, often polygenic, process and we need to know more about it in order to link it confidently with genomic information. But two articles that have just appeared this month, in Science (Paez et al., Science 2004, DOI: 10.1126/science.1099314) and the New England Journal of Medicine (Lynch et al., N Engl J Med 2004, DOI: 10.1056/NEJMoa040938), make it clear that the era of pharmacogenomics has nevertheless arrived. If they are any indication, and I think they are, this era will begin not with ruling patients out on the basis of likely toxicity, but rather with ruling them in on the basis of likely efficacy.

Both articles deal with the response of patients with non-small-cell lung cancer (NSCLC), the leading cause of death from cancer worldwide, to a new drug, gefitinib. (Most drugs now have three names: a systematic chemical name, a generic drug name, and a specific product name from the company that first developed them. Thus the non-steroidal anti-inflammatory drug called Advil in the US is Wyeth Pharmaceutical's name for its brand of ibuprofen, which in turn is the generic name for the chemical substance isobutylphenyl propionic acid. Iressa is the product name given to gefitinib by the drug company AstraZeneca.) Gefitinib targeted a molecule that was known to be overexpressed in this cancer, and the drug looked very promising in animal model studies, so it was both surprising and disappointing when it was found in clinical trials that most NSCLC patients had no response to gefitinib at all. Yet a small subset, about 10%, not only responded, but did so spectacularly - a 'Lazarus response', according to one physician, with complete remission even of advanced disease. These patients tended to have certain common characteristics: the majority were nonsmokers and women. Moreover, Japanese patients responded more frequently (about 25%) than did Caucasians. All these data suggested a genetic basis for the efficacy of the drug in such cases.

The authors of both papers started with the same assumption, that the first place to look for allelic variations among patients was the gene for the target. Gefitinib is an inhibitor of the epidermal growth factor receptor protein kinase HER1, or EGFR. It binds to the ATP-binding site in the catalytic domain of the kinase, blocking the enzyme's ability to phosphorylate protein substrates. Both teams of investigators sequenced the EGFR gene from tumor samples of both responders and non-responders to the drug. They found that nearly all the responders had heterozygous mutations in their EGFR gene, while none of the non-responders did. The mutations, which included both short deletions and single amino-acid substitutions, tended to cluster around the ATP-binding site. Moreover, when the receptor gene was sequenced from a cohort of NSCLC patients who had not been treated with gefitinib, similar mutations were found in about 10% of them, exactly the percentage of responders in the clinical trials. One of the studies even found that female nonsmokers and Japanese patients showed a higher than average incidence of the mutations, also correlating perfectly with the clinical data. Taken together, these data strongly suggested that the favorable response to the drug not only correlated with, but was caused by, the mutated EGFR gene.

Heterozygosity of the mutations implied they might produce a gain of function. In vitro studies showed that the mutated receptor was indeed more active than the wild-type, which could account for its relatively high incidence in tumors - presumably it confers some survival or growth advantage. The assumption is that the altered ATP-binding site leads to the increased activity, as well as to increased affinity for gefitinib. Enzymological studies will be needed to establish exactly how this occurs and whether it is the whole story. No-one is concerned by the small number of responders who were not found to have EGFR mutations in their tumors; non-small-cell lung carcinomas, like other solid tumors, are probably polyclonal. Presumably, had a different sample of cells been sequenced, mutations would have been observed.

It now seems clear that, for a subset of NSCLC patients, gefitinib promises to be an effective treatment. Screening people who present with this cancer for EGFR mutations in the kinase domain is a trivial task, and ought to be the first step in deciding what therapy to use. But if this is really the dawning of the age of pharmacogenomics, the gefitinib story can't be an isolated case.

Recent data suggests that it is not. A subset of breast cancer patients overexpress a related receptor, HER2, on the surface of their tumor cells. Many of these patients show a good response to trastuzumab (Herceptin), Genentech's monoclonal antibody drug directed against this receptor. Novartis's drug imatinib (Gleevec), which also binds to the ATP-binding site of its target, the Bcr-Abl protein kinase, has shown considerable effectiveness against chronic myelogenous leukemia, a disease in which this kinase is activated by a chromosomal translocation (producing the so-called Philadelphia chromosome). The Bcr-Abl kinase can transform hematopoietic cells and is essential for tumor progression, explaining the efficacy of the drug for this cancer. Interestingly, imatinib also appears to be effective against a subset of gastrointestinal stromal cancers, and responsive tumors have recently been found to contain mutations in the c-Kit protein kinase (Heinrich et al., J Clin Oncol 2003, 21:4342-4349). The hope is now that for many cancers, at least a percentage will have proteins that are essential for tumor progression, either through overexpression or mutation, and that these proteins will form the basis for targeted therapy.

When the first report came out that gefitinib was effective in only a subset of NSCLC patients, science reporters and stock analysts bemoaned the loss of income that AstraZeneca would suffer. Given the pharmaceutical industry's need for blockbuster drugs, it might indeed seem that pharmacogenomics would be little, if any, help, if all it did was drastically reduce the size of the potential market for a given drug. But let's do the sums. In the US alone, 140,000 people are diagnosed each year with NSCLC (the figure is about a million worldwide). If about 10% of these turn out to have gefitinib-responsive tumors, then the US market is on the order of 10,000. Gefitinib is expected to cost about $3,000 per month per patient, so revenue from sales could reach, theoretically, around $360 million per year. But 10,000 patients per year is the rate of incidence, not prevalence: that many new patients are expected to present with gefitinib-responsive NSCLC each year. And each of them will probably need to take the drug for the rest of their life. So the market for gefitinib should rapidly grow to blockbuster size, even if only the US market is considered. And for any such patients, for some time to come, gefitinib will clearly be the front-line treatment, not one of a host of alternatives as is the case with other forms of cancer. That's a recipe for the kind of profits even the biggest drug company should be happy with.

Pharmacogenomics might turn out to be an even bigger boon to the biotechnology industry. Any biotech company would be thrilled to have a revenue stream of a few hundred million dollars a year: the problem is the cost of getting there. But if clinical trials could be conducted with fewer patients than is now the case, because the likely responders could be identified in advance, and if that also translated into fewer drug failures in late-stage clinical trials, then both the cost and time to gain approval of a new drug could drop substantially, perhaps to the point that even a small company, or a joint venture of several of them, could go it alone. Of course, for that to happen, the problem of adverse reactions would also have to be solved, or at least greatly mitigated. Pharmacogenomics hasn't made an impact on toxicity yet, but give it time. It's only just arrived.

Published: 28 May 2004

Powerless to stop myself

Genome Biology 2004, 5:110

Therapists say that the first step in overcoming an addiction is to admit that one has a problem and needs help. OK, I admit it: I have a problem, and I need help. I really need help. I'm addicted to PowerPoint. PowerPoint, for those of you who have spent the last five years on some other planet, is a computer program for the creation, organization, and presentation of slide shows. Although not the only software for this purpose (Apple, Inc.'s Keynote is among a handful of quite good competitors), PowerPoint - from the same sadists at Microsoft who gave us the maddeningly supercilious word-processing program Word - is the best-known presentation program (there are over 400 million copies in circulation, many of which actually, sort of, work as advertised) and its name, like that of Xerox, has become synonymous with its function, so I shall use it exclusively here.

Most technological change is gradual, but once in a while an invention comes along that is so superior to what was there before that it takes over in an amazingly short time. Compact discs, which replaced records so fast and so completely that most children under the age of ten have never seen a record, are an example of such an all-conquering technology. Much the same thing has occurred with PowerPoint. When the first few brave speakers - undoubtedly descended from pioneer stock - began to use PowerPoint to illustrate their talks, the necessary infrastructure was so rare that many of them had to lug a special projector with them, like explorers toting vital supplies into the uncharted wilderness. I, along with many of my colleagues, observed their struggles with hardware incompatibility and software glitches with the smug superiority of a blacksmith gazing at the wreckage of one of the first automobiles that has just broken down outside his shop.

Some of these problems still occasionally bedevil PowerPoint users (think how much time we've all spent staring at a giant image of someone's desktop as they frantically reboot), but for some reason that didn't seem to matter. In less than two years, the ratio of PowerPoint talks to talks using traditional audiovisual aids had completely reversed, and now, if one wants to give a presentation involving, say, overhead transparencies, it is frequently the overhead projector that must be special-ordered in advance; the PowerPoint computer-connected projector is standard equipment in every lecture hall. Microsoft and other software vendors would have us believe that this transformation is due to the inherent superiority of their method of showing visual aids. They would further claim that our productivity has been greatly increased by its intrinsic greater efficiency.

Rubbish. There is nothing inherently superior about a method that has led to more overcrowded, weirdly-colored, and background-dominated graphics than can be found in a psychedelic music video. PowerPoint, with its plethora of options, has given people with too much imagination and limited artistic common sense a license to break the most fundamental rules of slide design. (Rule number 1: The background should be white. If one insists on having a color other than white for the background, it must be of a uniform hue. Backgrounds that progress, for example, from light at the top of the slide to dark at the bottom of the slide render the text at the bottom of the slide invisible, which is a bad thing. Rule number 2: All text should be a sharply contrasting color, usually black, and when projected should be larger than a bacterium. If several colors are to be used, they should be kept to a minimum, and used to make a point, not to reproduce the effect of a van Gogh painting. Rule number 3: Each slide should make only one point. Not, as I've seen attempted, four or more quite distinct points, none of which could be comprehended because the slide contained more information than the human genome sequence, and was about as much fun to read.)

I'm not the only one who has a problem here. Edward Tufte, the information theorist, has written a blistering critique of PowerPoint and its ilk ("The Cognitive Style of PowerPoint", available online http://www.edwardtufte.com/tufte/powerpoint), concluding that "slideware often reduces the analytical quality of presentations. In particular, the popular PowerPoint templates (ready-made designs) usually weaken verbal and spatial reasoning, and almost always corrupt statistical analysis."

Lest you think that this is merely the ramblings of a few technophobes, or in any case is all relatively harmless, let me point (or should that be PowerPoint?) out that last August, when the Columbia Accident Investigation Board issued its report on why the space shuttle Columbia crashed, one of its conclusions was that NASA had become too reliant on presenting complex information via PowerPoint, instead of by traditional paper reports. Apparently, when NASA engineers presented their assessment of possible damage to the shuttle wing during liftoff, they did so in a PowerPoint slide so crammed with nested bullet points and other complicated formats that it was impossible to comprehend. The board stated that "it is easy to understand how a senior manager might read this PowerPoint slide and not realize that it addresses a life-threatening situation." In another instance, U.S. Secretary of State Colin Powell used a PowerPoint presentation last February when he made his case to the United Nations that Iraq possessed weapons of mass destruction (you can view it online http://www.state.gov/secretary/rm/2003/17300.htm). Right now, he's probably wishing he hadn't.

And as for efficiency, the overabundance of options has made it impossible to realize any productivity gains from the new technology. Brothers, this finally justifies the Luddites: with PowerPoint someone with a machine can accomplish in a week what it used to take a human laborer a day to do. Yet paradoxically it is this very inefficiency that, in my opinion, is responsible for its overwhelming popularity and, I confess, for my own addiction. Because PowerPoint is one of the greatest time-sinks ever invented.

It used to be that one created one's research talk and then didn't change most of it for months, or even years. Not any more - with PowerPoint one can change it constantly - so much so that most of us create a 'new' presentation for every talk we give. (My laptop has a 40 gigabyte hard drive, 39.99 gigabytes of which is taken up with different versions of the same presentation.) Genomics talks are particularly susceptible to such fussing, because the field changes so rapidly that updating can easily be justified. Has this customization led to better talks? Maybe, but much of the time I seem to spend 'improving' a talk actually involves resizing graphics, adjusting contrast levels, trying out different color schemes, and making numerous minor - albeit, of course, brilliant - changes to text. I know that most of this endless tinkering is probably a silly waste of time, but the problem is, it's tremendously satisfying. There's a mindless, Zen-like quality to it. Because it ostensibly involves work, it feels much more virtuous than sitting in front of the television, yet it has the same pacifier-like effect. And because no presentation is ever perfect, the process is endless, so one never has to worry about what to do with oneself when one is finished.

To make matters worse, I'm constantly discovering new things you can do with PowerPoint. I still remember, with the same euphoria that I recall I felt at my first teenage romance, the moment when I discovered the crop tool. I love the crop tool. I love the crop tool so much that it is probably fortunate that most of my PowerPoint work is done in the evening, in the privacy of my own home, or on long airplane trips, because it might be a tad disconcerting for the people in my research group to see their leader, with a wild gleam in his eye, feverishly cropping some borrowed (pirated) illustration exactly right. Last spring I started embedding movies of rotating protein structures into my talks. Each PowerPoint file now has more movies in it than a multiplex cinema, and takes so many megabytes of disc space that it won't fit on one CD. As for artistic quality, well let's just say that in terms of plot and character development, not to mention cinematography, Frederico Fellini and Akira Kurosawa have nothing to worry about. It isn't even clear that these movies add anything to the information content of the talk. But I love making and embedding movies, and I can't stop.

But I want to stop, I really do. I admit I have a problem and I need help. I even know exactly what kind of help I need. I need someone to invent a way of giving presentations that doesn't allow this infinite refinement loop. If each slide were a separate physical object that, once made, could not be altered, then I would have to think carefully about what I wanted to say and how I wanted to say it before producing the slide, instead of constantly experimenting with alternatives. My ability to customize presentations would then be limited to adding and subtracting a few slides, and perhaps rearranging their order. I could take just those physical slides with me instead of schlepping my laptop everywhere, and I would never be at the mercy of computer crashes or hardware/software incompatibility. Of course, there would need to be some device for holding the slides in the chosen order and delivering them, one by one, into the projector. Some sort of cartridge with slots, perhaps - it could even be circular and rotate between slides, like a merry-go-round. I realize that what I'm describing is such a radical and sophisticated concept that it may take years to develop, but I'm hoping that my plight, and the plight of those countless scientists who suffer from the same dependence, will prompt inventors all over the world to get busy. Until they succeed, you can find me at the next meeting of PPA - PowerPoint Anonymous.

Published: 23 June 2004

A drop in the bucket

Genome Biology 2004, 5:112

One hundred and fifty-one billion dollars. That's the cost to the US thus far of the war in Iraq. (I base this figure on the $126.1 billion appropriated to date plus the additional $25 billion requested through the end of the year, which is certain to be approved. Some other estimates of the true cost are higher - as high as $186 billion.) That sounds like a lot of money, but it's less than 10% of the annual federal budget of almost $2 trillion. And compared with the gross domestic product of the US, which is about $11 trillion, it's nothing, really. A drop in the bucket, as we say here.

Still, even though it's not much money, it's instructive to think about what other things could be done with $151 billion - and some people have. It would have paid the salaries of three million new elementary school teachers, for example. It would have fully funded all of the current global anti-hunger efforts for the next five years. It would have provided more than three million students with full four-year scholarships at typical public universities ... and so on. But these aren't really serious ideas - they're mostly proposed for comparison purposes, and to make a social or political point. I much prefer ideas that fix problems completely, or that make a colossal and permanent difference. And it's in the areas of health and science that I think such ideas can be found. Here are a few things we could do with this particular drop in the bucket.

With $151 billion, every child in the world could be given a complete set of basic immunizations. And this could be done every year for the next 40 years. Or, with $151 billion, all world-wide AIDS programs could be fully funded for the next 12 years. This includes the Global Fund to Fight AIDS, Tuberculosis and Malaria, a multilateral initiative created three years ago to mobilize and quickly disburse billions of dollars a year to programs proven to prevent, contain, or treat HIV. The Global Fund is running out of money and may not have enough on hand to fund any new programs until 2007, according to the latest estimates. Activists say that US President Bush, whom they blame for the shortfall, urgently needs to commit significantly more aid to the Fund - at least US$1.2 billion next year, compared to the mere $200 million he has requested from Congress. The $151 billion would, of course, take care of that for the next 100 years if it were devoted solely to that Fund. Bush, it should be added, promised to put two million people on life-saving drugs when he launched the PEPFAR (President's Emergency Plan for AIDS Relief) program. This program has so far provided treatment to only roughly 20,000 people in the 14 African and Caribbean countries that are eligible to benefit from it, according to estimates from the Global AIDS Alliance. The Global Fund, on the other hand, is currently treating at least that many in Rwanda alone. The president had pledged $15 billion over 5 years to keep his promise - less than 10% of the cost of the war in Iraq thus far. Fully funding all AIDS programs for the next 12 years would go a long way towards bringing the disease under control in the developing world.

With $151 billion, 10 foundations could be set up, each with roughly the same endowment as the Howard Hughes Medical Institute. If each foundation were required by law to spend 5% of its endowment every year, as is the case with tax-exempt foundations in the US currently, a total of $7.5 billion per year would be spent on whatever their missions happened to be. And since each foundation would be endowed by the initial expenditure, the government - and its taxpayers - would never have to spend another penny on any of them. Imagine the impact even one such foundation could have on the arts or humanities. And I like the notion of having one of them spend its $750 million a year endowing 250 new professorships in the life sciences at research universities across the US. Every year. Forever.

With $151 billion, we could build, equip and fully staff 500 new genomics centers, and provide an endowment to support their operating expenses and infrastructure maintenance. That's roughly one such center at every major college and university in the country. With $151 billion, we could set up 10 new universities, each with a $10 billion endowment (approximately equal to that of Princeton University), and provide them at the same time with $5 billion to buy land, construct buildings and hire faculty. I'd like at least one of them to focus on biomedical engineering; I don't particularly care what the others do, but law schools and business schools should be forbidden. With $151 billion, we could fund a $20 billion research program over the next 10 years aimed at bringing the cost of sequencing a human genome down to $1,000 or less. During this time, the remaining $131 billion would be invested and, assuming a reasonable rate of return, at the end of the program there would be enough money left to pay for sequencing the genome of every man, woman and child in the US.

With $151 billion, we could invite the ten largest pharmaceutical companies plus the three largest biotech companies into a room and say to them, "OK, we know it costs you $1 billion over 12 years to develop a drug, and that it isn't worth your while to invest that kind of money in treatments for third world diseases, which don't provide enough return to even make your investment back. So here's what we're going to do. The five biggest health problems in the third world are AIDS, tuberculosis, malaria, sleeping sickness and rotavirus. We'll help each of you select one of them, based on your expertise and interest. No more than two of you can work on the same one. We will give you $1.1 billion each over the next twelve years for you to work on the disease you've selected, which includes money to hire new people so you don't have to stop working on the things you're doing now. If, at the end of that time, you have produced an approved drug or vaccine to treat this disease, we will pay you an additional $10 billion in guaranteed profits so that you can make the treatment available at or below cost to the people who need it. At most, this will cost a total of $111 billion. The remaining $40 billion will be spent in a similar way, but the target will be multi-drug resistant Staphylococcus aureus and Streptococcus pneumoniae, the burden of which affects all nations, including our own. In this program, you will be guaranteed a very large profit if you succeed, and there will be absolutely no cost to you for trying. Who wants to be first?"

I guess some of these ideas may be unrealistic, but at least a few of them seem to me to be well worth doing. Yet if we were to propose any of them to the government, I suspect the immediate reaction would be, "That costs way too much. There isn't nearly enough money for that." Maybe the government's right. I do realize that times are hard. But still. Somehow there always seems to be enough money for another war.

Published: 22 July 2004

Fame is a bubble, but not for some

Genome Biology 2004, 5:114

The death of Francis Crick, who succumbed to colon cancer on 28 July at the age of 88, does more than mark the end of one of the most distinguished, and influential, scientific careers of the last century. It also helps mark the end of an era: the remarkable era when biology was transformed from a descriptive, largely organism-based science into a molecular one. Now we are living through another period of transformation, as genomics allied with molecular biology changes the subject into one that is more quantitative, more dependent on computational and engineering tools - and, perhaps, one that once again will put the whole organism, rather than just its parts, at the center of its world. It's rather a pity that Crick won't be around to see that through, because even if he didn't participate in it directly, he certainly would have had some pithy things to say about it.

Crick came to biology late - he started out in physics but fled that field after World War II, as did many other bright young physicists, perhaps in search of something more life-affirming. Whatever the motivations, the trend resulted in an influx of quantitative reductionists who were expert in doing very precise experiments, and they arrived at exactly the moment that biology was ripe for change. By the early 1950s, scientists had identified the major components, in molecular terms, of the cellular machinery and were just starting to develop and use sophisticated chemical and physical techniques that could reveal their structures and functions. Cambridge, England, was a Mecca for such people: in less than 20 years, Kendrew and his associates would use X-ray crystallography to produce the first atomic resolution structure of a protein molecule; Ingram and Perutz would characterize hemoglobin structurally and define the first molecular disease (the sickle-cell trait); Kendrew's collaborator Phillips would determine the first structure of an enzyme and propose a detailed explanation for its catalytic power; DeRosier, Caspar and Klug would lay the foundations for electron microscopy as a tool for structural biology and use it to unravel the structural principles of viruses; the molecular mechanism of muscle contraction would be proposed by Huxley; pioneering work on the antibody molecule by Porter would lead eventually to Millstein's development of monoclonal technology. And, of course, the structure of the genetic material would be determined.

It's interesting to speculate on what would have happened to Francis Crick had he not fallen in with a brash American postdoc (do the British think there is any other kind?) named James Watson and been introduced by him to the problem of finding the structure of DNA. At the time, Crick was a graduate student in his mid-30's, trying to deduce the structure of the protein hemoglobin by examining the autocorrelation function of its diffracted X-ray intensities (in projection, no less), a thesis project that seems in hindsight little short of lunacy. Ironically, he was to earn his PhD for this unsuccessful effort, not for the double-helical structure of DNA, which was only a side project and one that was not always sanctioned by his superiors.

By now, the story of how he and Watson (using fiber diffraction data 'borrowed' from the immensely talented crystallographer Rosalind Franklin without either her permission or her knowledge) deduced that the DNA molecule formed a self-complementary double helix has almost passed into the category of folklore, so there is no need to review it here. Ten years later, Watson and Crick were Nobel laureates, and Watson (after some very pretty work on viruses and an outstanding teaching career at Harvard) was on his way to becoming a full-time science administrator whose accomplishments included being one of the instigators of the effort to sequence the human genome. Crick, who eschewed administration as though it were a terminal disease (it often is), had by that time become the world leader in figuring out the implications of the DNA structure and, abetted by Cambridge colleagues like Sydney Brenner, had done much to chart the course of the fledgling field of molecular biology.

Brilliant, acerbic, not given to suffer much of anybody gladly, let alone fools, Francis Crick had enormous influence that was not due to his having trained anyone but rather to his style (he made proposing detailed models for biological systems respectable) and high scientific standards. I suspect the desire on the part of his colleagues to uphold those standards had a lot to do with the exceptionally high quality of the research that flowed out of so many of the young scientists who flocked to the field he largely created. In the last few decades of his life his interests veered off into neurobiology, including such seemingly philosophical topics as the nature of human consciousness. My neurobiologist friends differ in their assessments of the quality and value of this work. From what I can make of it, I'd be surprised if it lived up to his earlier contributions. But then, if anyone in science ever deserved a free pass, it certainly would be Francis Crick.

Which brings me to the main point of this essay. I hadn't meant for it to be an obituary because, to be frank, his monumental accomplishments weren't the first thing I thought of when I heard the news of his death. My immediate reaction was that he was one of the few scientists in my lifetime who had managed to beat the "what-have-you-done-for-me-lately" syndrome that consigns so many senior investigators to the dustbin of history. Winning a Nobel Prize helps, to be sure, but how many of you who are chemists or studied chemistry have ever heard of W.F. Giauque, who won that very prize for liquefying helium? My guess is that at least half of the Nobel laureates are not recognizable names to a majority even of scientists in the same broad field. Immortality, it seems, can be pretty fleeting.

But not for a few, and Crick clearly was one of those. It helped that he was part of a revolution: paradigm shifts have a way of conferring name recognition that lasts a while. Regular readers of this column will know that I believe we are in the midst of another revolution: genomics is moving biology to a new era of data-mining, where the organism once again may take center stage. But this is a different sort of revolution, one that is currently driven more by advances in technology than by advances in understanding. We're generating a lot of data, but the unifying hypotheses and ground-breaking conclusions that must eventually spring from these data are pretty scarce at the moment. It's not clear that such times are as conducive to the anointing of larger-than-life figures.

One could argue, I suppose, that it takes a little historical perspective to recognize a special scientific generation, but I'm not convinced of that. People like Crick knew they were special, acted like they were special, and expected others to share that opinion, in part because the cosmic importance of their results was quickly apparent. A few of the fathers of the genomics revolution have those personality traits, but it remains to be seen whether their contributions will come to be associated with their names in the way the double helix will forever be linked with the names of Watson and Crick (so much so that in genome sequences the two strands are named after them).

Most of us, even the best of us, make our contributions, perhaps even win some prizes, and then our names are forgotten as a new generation or two comes along. The young have little respect for, or knowledge of, the history of their field. They take our contributions for granted, and they should. Their focus is not on our past, it's on their present and future, their ideas, their problems. The Francis Cricks of the world are pretty rare - not because smart, talented people are that rare but because few are fortunate enough to make a discovery that, quite literally, changes the world. He did, and for that reason he would be on most people's list of the five most important biologists since Darwin and Wallace. The rest of us live out our working lives in a scientific culture that only values us for what we've done lately, not for what we once did. That's the worst, and best, thing about it.

Published: 24 August 2004

Twilight of a hero

Genome Biology 2004, 5:116

At the height of his fame, he could walk past a monastery in Tibet and Buddhist monks would look up from their prayer wheels, point their bony fingers, and shout out his name. He has always been one of my heroes, not for what he did in the boxing ring (though that was magical, almost more ballet than prizefighting, at least in his early years), but for what he said and did outside of it. In the late 1960s, when, like a lot of other young men, I was trying to prove to people, including myself, that being against the Vietnam War didn't necessarily mean that you were a coward, he went to jail for refusing to be drafted into what he considered an unjust war ("No Vietcong," he said memorably, "ever called me a nigger."). With that gesture, the problem was solved. No one could ever accuse Mohammed Ali of being a coward.

Now he is a shaking, slurred-speaking shadow of that quickwitted, loud-mouthed, powerful, graceful young man. Parkinson's Disease has done what no single opponent, not even the United States government, could do: it has taken away the essence of the man and left us with a shadow -externally, for the real cruelty of Parkinson's is that its victims are usually fine mentally. They know exactly what is happening to them, they simply can no longer control their bodies because the dopaminergic neurons in the substantia nigra of their midbrain, the region that generates smooth movement, are dying.

Mohammed Ali's Parkinson's Disease was brought on by inflammation caused by years of repeated trauma to the brain from his chosen profession. It will kill him eventually, as it does most sufferers unless they die of something else first. Over a period of about twenty years, the afflicted slowly lose all voluntary mobility, becoming prisoners inside their bodies, until at last, unable to even swallow, they succumb to pneumonia or some other proximate cause of death. Parkinson's is an ancient disease, and it is likely that some of the fables of people turning to stone (the Medusa's lethal gaze in Greek mythology; the petrification of trolls in Scandinavian legends - virtually every country has such stories) represent attempts by primitive people to explain something that must have seemed an incomprehensible horror.

The same fate awaits the actor Michael J. Fox, whose Parkinson's Disease is probably the result of some genetic flaw, given that its age of onset was so early. It also awaits Pope John Paul II, whose Parkinson's appeared in old age, as it most often does. The disease affects around 1% of those over 65; their condition is referred to as idiopathic or 'sporadic' Parkinson's, since no single cause, genetic or otherwise, has been identified. (Like a lot of other 'sporadic' disorders, including Type I Diabetes, Alzheimer's Disease (the non-familial form) and schizophrenia, Parkinson's Disease is probably polygenic, with multiple contributing factors that dispose towards getting it, combined perhaps with environmental factors.) That fate also awaits the close to 1 million Americans and millions worldwide who currently suffer from this affliction.

And if US President George W. Bush and others in his administration have their way, that fate is certain. Currently there is no effective treatment for Parkinson's Disease; dopamine replacement is palliative only and loses its effectiveness over time. Despite some new therapies that seem to help ease the disease's debilitating symptoms in some patients, nothing can either replace the faulty nerve cells that cause the disease or stop Parkinson's from progressing. Medical care for those afflicted with Parkinson's, combined with their loss of productivity, cost US$ 5.6 billion a year in the US alone, and right now there is only one real hope for these sufferers. That hope is embryonic stem (ES) cell therapy, which depends on research that the Bush administration is doing its best to strangle.

They will tell you otherwise, but they're not telling the truth. In a recent speech, Laura Bush, the President's wife, claimed that Bush is the only president to authorize federal funding for (ES) cell research. That is true, but no other president ever had the opportunity before. She went on to claim that this authorization has led to $25 million in federal grants last year. Also true, but misleading: $25 million is an insignificant sum for such work, and the reason the amount is so small is that Bush has hamstrung those trying to do the research with untenable restrictions. In an address to the nation in July of 2001, Bush prohibited the use of federal funds to create new lines of ES cells or to carry out research using lines so created. He stated that federal funds could be used to work with any of the 78 lines of ES cells then in existence, but this was disingenuous for several reasons. First, only about 20 of these lines were thought suitable for most studies - as has proven to be the case. Second, none of these lines were genetically matched to any patient, the most important direction of research for disease treatment, and under the Bush guidelines no patient-matched lines could be created with government support and no federally funded research could be done with them regardless of where they came from. These restrictions have had two consequences: to drive some stem cell researchers out of the US to Europe (especially Great Britain) or Australia, where policies are more enlightened, and to force US-based scientists to try to find private support (from industry or foundations, such as the Howard Hughes Medical Institutes). And the whole notion that the Bush administration has been supportive of ES-cell research within limits is also disingenuous, because it is very clear that the ultimate objective is to ban it completely, regardless of the source of funds. The US House of Representatives passed just such an administration-supported ban last year, but the Senate defeated it. If the Republicans hold onto their majority in the upcoming elections this November, a ban is certain to be brought up again.

Moreover, the Bush administration is trying to export its policy to the rest of the world. On Monday 8 December 2003, the United Nations General Assembly almost voted to ban all forms of human cloning, both reproductive and therapeutic (ES cell research is sometimes referred to, inappropriately and foolishly in my view, as therapeutic human cloning). In the end, it was decided to delay action to allow more deliberation. Sometime this fall the matter will probably be reconsidered. The United States is a prime sponsor of the resolution, along with - here's an example of strange bedfellows if ever there was one - a group of fundamentalist Muslim countries.

What is so controversial about a technology that has the potential to help people who suffer from incurable conditions such as Parkinson's and Alzheimer's Diseases, spinal injuries, and Type I (juvenile onset) Diabetes, all of which are characterized by the loss of particular types of cells and therefore can only really be cured by the generation of replacement cells? The crux of the matter lies in the way in which new lines of ES cells are created, a process most properly called somatic cell nuclear transfer (SCNT). In this procedure, the nucleus of an unfertilized egg is removed and replaced with, for example, the nucleus of a patient's own cells (including skin, heart and nerve cells), which are called somatic cells. When the resulting egg has divided into a small number of stem cells, which have not yet differentiated but are capable of doing so, these cells can be harvested for research or for disease treatment. The goal of SCNT is to develop stem cells that will not be rejected or destroyed by the patient's immune system and that can differentiate into any desired cells, such as neurons of the substantia nigra, or pancreatic islet cells. Somatic cell nuclear transfer could thus, in principle, allow patients to be cured using their own DNA. To call it a form of human cloning demonizes it by associating it with cloning for reproductive purposes, and ignores the fact that SCNT produces only stem cells, never babies. No sperm is used in SCNT and the cells are not transplanted into any womb. But religious conservatives object to the procedure because it involves the formation and subsequent destruction of a very early stage embryo (or, at least, destruction in the case of harvesting ES cells from existing embryos obtained from fertility clinics. Such ES cells would not be genetically matched to any person, but are still very useful; nearly all existing lines of ES cells have been obtained this way. Genetically matched ES cell lines are necessary to treat or model diseases, but their creation is a new development.)

I have a great deal of respect for those who are against this research for sincerely held, consistent moral beliefs, although I disagree with them. But I'm not sure the Bush administration fits that description. There is much in the administration's words and actions to suggest that this issue is actually a stalking-horse for something else: an attempt to ban all forms of pregnancy termination (abortion), even in cases of rape and incest. And I have a problem with the inconsistency of claiming to be pro-life by favoring embryos whose status as 'living' is open to debate while condemning people who are unequivocally alive to certain death. That stance also ignores the suffering of their friends and families (to get a sense of what they go through, I recommend 'Saving Milly', by Morton Kondracke, published by Balantine Books: New York; 2001; if after reading it you can still argue that a collection of undifferentiated cells should take precedence over human beings like those in this book, then nothing I can say is likely to change your mind).

To be fair, scientists haven't helped themselves much in this debate. Like gene therapy and the war on cancer and the human genome project, stem-cell research has been oversold by some, especially for Alzheimer's Disease where its applications are tenuous and very far away. Replacement of cognitive neurons, with their complex web of synapses, is likely to be extremely difficult. Nor will it replace the lost memories that are a large part of the burden of the disease - for we are our memories, they create the shape of our life. But for Type II diabetes, spinal cord injuries, Parkinson's Disease and other motor neuron diseases, it really does represent, in my opinion, the most promising line of research at the moment.

Ron Reagan, the son of the late President Ronald Reagan, understands that well. At the Democratic National Convention in Boston at the end of July, he spoke with passion and eloquence about the importance of embryonic stem-cell research. The whole speech is worth reading (you can find a transcript online at http://politicalgateway.com/news/read.html?id=535); here are some parts of it: "There are those who would stand in the way of this remarkable future, who would deny the federal funding so crucial to basic research. They argue that interfering with the development of even the earliest stage embryo, even one that will never be implanted in a womb and will never develop into an actual fetus, is tantamount to murder. A few of these folks, needless to say, are just grinding a political axe and they should be ashamed of themselves. But many are well-meaning and sincere. Their belief is just that, an article of faith, and they are entitled to it. But it does not follow that the theology of a few should be allowed to forestall the health and well-being of the many. And how can we affirm life if we abandon those whose own lives are so desperately at risk? It is a hallmark of human intelligence that we are able to make distinctions. Yes, these cells could theoretically have the potential, under very different circumstances, to develop into human beings -that potential is where their magic lies. But they are not, in and of themselves, human beings. They have no fingers and toes, no brain or spinal cord. They have no thoughts, no fears. They feel no pain. Surely we can distinguish between these undifferentiated cells multiplying in a tissue culture and a living, breathing person - a parent, a spouse, a child...

"What might we tell... the millions of others who suffer? That when given an opportunity to help, we turned away? That facing political opposition, we lost our nerve? That even though we knew better, we did nothing? And, should we fail, how will we feel if, a few years from now, a more enlightened generation should fulfill the promise of embryonic stem cell therapy? Imagine what they would say of us who lacked the will... The tide of history is with us. Like all generations who have come before ours, we are motivated by a thirst for knowledge and compelled to see others in need as fellow angels on an often difficult path, deserving of our compassion... We have a chance to take a giant stride forward for the good of all humanity. We can choose between the future and the past, between reason and ignorance, between true compassion and mere ideology. This is our moment, and we must not falter."

I hope our leaders will find the wisdom to heed his call. Even if they do, any cure for Parkinson's Disease will certainly come too late to save Mohammed Ali. But if his suffering moves even a few to the compassion needed to support the best hope for those like him, then his torment will have meant something. The death of a hero should have some meaning.

Published: 28 September 2004

The emperor's new shibboleth

Genome Biology 2004, 5:118

I didn't pay much attention to it at first. It was an item in the morning paper saying that Jacques Derrida, the Algerian-born philosopher, had died of cancer at the age of 74 in a Paris hospital on 8 October. Then I remembered. Derrida, the inventor of what is called 'deconstruction theory', was partly responsible for my being a scientist. Before I explain, let me respond that yes, I know that means he has a lot to answer for. But I'm half serious. I was a literature major in college in the 1960s, when Derrida's new theory swept through the world of the humanities like a rampaging elephant. In essence, deconstruction theory posits that every word in a text has hidden layers of meaning that have been accrued through centuries of historical and cultural processes. The writer is typically unaware of these layers but they can be uncovered by the expert: this is the process of 'deconstructing' the text. Derrida and his followers often argued that these hidden meanings were much more important than the ones that the author intended to convey.

As I said, it was clear at the time that this theory, and others that developed from it, represented the future of the humanities, especially comparative literature, and that was something of a problem for me, because I thought the theory was a load of crud. This was only partly due to the fact that I couldn't understand practically anything that Derrida, or his followers, wrote. It was then that I decided that I might have to consider other career options. It has now become almost impossible for me - and, I think, for nearly anyone other than a handful of cognoscenti - to read a serious book or paper in comparative literature, social criticism, and a number of other branches of the humanities without developing a splitting headache and learning little or nothing. Physics was partly to blame for this. Non-sciences like to cloak themselves in the mantle of theory, and quantum mechanics, with its strange, almost mystical language, not to mention relativity, resonates with many concepts in literature and the social sciences. Unfortunately, this makes it easy for some to invent pseudo-scientific babble that gives their ideas an illusion of greater depth. And for reasons that I don't really understand, this fashion took hold in much of academia right through the 1990s.

For an example of what I'm talking about, try this one, from the cultural theorist Homi Bhabha in "The Location of Culture" (London, New York: Routledge; 1994): "If, for a while, the ruse of desire is calculable for the uses of discipline, soon the repetition of guilt, justification, pseudo-scientific theories, superstition, spurious authorities and classification can be seen as a desperate effort to 'normalize' normally the disturbance of a discourse of splitting that violates the rational enlightened claims of its enunciatory modality."

To which I say, "Obviously".

Reading this drivel, it is tempting to conclude that, if the emperor isn't naked, he's at least walking around in his skivvies. The humanities once had a great advantage over the sciences. They were largely a jargon-free zone. Jargon - not to be confused with slang - is specialist technical terminology used by those who work in a particular profession. The word was once neutral but it has come to have pejorative connotations, chiefly because a prime function of jargon nowadays is to create a sense of exclusivity and self-importance. I think that makes it dangerous. And regrettably, the jargon that has polluted the humanities is very much like the jargon that dominates the world of information technology, or the world of physics, or the world of genomics. They all serve as shibboleths.

The Hebrew word shibboleth literally means 'torrent of water'. In the Bible, the word was used to distinguish the Ephraimites, whose dialect lacked a 'sh' sound (they used an 's' in its place), from the Gileadites, whose dialect included such a sound. "And the Gileadites seized the passages of the Jordan before the Ephraimites; and it was so, that when those Ephraimites who had escaped said, "Let me go over," that the men of Gilead said unto him, "Art thou an Ephraimite?" If he said, "Nay," then said they unto him, "Say now 'Shibboleth.'" And he said "Sibboleth," for he could not frame to pronounce it right. Then they took him and slew him at the passages of the Jordan; and there fell at that time of the Ephraimites forty and two thousand."

(Judges 12:5-6, King James Version of the Bible).

(See, I told you jargon could be dangerous.) In modern parlance, the term shibboleth is used for any word or expression that serves to distinguish one group from another, or to identify someone as a member of a group. Words or phrases that form part of the specialized jargon of a group are shibboleths because they reveal their users to be members of that group. But shibboleths do more than that. They also keep others out.

It was never easy for non-scientists to read scientific papers, and that's a pity, but as jargon has proliferated it's becoming difficult, and sometimes impossible, for even scientists to read outside their own areas. In an era when genomics needs people who can assimilate data and concepts from a wide range of fields, jargon locks us into narrow specialties. What are physical chemists or computer scientists or biochemists to make of clades and paralogs and LOD scores and all the other shorthand we use?

So here's a simple solution, prompted by my memory of sociology, history and literature before Derrida. I think that all papers published in the life sciences, and especially in genomics, should be required to have their abstracts written in non-specialist prose, using terms that can be understood by anyone with a basic knowledge of modern biology. To illustrate my point, and to show that I'm casting stones at jargon-users without being free of sin myself, here's an abstract from one of my own recent papers, first as it was originally published:

Xylose isomerase (E.C. 5.3.1.5) catalyzes the interconversion of aldose and ketose sugars and has an absolute requirement for two divalent cations at its active site to drive the hydride transfer rates of sugar isomerization. Evidence suggests some degree of metal movement at the second metal site, although how this movement may affect catalysis is unknown. The 0.95 Å resolution structure of the xylitol-inhibited enzyme presented here suggests three alternative positions for the second metal ion, only one of which appears positioned in a catalytically competent manner. To complete the reaction, an active site hydroxyl species appears appropriately positioned for hydrogen transfer, as evidenced by precise bonding distances. Conversely, the 0.98 Å resolution structure of the enzyme with glucose bound in the alpha-pyranose state only shows one of the metal ion conformations at the second metal ion binding site, suggesting that the linear form of the sugar is required to promote the second and third metal ion conformations. The two structures suggest a strong degree of conformational flexibility at the active site, which seems required for catalysis and may explain the poor rate of turnover for this enzyme. Further, the pyranose structure implies that His53 may act as the initial acid responsible for ring opening of the sugar to the aldose form, an observation that has been difficult to establish in previous studies. The glucose ring also appears to display significant segmented disorder in a manner suggestive of ring opening, perhaps lending insight into means of enzyme destabilization of the ground state to promote catalysis. On the basis of these results, we propose a modified version of the bridged bimetallic mechanism for hydride transfer in the case of Streptomyces olivochromogenes xylose isomerase.

And here it is shorn, I hope, of most of its jargon: There is a protein called xylose isomerase that is important industrially because it's used to make high-fructose corn syrup, which is the sweetener in almost everything these days. This protein takes a molecule of the sugar glucose and converts it to a molecule of fructose, which is sweeter. Exactly how the protein does this is not well understood. We know that the protein uses two atoms of magnesium to help it function, and we also know that the first step in what it does is to bind glucose to these metal atoms. Glucose is a ring-shaped molecule but somehow the protein opens the ring up and converts glucose to a linear form before converting it to fructose. We have used X-rays to look at the structure of this protein with something that resembles glucose bound, in both the ring form and the linear forms. With the help of X-rays we can see every atom in the protein and the bound sugar, and from this we have gotten new information about how this protein works. We believe that the protein puts strain on the ring form of glucose, which makes it easier to open up the ring. We also believe that a particular chemical group in the protein, called His53, actually opens up the ring by acting like a solution of a weak acid. Finally, we also believe that during the transformation of glucose into fructose one of the two metal ions moves around a lot, and that this movement helps carry out the chemistry.

That didn't take me any longer to write than the original abstract, it came out shorter, and it was a lot more fun to compose. I bet it's also a lot more fun to read. I don't think we can dispense with jargon altogether - it really does serve as a useful shorthand, so the body of the paper will probably need it. But a jargonless abstract would provide a very nice test for the quality of a piece of work, as well as a built-in detector of deliberate obscurity. If an idea or result can't be conveyed in plain language, how important can it really be? Who knows, maybe even the humanities could give my idea a try.

Published: 29 October 2004

Color blind

Genome Biology 2004, 5:119

By the time you read this, the result of the 2004 US Presidential election will be known - assuming, of course, that there isn't a repeat of the travesty of 2000, when the Supreme Court of the United States, by a vote that split along the lines of which political party had appointed which particular judge, awarded the election to George W. Bush by the slimmest of margins (less than 1,000 votes) in the state of which his brother was governor. Contested ballots notwithstanding, I never cease to be amazed when I cast my vote on election day. After the cacophony of the seemingly endless campaign, on election day a curious quiet descends on the country. No bands play. No troops march. People waiting in line to vote tend to speak in hushed tones, almost as though they were in church. I didn't see a single cell phone in use. The transfer of power in what is arguably the most powerful nation in the history of the world happens softly, like a whisper in the dark. That's the wonder of democracy.

Contrary to what many Americans think, democracy wasn't invented here. It has a long history, going back at least to ancient Greece. And, especially if we have another disputed election this time, I would have trouble arguing that it was perfected here either. But if not the practice of democracy, I think the concept of democracy may have reached its zenith on these shores, in the city of Philadelphia, in the month of June, in the year 1776. At that time and place, Thomas Jefferson composed these words for the document in which the thirteen former British colonies declared their independence: "all men are created equal". As a weapon in a war, which it was, that phrase was powerful. It was meant to convince and to confound, and it did both. Then it developed a life of its own, and began to reverberate around the world like the sound of an exploding volcano. It echoed in the French Revolution thirteen years later. It could be heard in 1848, the year of revolutions in Europe. It was still echoing more than a hundred years later when India broke from Britain. It can still be heard today, as loud and potent as ever. Not bad for an idea that is biological nonsense.

Basketball star Michael Jordan could jump through the roof of a building; I never could. Footballer David Beckham can bend a corner kick around a goalpost; I can barely kick a soccer ball straight. I can't run a marathon in under three hours and I never would be able to no matter how hard and long I trained. Neither could most people, nor do they expect to. Implicit in the meritocracy of sport is the idea that, although practice and coaching are important, there are vast differences in talent among individuals. Such limitations are understood in other areas as well: most people cannot do high-level mathematics and probably never could no matter how long they studied. I took piano lessons for five years, but Horowitz is a pianist; I'm not, and never will be. We all know these things, and accept them. But taken literally, "all men are created equal" could imply that such facts aren't true. Of course, the phrase was never meant to refer to physical abilities, or talent for music or abstract reasoning. It meant that all men (alas, the Founding Fathers probably really did mean only men - there were no Founding Mothers to set them straight) should be equal in the eyes of the law, and the government. Since I live in a country where the wealthy and influential often receive preferential treatment by both, I understand that this is an ideal not always achieved in practice.

But the extreme interpretation is always there, in any democracy. It's responsible for the contempt of 'the elite' or 'intellectuals' that one hears, especially around election time. It underlies our iconoclastic tendencies. Somewhere, in some inner place that is hard to reach, a lot of us harbor the secret belief that we're just as good as anybody, in just about everything. Maybe this delusion is harmless, but I doubt it. I think it contributes to the streak of anti-intellectualism that has a foothold in Western culture right now. I think it also makes it easier for populists and demagogues to coax people into voting against their self-interests. But even if I'm wrong about these consequences, there is one area in which the notion of absolute equality is certainly dangerous: the area of medicine.

This month, a report appeared in The New England Journal of Medicine (351:2049-2055; issue of 11 November 2004) entitled "Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure". The article was written by Anne L. Taylor MD, Susan Ziesche RN, and a number of other authors, on behalf of the African-American Heart Failure Trial Investigators. The paper presents the results of a study of 1,050 black patients with advanced heart failure. Half received a placebo, while the other half received BiDil, a combination of two generic drugs (isosorbide dinitrate, which stimulates the production of nitric oxide, and hydralazine, an antioxidant and vasodilator that appears to prevent the nitric oxide from deactivating). The results were so striking that the study was terminated prematurely so that all remaining patients could be given BiDil. Over the two years of the study, 6.2% of the patients given the drug died, compared with 10.2% of those given the standard treatment, a 43% improvement. First hospitalizations were also reduced by 33%. Ray Gibbons, a cardiologist at the Mayo Clinic and spokesman for the American Heart Association, says "When you have this level of risk reduction in a high-stakes disease like heart failure, it's at least a home run." The study was initiated by NitroMed, Inc., a biotechnology company in Lexington, Massachusetts. Combined use of the two generic drugs would allow NitroMed to receive a new patent for the joint formulation. An earlier trial of the mixture, by Dr Jay Cohn of the University of Minnesota in the 1980s, had been disappointing: in a test against the general population, the drugs fared worse than angiotensin converting enzyme (ACE) inhibitors. But Dr Cohn reanalyzed the data when it became clear years later that one reason African-Americans die from heart failure at 2.5 times the rate of Caucasians was because ACE inhibitors appear to be much less effective in black patients than in non-blacks. Sure enough, in the 395 black patients in the original study, the drug combination appeared better than the standard therapy. The new trial, exclusively in African-Americans, was begun as a consequence.

So why isn't everybody cheering? Many are, including the Association of Black Cardiologists, who cosponsored the trial. But others are not. In a perspective in the same issue of The New England Journal of Medicine, Dr M Gregg Bloche of Georgetown University Law Center asks, "Are we moving into a new era of race-based therapeutics?" He believes the answer is yes, especially since the US Food and Drug Administration has already indicated that if the drug is approved, it will be labeled as indicated for patients of African-American descent, an unprecedented situation. (Although at least 29 drugs are known to have different efficacies between blacks and Caucasians, none of them is labeled in this way.) JudyAnn Bigby, director of the Office for Women, Family and Community Programs at Brigham and Women's Hospital in Boston, fears that "if people get one little inkling that there's a biological basis to race, we could potentially lose ground in understanding racial differences in disease. Biology could be an excuse for not looking at the social basis" of diseases like heart disease, which is known to be affected by stress, income, diet and access to health care, among other non-genetic factors. "You have the federal government giving its imprimatur, its stamp of approval, to using race as a biological category," warns Jonathan Kahn, of Hamline University, who wrote a paper in the Yale Journal of Health Policy, Law, and Ethics on the danger of approving BiDil. "To my mind, it's the road to hell being paved with good intentions."

This concern is understandable given the sorry history of the US when it comes to matters of race. Yet we have known for half a century that sickle-cell anemia is overwhelmingly a disease of blacks, that Tay-Sachs Disease is overwhelmingly a disease of Ashkenazi Jews, and that cystic fibrosis is overwhelmingly a disease of Caucasians. Somehow that knowledge has not set us on the road to hell. Why not? I think that main reason is that 'race' in these diseases is only a surrogate marker: in each case the specific genetic abnormality is known. Blacks do not suffer disproportionally from sickle-cell anemia because they are genetically inferior to whites, they suffer from it because the sickle cell mutation is more commonly found in people of African origin, and because the presence of the mutation in such individuals appears to confer protection against infection by the malaria parasite. But there are 'non-blacks' who have the same mutation and suffer from the same disease. Race isn't the issue; the issue is who has the relevant genetic trait. Once the affected gene is known, anybody can be tested for the disease-causing mutation. Race becomes irrelevant.

BiDil works in African-Americans because there is some gene - possibly more than one, but probably no more than a few - that differs between most people of African-American descent and those of, say, Indo-European descent. The tools of genomics can be used to find that gene or genes, and when that is done it will be possible to test everyone who suffers from heart failure for the mutations that confer susceptibility to BiDil therapy. When that happens, it will certainly become clear that many non-blacks would also benefit from BiDil. Since this would increase the market for the drug considerably above, say, the 375,000 African-Americans who suffer from moderate to severe heart failure, it would be in the interest of NitroMed to support the search for those genetic differences. Then the drug could be labeled the right way: according to its molecular targets, not the color of the patient's skin.

Last spring, The Magic Theater in San Francisco presented a play by Cassandra Medley entitled 'Relativity'. It concerns an African-American woman scientist who is asked by her mother to disprove that all racial groups are genetically similar (you can read a synopsis of it in Sandra Soo-Jin Lee's thoughtful review in PloS Biology 2004, 2:1263-1264). The play raises the question: does identifying genetic differences between groups itself constitute an act of racism? Obviously I don't think so, but I do realize that any statement of differences between races can never be neutral. That is why we must shift the discussion away from color and towards those things that make us different as individuals, not as members of some group.

Genomic data indicate that all humans share about 99.9% of our genetic make-up. As more data accumulate and it becomes clear that the concept of race is meaningless biologically, we should be able to agree that all 'men' are almost equal biologically, and to shift our focus once and for all to those genetic differences that are meaningful, such as those that determine our susceptibility to disease and our responses - beneficial and adverse - to therapy. One of the great future benefits of the Human Genome Project may be that, in years to come, when someone is described as being a credit to their race, it will be understood by everyone that what is meant is the human race.

Published: 26 November 2004

Identity crisis

Genome Biology 2004, 6:102

Regular readers of this column (both of you know who you are) will have noticed that my feelings about the holiday season are a bit ambivalent, to say the least. Of course, on the one hand there is the abundance of delicious food, the constant good cheer, the visits from friends and relatives. Then on the other hand there's the good stuff. But one of my major problems with the holidays is that with holidays come holiday parties. And with holiday parties comes the problem of sustaining a conversation with people one doesn't know. Now, I consider myself a pretty good conversationalist, but I have never found a satisfactory solution to the situation that inevitably develops a few minutes into any such encounter, when the other person says, "So what is it that you do?" I have only to reply, "Me? I'm a structural biologist," when the eyes of my companion begin to glaze over, and he or she excuses themselves as rapidly - and unconvincingly - as possible. "A structural biologist. That's very interesting. But you must excuse me - I suddenly realize I have to have a tooth pulled."

I've tried to modify what I call myself in order to seem more hip, but it only postpones the inevitable:

Interesting Person at Party: "So, what do you do?"

Scientist at Party: "Me? I do, um, genomics."

IPAP (wishing they could escape but trying to be polite): "What's genomics?"

SAP (with typical scientist's enthusiasm): "Well, all organisms have their genetic material arranged in one or more chromosomes, and if you consider for example the Archaea -"

IPAP (abandoning politeness for survival): "Excuse me - I just remembered I have to wash my car."

I don't want to give the impression that I think this happens because most of the rest of the world are anti-intellectual, science-phobic boobs. If only they were. If that were the case, then I could absolve myself, and my profession, from blame. But I'm afraid that isn't the case. I don't think most people are afraid of science at all. What they're afraid of is scientists. Or, to be more precise, scientists at parties talking about their work. I don't think the average layperson flees from us as though we were carrying the Ebola virus because they think they couldn't understand what we would say. I think it's because they know, probably from bitter personal experience, that most scientists love to talk about what they do. Interminably. It's not incomprehensibility they're fleeing; it's boredom. This also explains why so many scientists end up marrying other scientists. It's not that our social circles are restricted to people we work with; it's that no one else will listen to us.

Years of attempting to chat up various interesting, attractive people at holiday parties have made me feel a bit like George Costanza, the short, overweight, balding, perpetually unemployed man on the classic television comedy Seinfeld who still lives with his parents. These qualities make him about as appealing to the opposite sex as - well, as a short, overweight, balding, perpetually unemployed man who still lives with his parents. Desperately trying to appear more desirable, on meeting beautiful women George frequently pretends to have an interesting, exciting job (in one case, he claimed to be a marine biologist). His favorite assumed identity, however, is that of an architect. I must confess I find this idea tempting. Everybody thinks architects are interesting. (Well, everybody except Prince Charles and Tom Wolfe, and who cares what they think.) People could listen for hours to architects. Beautiful women and interesting men flock around architects like graduate students around pizza. But with my luck, I can just imagine what would happen:

IPAP: "Wow! That is so great! I love architecture. What are some of your buildings?"

SAP: "Have you heard of the new Guggenheim Museum in Bilbao?"

IPAP: "Of course. I love that building! But I thought Frank Gehry did that. You mean that was you?"

SAP: "Uh, no."

My guess is things would just deteriorate further from there.

A big part of the problem is that few of us call ourselves scientists, or even biologists. Biologist wasn't good enough; it had to be Molecular Biologist. Now it's Cell Biologist, or Genome Biologist. What makes us feel we have to give ourselves identities that are more overblown than if we were simply to call ourselves biologists? Why do we have to say that we do proteomics, or systems neuroscience, or structural genomics? One of the great things about biology is that biologists can usually understand at least some aspect of what any other biologist does - something that's not true in chemistry, for example, where as far as most organic chemists are concerned the average physical chemist might as well be speaking Swahili, and vice versa. Many of us got into biology in the first place because of a love for living things, so why do we think it sounds more learned, or more glamorous, to say that we do cellular immunology or biophysical chemistry? OK, it may sound more learned, but if the reaction I get at parties is any indication, it certainly doesn't sound more glamorous.

With this in mind, last year I tried not to get bogged down in details. It didn't work very well:

IPAP: "So what do you do?"

SAP: "Me? I'm a biologist."

IPAP: "Wow, it must be great to be able to be outdoors all the time observing wildlife."

SAP: "Um, well, I'm sure it is, but you see, I don't actually do that. I use synchrotron radiation to -"

IPAP: "Excuse me, but I just realized I'm supposed to clean out my gutters."

This experience convinced me that what we scientists need is a new name for ourselves. Something that would give us the proper air of glamour, intrigue, and fascination. Something that wouldn't leave us standing in the middle of the room with a drink in our hands wondering why everyone was acting as though we had just grown a pair of horns and a pointy tail. Fortunately I didn't have to look very hard to find it. The Italians, who possess a legendary capacity to see conspiracies behind every event, have coined a wonderful term: dietrology. It means the study of that which is hidden. Dietrology. Isn't that what we all, as scientists, do? The word sounds mysterious, and maybe even slightly dangerous. Indiana Jones could have been a dietrologist (come to think of it, he was). It's perfect. So at another party last holiday season I tried it out:

IPAP: "What do you do?"

SAP: "I'm a dietrologist."

IPAP: "Really? Cool. I was born on 5th March. That makes me a Pisces, right? So -"

Finally, I decided the whole business was stupid. A grown man shouldn't be inventing sexy-sounding names to cover up what he does. I have nothing to hide. I am a member of an honorable, well-respected profession. That's why this year, when some interesting, attractive person at a holiday party asks me what it is that I do, I'm going to hold my head up, look them straight in the eye, and say proudly, "Me? I'm an architect."

Published: 15 December 2004

Tsunami

Genome Biology 2005, 6:104

It began at the bottom of the ocean, off the west coast of Indonesia. From there it spread outward, silently, invisible under the surface of the water. When it came ashore, in forty countries, some as far as 4,000 miles from where it started, it killed upwards of 150,000 people. There have been deadlier catastrophes - the earthquake in China in the mid-1970s killed a quarter of a million in that country, and the cyclone that devastated Bangladesh in the decade before that is thought to have caused half a million deaths - but none that involved so many different nations scattered across so much of the earth's surface. The tsunami spawned by the magnitude 9.0 earthquake of 26 December 2004 was perhaps the first truly global natural disaster in modern history: a third of the world's countries were directly affected. The worldwide scope of the destruction reminds us of something that genomics is also starting to make clear: that we are all truly one people, that national and racial differences are artificial and insignificant compared to the common bond of our humanity. Despite all our technological prowess and environmental hubris, we also have yet another grim reminder that Nature, not Man, is still boss of this planet.

The word 'tsunami' comes from the Japanese words for harbor (tsu) and wave (nami). It refers to a series of giant undersea waves that travel at high velocity for very long distances, and that crest when they hit a shoreline in the form of a devastating surge, sometimes as much as 30 meters high. Tsunamis are often called 'tidal waves' but that's a misnomer: the phenomenon has nothing to do with the tides. It has its origins, like everything else that involves the earth's surface, in plate tectonics.

It is hard to imagine that the theory of plate tectonics, which is at the heart of all modern geological science, is only a hundred years old and was not widely accepted until the 1970s. Schoolchildren had noticed for hundreds of years that the facing shapes of South America and Africa could be fitted neatly together like pieces of a jigsaw puzzle to make a single entity (Francis Bacon had noticed it in 1620 but drew no conclusion), but it wasn't until 1908 that the amateur American geologist Frank Bursley Taylor proposed that the continents had once slid around and that this motion might have thrust up the world's mountain chains. His theory was taken up by the German planetary astronomer-turned-meteorologist Alfred Wegener, who in 1912 proposed that all the world's continents had once been part of a single giant landmass he called Pangaea, which had split apart in a process of lateral motion that was still continuing. Traditional geologists attacked both Wegener and his ideas viciously, and it wasn't until the decade after his death (he froze to death on a scientific expedition in Greenland in 1930) that the great English geologist Arthur Holmes provided an explanation for how Wegener's motion could occur. In a textbook published in 1944 he speculated that heat caused by the decay of radioactive elements in the earth's crust could produce powerful convection currents that could slide the continents around on the earth's surface. He has probably as good a claim as anyone to be the father of the modern view of continental drift, although, curiously, he often expressed skepticism about his own theory. Harry Hess, a Princeton University geologist, figured out in the 1950s that there were two large plates of land under the floor of the Atlantic Ocean and that their relative motion was responsible for the topography and geology of the seafloor. Finally, in 1963, Cambridge University geophysicist Drummond Matthews and his graduate student Fred Vine used magnetic readings to prove that the seafloor and the continents were in motion. (Canadian geologist Lawrence Morley came up with the same result at the same time but his paper was rejected by the Journal of Geophysical Research.) J. Tuzo Wilson of Toronto showed at about the same time how plate tectonics could explain the behavior of the ocean floor at mid-ocean ridges. Still, even in the 1970s, many textbooks of geology continued to dismiss plate tectonics as physically impossible.

Today we know that the surface of the earth is composed of about a dozen large plates and almost two dozen smaller ones, all moving in different directions. Where they grind against one another (regions geologists call 'subduction zones'), the tremendous force can be released either slowly and steadily, giving rise to thermally active regions like Iceland, or sporadically and violently, giving rise to earthquakes and volcanic eruptions. That is what happened on 27 August 1883, when subduction along the Java Trench, where the Indo-Australian plate is moving under the Indonesian Island chain, caused the explosive eruption of the volcano on the Indonesian island of Krakatoa that in turn generated waves that reached 41 meters in height, destroying 165 coastal towns and villages along the Sunda Strait between the islands of Java and Sumatra and killing 36,417 people. (Hollywood made a movie about this great disaster in 1969: Krakatoa, East of Java. In case you are ever tempted to equate Hollywood productions with history, let me point out that Krakatoa is west of Java.) That is probably what happened in 1648 B.C., when the entire Minoan civilization on the island of Crete was wiped out, in a single day, as the result of a tsunami created by the explosive eruption of the volcano on Santorini.

And that is what happened on 26 December 2004, when the Indian plate slid underneath the Burma plate (a subduction zone), driving a 6oo-mile long piece of the earth's crust 20 to 50 feet upwards on the floor of the Indian Ocean. This sudden rise in the seafloor displaced an enormous volume of water - exactly as if the ocean were a swimming pool and someone had just dropped a large block of concrete into it. The displacement spread outward in all directions, like the ripples that would spread from that block. But because the event occurred underwater, the displacement traveled underwater until it encountered the sharply rising seafloor on the edge of an island or continent. When the undersea waves hit this obstacle, they were pushed straight up, compressed into walls of water that surged over the landmass.

The speed of a tsunami depends on the square of the depth of the ocean: the deeper the water, the faster the displacement travels. The Indonesian tsunami formed in deep water, which meant that the wave velocity reached upwards of 800 km/h, the speed of a commercial jet aircraft. When they encounter the shallow depths of a coastline the speed of tsunami waves slows to perhaps 45 km/h, still fast enough to do tremendous damage. At top speed it took the tsunami less than 7 hours to cross the Indian Ocean and reach the east coast of Africa, where the waves came ashore in Somalia and killed 150 people who cannot possibly have understood that the power that was destroying them had been spawned more than 3,000 miles away.

The Great Wave off the Coast of Kanagawa. From Thirty-six Views of Mount Fuji by Katsushika Hokusai (1823-1829); woodcut, 10 x 15 inches. From the Metropolitan Museum of Art, New York, USA [http://www.moma.org].

Like the ripples from that dropped block of concrete, a tsunami is actually a series of waves, usually spaced about 15-20 minutes apart, with troughs in between them. To the observer on shore, the approach of a tsunami often begins with a rapid receding of the shoreline, much further out than normal. This is followed, 8-10 minutes later, by the first wave, which surges onto the shore, often traveling a half a mile or more inland. As the cycle repeats, the first wave recedes, carrying anything loose back out to sea. Then the next wave hits. In Thailand, Sri Lanka and Indonesia, where the worst damage occurred, many people who survived the impact of the first wave were swept out to sea as it receded, or were killed by one of the surges that followed. But what fascinates me the most about tsunamis is that, until they reach land, they are practically unnoticeable on the surface of the ocean. Their amplitude in deep water is often only a meter or less. An ocean liner or a fishing vessel would pass right over them, completely unaware that underneath it a force was racing onward that, when it surfaced, could obliterate an entire country.

I've been thinking a lot about that sort of thing recently, because it seems to me that it's a pretty good metaphor for what is going on in science. I started writing this column because I believed that genomics was like a tsunami: a force that, when it crested, would change everything, and I wanted to have an excuse to think about what that would mean. The true impact of the genomics revolution is only starting to be apparent now, and it's very different from what it was predicted to be when the Human Genome Project began in the late 1980s. It has not had a significant impact on human health yet - the disease genes that have been discovered have generally come from specific individual research programs, and pharmacogenomics has initially focused on polymorphisms in genes that were already identified before the human genome was sequenced. Genomics has produced technology, such as cDNA microarrays and mass spectroscopy-based proteomics, that is likely to play a major role in diagnostics in the near future, but not necessarily in treatment. No, the major effects, which are now rolling across biology like a series of waves, are cultural.

Because of genomics, data gathering and analysis is now valued highly - in some instances above hypothesis-driven research. Because of genomics, targeted big science projects, such as structural genomics, that aim to produce easily appreciated results (usually in the form of large amounts of data), are consuming a large chunk of funding that would otherwise go to individual investigator-initiated basic research. Because of genomics, there is a perception in some quarters that when you have analyzed something you have understood it; mathematical modeling of biological processes is beginning to become a substitute for experimental probing. Because of genomics, a kind of mysticism is creeping back into biology: we use terms, like 'systems biology' and 'emergent properties', that have echoes of vitalism in them -almost as though we are starting to believe that we cannot explain the behavior of living systems in terms of the physics and chemistry of their component parts. We can argue about whether this is good or bad for our field. We can argue about how we should react to it. But we cannot ignore it. None of this could have been appreciated in 1990. It was all moving beneath the surface, moving rapidly and inexorably and now it is upon us. Until the next tsunami comes along, genomics, like molecular biology before it, will change our scientific world whether we like it or not.

So one of the lessons I take from what happened on 26 December is the folly of believing that things will remain as they are today. We go about our lives and our careers unaware of the great forces that move, unseen, beneath the usual tide of events. Until they crest they are almost undetectable, so we don't talk about them or plan for them. And once they do crest, they can change our careers and our lives in a very short time. It would seem that, of all the qualities we need to survive and thrive in an unpredictable world, flexibility - adaptability if you will - might just be the most valuable. The other lesson is a practical one. If you're standing on shore, looking out at what seems to be a perfectly calm ocean, and you suddenly see the shoreline receding rapidly, exposing the sea bottom much farther out than usual, turn around and run like hell away from the water. You need to get a half mile inland; a mile would be better. You have, if you're lucky, maybe 10 minutes.

Published: 31 January 2005

Feet in mouth disease

Genome Biology 2005, 6:105

The fascinating thing about Dr Lawrence H. Summers, Harvard University's beleaguered President, is not that he often puts his foot in his mouth. We all do that. It's human nature to blurt things out and later wish we hadn't. I can't count the number of times I should have put my brain in gear before letting up the clutch on my tongue. (When I was interviewed for my first job, I actually said, "Oh, salary isn't that important to me." They never forgot that.) No, what makes Summers-watching such an irresistible sport - albeit a morbid one, rather like auto racing fans who attend to see crashes - is not seeing him put his foot in his mouth; it's wondering how he'll manage to get the other foot in there with it.

To be fair, during his three years as Harvard President, Summers, an economist by profession, has instituted what I believe to be important financial reforms, championed the cause of undergraduate education, and begun plans for an ambitious third campus between the existing main campus and the medical school site. But, prior to becoming president of Harvard, he endorsed an internal World Bank memo suggesting that the US should move its worst-polluting industries to developing countries, who would be more inclined to accept them because they need to boost their economies. As president, he denounced as anti-Semitic a movement that seeks to have institutions like Harvard divest themselves of investments in Israel because of that nation's treatment of the Palestinians. And he alienated a renowned black professor, who promptly decamped to Princeton - a departure that destabilized Harvard's once excellent African-American Studies department, which has since lost other members. Now I guess I have as much Schadenfreude as anyone, and there is something that appeals to all of our iconoclastic tendencies in the spectacle of an enormously talented, accomplished individual behaving - and there really is no other way to put this - like the opposite of the front end of a horse. But the recent flap over remarks made by Summers at a 14 January conference of the National Bureau of Economics Research represents a new high in lows, even for him.

Unless you're a cave-dweller you probably have heard that this incident concerns the issue of women in science. Women, on average, get better grades in school, earn as many bachelor's degrees in science and engineering, and nowadays attend graduate school in the sciences in about the same numbers as men. But by the time men become tenured faculty in science and engineering, they vastly outnumber women. The conference, which concerned the topic of diversity in the workplace, asked Summers to comment on this drop-off. "It is, after all, not the case that the role of women in science is the only example of a group that is significantly underrepresented in an important activity and whose underrepresentation contributes to a shortage of role models for others who are considering being in that group", he said. "To take a set of diverse examples, the data will, I am confident, reveal that Catholics are substantially underrepresented in investment banking; that white men are very substantially underrepresented in the National Basketball Association; and that Jews are very substantially underrepresented in farming and in agriculture... There are three broad hypotheses about the sources of the very substantial disparities that this conference's papers document and have been documented before with respect to the presence of women in high-end scientific professions... The first is what I would call the high-powered job hypothesis. The second is what I would call different availability of aptitude at the high end, and the third is what I would call different socialization and patterns of discrimination in a search. And in my own view, their importance probably ranks in exactly the order that I just described." He went on to elaborate, defining the first hypothesis as the idea that married women are not prepared to make a near-total commitment to their work, and the socialization hypothesis as the notion that women are driven away from mathematics and science by societal pressures. He stated that he would not assign much weight to the socialization hypothesis. And he went on to make the explicit statement that, "in the special case of science and engineering, there are issues of intrinsic aptitude, and particularly of the variability of aptitude." (You can read the full transcript of his remarks at http://www.president.harvard.edu/speeches/2005/nber.html. It's a pity there isn't a recording of his speech, because tone of voice can make a big difference in matters like this. A letter from Summers to the Harvard faculty explaining and apologizing for his remarks can be found at http://www.president.harvard.edu/speeches/2005/facletter.html).

Several times in his speech, Summers stated that it was his intention to be "provocative". He certainly succeeded: one woman scientist who was attending the meeting walked out in the middle of his remarks (a gesture that strikes me as counterproductive; I've always felt that ideas that are wrong or biased or stupid need to be confronted and exposed for what they are), and within days there were calls for his resignation from both men and women faculty, in the sciences and the humanities. Some colleagues - nearly all fellow economists, interestingly - rushed to his defense, claiming that he was performing a valuable service by focusing attention on a subject that needed more research, and that his detractors were egregious examples of political correctness gone amok.

I don't accept those arguments, for several reasons. First, they imply that what he said wasn't so bad. To judge that, try this simple exercise: take his comment on "intrinsic aptitude" and replace "women" with, say, "African-Americans" (another group underrepresented in high-end science positions), and then ask yourselves how long he would have remained as Harvard President had he said that. My guess is about five minutes. The fact that he has defenders at all says more about the relative powerlessness of women in our society than it does about the merit of what he said. And doesn't it smack of colonialism for a member of the majority to assume that because a different group is underrepresented in some profession they must be in part responsible for that? Up until the 1950s, Jews were underrepresented in nearly all academic departments at high-end universities in the United States. As Summers surely knows, that wasn't because of any "intrinsic aptitude" differences; it was because of a discriminatory quota system that limited their numbers.

As for the need for more research on this topic, I've found that Summers has a somewhat complicated history on the issue of data. He is famous among economists for an aphorism he coined to illustrate the importance of private property: "In the history of the world, no one has ever washed a rented car." Coincidentally, when the commotion arose over his comments on women in science, I was on a trip where I needed to rent a car, so while I was at it, I went and asked the Avis manager whether anyone ever washed their rented cars before returning them. "Sure," he said, looking surprised I would need to ask, "it happens all the time." When I asked why they would do that, he said that some people were simply nice and hated to return a car that had become too filthy, while others, usually business people, washed them because they wanted to make the best possible impression on the customers they were driving around. Now I don't want to make the mistake of generalizing from my own experience - that may be exactly the sort of thing that has gotten Summers in trouble - but this little episode does make me wonder if he might not have a habit of stating things that he believes ought to be true without bothering to check on the facts.

And in the case of women in science, the facts are quite clear: there isn't a shred of credible evidence to suggest that there is a difference in "intrinsic aptitude" between men and women when it comes to mathematics and science, and quite a lot of evidence to suggest that there is no significant difference at all. One observation that is sometimes cited to support the idea that there might be a difference is the greater spread of men's standardized test scores compared with women's. Stephen Pinker, a Harvard psychologist and defender of Summers, calls this the "more geniuses, more idiots" phenomenon. Unfortunately, when one looks at the same statistics in other countries, many, such as Japan, do not show this difference at all, while in other countries, like Iceland, the curves are reversed and it is women who have more top scores than men. That seems more like "socialization" than any difference in innate abilities to me. Nor is it reasonable to argue that the Japanese and Icelandic results reflect some ethnic variability in aptitude. Anyone who has followed the genomics revolution will know that the genome sequences of humans show so little variation from one 'race' to another that genetic differences should never be invoked as the first explanation for any differences in behavior or apparent abilities. Research by Elizabeth Spelke, a professor of experimental psychology at Summers' own institution, also seems to disprove the idea of any intrinsic differences. She has studied the cognitive abilities of infants and young children for years and found that boys and girls show no significant differences at those ages. Any latter discrepancies, then, would seem more likely the product of environment than genetics.

Besides, I think the whole notion that performance on standardized tests is a useful predictor of who will succeed in mathematics or science careers is suspect. I don't know of any studies that show such a correlation, and my own experience suggests that matters of character and temperament (persistence, imagination, curiosity, and so on) are much more important to later success. And if Summers wants to use the fact that Harvard has few tenured women in the sciences as evidence that there is some intrinsic inability that hinders their success at the highest levels, the fact that Harvard also has one of the most dismal records in American academia for hiring and promoting women would seem to me to be the more likely reason.

With all that in mind, let's look at Summers' other two hypotheses again. The first was that women are much less likely to want to put in 80-hour work weeks than men. Well, gee, Larry, if that's true, don't you think that might just possibly be because in addition to that they have to put in about another 80 hours a week of child care and housework? I know of very few instances of families in which the woman doesn't do a lot more than 50% of the parenting and household chores, even when her husband is quite supportive. If the high-powered job hypothesis has any validity, then the obvious solution is for organizations like Harvard, which has a $24 billion endowment, to spend some of that money on services that alleviate the other time sinks a woman faces. Providing affordable, convenient day care for her children would be one helpful action. Paying her enough so that she can afford some additional household help would be another. Yet another would be to hire a large bolus of women immediately, enough so that they would no longer be such a minority that those who do succeed find themselves disproportionately deluged with committee assignments and other responsibilities where gender balance is needed.

The third hypothesis was that of socialization, and I think we must never underestimate that. Even in our supposedly enlightened era, women face discrimination, both overt and unconscious, when they try to make careers in formerly male-dominated professions like mathematics, many of the sciences, and engineering. Small slights and small disadvantages add up over a lifetime, leading to severe inequalities of pay and promotion, which in turn makes those professions less desirable. I've always felt that the best argument for affirmative action (positive discrimination) is that, left to themselves, most people prefer to be surrounded with others who look like them, a trait that tends to perpetuate male-dominated environments even when bias seems absent. I suspect that many women shun testosterone-saturated fields such as surgery, synthetic organic chemistry and nuclear physics in large part because they aren't made to feel welcome and they don't wish to feel isolated all the time. I remember vividly when my Brandeis colleague Dagmar Ringe - a world-class scientist, Dr Summers - walked into my office and said with a sigh, after some meeting in Washington, "I am so tired of being the only woman in the room." I realized with a shock that I have never been the only man in the room, and I bet Summers never has been either. One of the best things we can do to encourage young women to enter mathematics and science is to provide them with lots of role models, and to treat those role models as fairly as possible.

I wonder how many women Summers has trained in his profession. I've trained quite a few in mine and I have noticed one difference between them and my male students. Almost without exception, the talented women I have known have believed they had less ability than they actually had. And almost without exception, the talented men have believed they had more. Now, I don't know what the origin of this difference is, whether it's innate or cultural, and I don't really care either. But I bet it's largely cultural. Any teacher will tell you that if pupils are told they're likely to fail, they will. I don't see how women can go through life constantly being told that they can't do mathematics or science and not doubt themselves.

Isn't it ridiculous that in many cases we are trying to solve 100% of our problems with only about 50% - perhaps a lot less if my mother is right - of the available brainpower? If we want to do something about that, we can, and should, use the financial resources of our institutions to redress the serious inequities and problems that bright, ambitious women face in the scientific workplace. And we can, and should, fight discrimination wherever we find it in that workplace, and in the training environment that leads to there. But perhaps most of all, we should do everything we can to encourage women to believe that they can succeed in science and engineering. If many bright women constantly struggle against a voice inside their heads that keeps repeating, "You're not good enough," the last thing they need is some powerful male, with both feet firmly in his mouth, spouting the same nonsense.

Published: 28 February 2005

Who owns the data?

Genome Biology 2005, 6:107

Besides an astronomical amount of sequence data and a lot of useful technology, perhaps the most significant legacy of the genomics revolution has been an insatiable appetite for data. This hunger was part of the reason that the privately funded human genome project at Celera Corporation released its sequence information sooner than intellectual property considerations would have made desirable (competition from the publicly funded human genome sequence project was the other part). The same hunger motivated the US National Institutes of Health (NIH), the National Science Foundation, and the Howard Hughes Medical Institute to require that structural biologists funded by those agencies deposit their atomic coordinates into a public database in a timely manner. But this flood of information hasn't curbed the appetite at all. Like Cleopatra in Enobarbus's marvelous description from Shakespeare's Antony and Cleopatra, it seems genomics makes hungry where most she satisfies.

Of course, this desire wars with another fundamental human appetite: that for money. Much of modern life science is driven by the longing to make a profit. It fuels the biotechnology and pharmaceutical industries. It underlies the choice of research problems in many academic laboratories. And at its heart is the concept of property, of ownership, both of ideas and of data. This concept would seem to be perpetually opposed to that of free, publicly available sequences, structures and technologies.

Historically, the battlefield on which this conflict was fought was the courtroom, where scientists and corporations would engage in Talmudic-style disputes over dates in notebooks, interpretations of patents, and other claims to priority. In the immediate post-World War II era these arguments tended to be over technology developed by physicists, chemists and engineers. Biologists didn't join the fray until after 1980: in part there was no biotechnology industry until about then, but it was largely because most academic biology was publicly funded, in the US by the NIH. That would seem to make the results of such research public property.

The Bayh-Dole Act, passed by the US Congress in 1980 and named for its co-sponsors Senators Birch Bayh and Robert Dole, changed all that. The Act provided recipients of federal research and development funds with the right to retain ownership of their patents. It did even more: it charged them with the responsibility of ensuring commercial use of inventions created with federal financial support. While it is technically possible for a university to have different policies regarding the patenting and licensing of inventions which were not developed as a result of federally funded research, in general the universities' interest in maintaining the flexibility to draw research funds from multiple sources, including the federal government, and the desire to avoid applying conflicting policies, have led to most of them having a single policy that is consistent with the Act. The underlying tenet of the Bayh-Dole Act is that federally funded inventions should be licensed for commercial development in the public interest. That principle is now reflected in virtually all university policies in the US, whether or not the invention is federally funded.

Since the Bayh-Dole Act permits universities, other non-profit organizations such as teaching hospitals, and, in most cases, commercial federal contractors to retain title to inventions that are conceived or first reduced to practice in the performance of a federal grant, contract, or cooperative agreement (in exchange for certain obligations on the part of the contractor), it immediately created a huge economic incentive for academic biologists to start their own companies or to become involved with existing ones. Bayh-Dole was directly responsible for the explosive growth of the biotechnology industry in the 1980s. It also created the culture of intellectual property that underlies that industry. For over twenty years, the answer to the question "Who owns the data?", according to the Bayh-Dole Act, has been "the scientist who collected it and the organization for which he or she was working at the time". Since raw facts could not be property (you may patent a mousetrap, but not data on mice; you may copyright an article, but not the data on which it is based - although the patenting of gene sequences is a blow to this tradition), this answer led to a culture in which data were hoarded, often to be published only after the application itself was developed.

This answer is now being challenged by a new one, driven by the cultural change genomics is creating in the life sciences - a culture of public databases and open access. The first area of modern biology to reel under the challenge has been the scientific journal publishing industry. Some journals, such as Science, are published by not-for-profit scientific societies (which derive a hefty chunk of their operating expenses from the subscriptions); more, like Nature, are revenue-generators of for-profit publishing houses. About ten years ago, a group of scientists headed by Nobel Laureate Harold Varmus, then Director of the NIH, began to argue that it was unfair to ask other scientists, who are after all members of the public, to pay to read the results of research that had been publicly funded. They quickly found allies in patients' advocacy groups, who believe advances in medicine would come about more quickly if everyone had equal access to discoveries. Despite considerable skepticism by many scientists - and much gnashing of teeth from publishers - about five years ago the first 'Open Access' journals began appearing. Their business model is that authors of papers appearing therein must pay a fee for the privilege (peer review is still required for acceptance), but in return, all rights to the material in the paper remain with the author and anyone can access the full text and any supplemental information free of charge forever. Scientists in developing countries, in particular, benefit greatly from such a policy, since many journal subscriptions, online or in print form, are beyond their means.

And on 3 February, NIH announced that as of 1 May this year it expects that all research papers resulting from research it funds will be deposited into an open-access electronic archive that will be maintained by the US National Library of Medicine (which currently runs the PubMed journal database and PubMed Central full-text archive, within a year of their appearing in any journal. Current estimates are that over one third of all highly cited papers in the life sciences report the results of NIH-sponsored research, so the policy is likely to have a big impact almost immediately, even though there is no active enforcement. If the existing open-access journals like PLoS Biology, Journal of Biology, and this journal (which makes all refereed research articles freely available online but charges a subscription price for access to other content, such as my Comment columns - which are worth every penny) are able to stay in business by, for example, charging authors rather than subscribers, and if they start to attract top-flight papers, the closed-access journals will come under severe financial pressure to adopt a similar business model. In any case, given the new NIH policy, it would seem that for much of their content, closed-access journals will only have a year - and maybe eventually a lot less than that - to make their profits. The Wellcome Trust in the UK is also a big supporter of Open Access, and is considering establishing a joint archive of papers with the US National Library of Medicine. Where Wellcome goes, the UK Medical Research Council is likely to follow. Add in Germany, France and Japan and most of the literature will be covered.

Even more intriguing is the advent of open-access technology. Here there is a model from outside biology: so-called 'open-source' software. Programs developed under the opensource concept have their source code freely available to users, with the restriction that any improvements made by anyone must be offered to the user community free of charge. A variation of this model levies a cost to commercial users while allowing academics and other non-profit groups to obtain the code free of charge. The first example, the Linux operating system (named after its inventor, Linus Torvards, who is popularly credited with the open-source model), has proven so successful that it is making Bill Gates and Microsoft nervous about the future of their closed-source, very much for-profit Windows operating system. Open-source software has begun to have a big impact in structural biology, where programs like Coot, PyMol, Phenix and so on are making high-quality crystallographic computing available to all.

And now this idea is being applied to biotechnology. Early in 2005 an exploratory project called Science Commons was launched. The mission of Science Commons - an offshoot of Creative Commons, which provides less restrictive copyright licenses to authors - is to develop open licenses for technologies. As a model, it could do worse than look to a remarkable new concept developed by CAMBIA, a non-profit biotech research group affiliated with Charles Stuart University in Canberra, Australia. In a paper published, ironically, in the closed-access journal Nature on 10 February (Broothaerts et al., Gene transfer to plants by diverse species of bacteria, Nature 2005 433:629-633), researchers at CAMBIA report a breakthrough in biotechnology by successfully transferring foreign genes to plants using several bacteria other than the usual Agrobacterium tumefaciens (At). They introduced a specially modified Ti plasmid into Rhizobium, Sinorhizobium and Mesorhizobium - all organisms closely related to At - and showed that the transformed strains could be used to express foreign genes from the plasmid in tobacco, rice and Arabidopsis. Integration of the inserted segment into the plant genomes was also confirmed. The work is exciting because many plants, especially crop plants, are resistant to gene transfer by At. But it's also noteworthy because of what CAMBIA is doing with it.

CAMBIA has applied for a patent on the technology, which they call TransBacter™. But they are offering this technology as an 'open-source' alternative to At technology, which is controlled by Monsanto, the large agricultural firm that holds the relevant patents. CAMBIA calls its license concept BIOS - Biological Innovation for Open Society. The way it works is simple. Others may commercialize products based on the procedure. But any improvements in the technology must be shared freely, to the benefit of all users. The intent is that researchers in poor countries especially, where agricultural research is very important, will thus have open access to a method that may help their efforts. There's a website, Bioforge [https://www.bioforge.net/], to help biotech researchers collaborate on this and other developments (among them new reporter/marker genes and microarray-style genotyping technologies). There are several levels of projects, some open only to BIOS licensees, some open to all and some open at intermediate levels. Joining a project enables the participants to see, use, and deposit information that will not necessarily be available in the public domain. It will allow them to share their improvements with other members of the protected commons community of BioForge. In order to join a project, organizations and individuals must agree to the community norms about confidential sharing of improvements and biosafety data, and must provide information on their institutional affiliation and policies that may apply to sharing of data. Access to certain projects may require a legal commitment to the sharing of improvements in return for being able to obtain the benefit of the technology and improvements.

For humanitarian efforts and work on crops that are of limited interest in developed countries, CAMBIA's model promises to be truly revolutionary. It doesn't do away with the incentive to invent, or to develop, but it makes the information needed to do such things available to everyone. If there is an untapped reservoir of creativity in the Third World, an idea such as this might unleash it. It will be interesting to see whether the concept catches on, as open-source software clearly has. No one wants to see the financial incentives that have fueled the biotechnology explosion removed. But companies can clearly live within the open-source model - IBM does, for example (open-source software even contributes to its revenues, since among other things IBM makes much of its money by selling services to people whohave open-source software and need help). CAMBIA, by the way, was funded by the Rockefeller Foundation, Horticulture Australia, and Rural Industries R&D Corporation, so in a sense its work represents a triumph of the Bayh-Dole concept. It remains to be seen whether the pharmaceutical industry, which in my opinion would benefit greatly from increased sharing of ideas and information, could find an open-source model it could live with. But if scientific publishing and software development are any indication, this is not an idea that's going to go away any time soon.

Who owns the data? Increasingly, at least for some things,the answer is starting to be nobody. Or everybody.

Published: 31 March 2005

A matter of life and death

Genome Biology 2005, 6:109

Terri Schiavo died at 9:05 on the morning of March 31, 2005. That's what her death certificate says. Thirteen days previously, at the request of her husband, Michael Schiavo, who said he was carrying out her wishes, her doctors removed the feeding tube that was keeping her alive. Without food or water, she eventually succumbed to heart failure at age 41. The death certificate doesn't come close to telling the real story of her death, however. Some people, including her parents, siblings, and a number of religious and political figures, would probably claim that, on that morning, Terri Schiavo was murdered, either by her husband or her doctors or both. Others think she should have been allowed to die at least seven years earlier, when her husband first requested it. And then there are those like me, who believe that on the morning of March 31, 2005, Terri Schiavo had already been dead for fifteen years.

Terri Schiavo (born Theresa Marie Schindler) was a young married woman of 26 when she went into cardiac arrest, possibly as a result of potassium imbalance brought on by an eating disorder. When her heart stopped, she lost oxygen to her brain for a considerable period of time before emergency medical personnel were able to restart it. From that moment on, Terri Schiavo never uttered a word, made a voluntary conscious movement (she exhibited involuntary reflex actions only), or responded to any external stimuli. Neurologists who examined her said she was in what they term a "persistent vegetative state", a condition that sounds as bad as it is. Her electroencephalogram (EEG) was flat, indicative of no higher cortical functions. A brain scan indicated that essentially all of her neurons were dead - presumably from apoptosis due to ischemia. Her brain stem still functioned, though, and such is the persistence of the autonomic nervous system that her lungs continued to work and her heart continued to beat for fifteen years. But there was no mind. Some years after she went into this condition her husband lost hope and petitioned the Florida courts to allow her feeding tube to be removed. The courts agreed, but her parents, the Schindlers, who never lost hope that a miracle could still happen, obtained an injunction preventing the tube's removal. The husband appealed. The appellate court sided with him; the Schindlers sought another injunction, and so on, back and forth year after year: a legal tug-of-war with a brain-dead woman as the rope.

Something like this can bring out both the best and the worst in human nature. The Schiavo case certainly did. For the best one only has to look to the health-care workers at the hospice who nursed the body of Terri Schiavo, gratis, for over a decade. Or perhaps to Michael Schiavo - if, as he said, his motivation was to carry out Terri Schiavo's wishes that her life not be prolonged artificially if something like this ever happened to her. Some would also look to the Schindlers, who, having convinced themselves that their daughter's condition might someday improve, did everything they could to keep her alive. (In any case, I certainly think one has to feel enormous pity for them. No parent should ever have to bury a child. To lose one's parents is the way of the world, but to lose someone young like that is like being cheated.)

As for the worst, sadly there are a number of contenders. The radical right-to-lifers and religious fundamentalists who intruded on what should have been a private family matter would surely garner plenty of votes. They seem to crawl out of the woodwork whenever a case like this can guarantee them publicity. Shamelessly preying on the Schindlers' grief and hope, they turned the whole affair into a media circus, with themselves as ringmasters.

But my vote for the conscienceless opportunism prize goes to those Congressional politicians who, seeing a chance to cater to their social conservative constituents, passed an ad hoc law referring the Schindlers' case to the Federal courts (which normally have no jurisdiction in such matters) in a display of pandering that hasn't been seen since Pandarus gave the activity a bad name. President Bush was also quick to use the sorry situation for his own political display: he could have signed the law at his Texas ranch, where he was vacationing at the time, but instead flew back to Washington so he could affix his signature in front of the maximum number of television cameras. Worst of all were the Republican leaders of the Senate and House of Representatives, respectively Bill Frist and Tom DeLay. DeLay, currently under investigation for several breaches of ethics (perhaps that makes him an expert on the subject), led the fight in Congress to take the Schiavo case to the Federal courts (which, in the end, upheld the state court rulings in favor of her husband) despite decades of legal precedents establishing such cases as state matters. "The time will come," he said, "for the men responsible for this to answer for their behavior. We will look at an arrogant, out-of-control, unaccountable judiciary that have thumbed their nose at Congress and the president." (Congressman DeLay seems to have overlooked the fact that thumbing their nose at Congress and the president is exactly what the judiciary is supposed to do - the US Founding Fathers called this the separation of powers in the Constitution. Perhaps he ought to try reading that document sometime.) And Bill Frist, an MD who was a transplant surgeon before entering the Senate, actually performed his own neurological examination by viewing a videotape of Terri Schiavo and then pronouncing her condition not as bad as the experts had stated. No neurologist would ever make a diagnosis without actually examining the patient in person.

Many commentators expressed amazement that Congress should have chosen to intervene in such a deeply personal dispute, but that didn't surprise me at all. Since many politicians have been in a persistent vegetative state for decades it seems only natural that they would identify with someone in that condition. If so, they had company: one vocal group of supporters for keeping Terri Schiavo alive were activists for disabled persons. Some of them apparently feared that the decision to let her die might be the first step down a slippery slope, leading eventually to the 'right to die' becoming an 'obligation to die' for the severely disabled. But Terri Schiavo wasn't in a wheelchair, or blind. By any reasonable definition, her condition was not a disability. To argue that this case had anything to do with the rights of the disabled is to force it into a mold it doesn't fit. For me this illustrates one of the main problems I have with activists in general: their frequent tendency to distort reality, probably because they see everything through the lens of their particular single issue.

You might wonder why I appear to dismiss the possibility that the politicians were motivated by a sincere moral principle, namely a belief in the sanctity of human life. I do think some of them, and many of their supporters, were - but the evidence points against it in the case of many of them. For me, the acid test for the presence of principles is a certain moral consistency, because that indicates there is something underpinning the decisions one makes. Moral cognitive dissonance - the holding of two opposing positions at the same time - strikes me as a pretty good basis for concluding that opportunism is at work. Most Congressmen who voted for Federal intervention in the Schiavo case were also staunch supporters of the war in Iraq. Perhaps their respect for life only includes Judao-Christian life. Yes, I do understand one might argue that it is sometimes necessary to sacrifice some lives to preserve many more. But most of these same politicians are also strong supporters of capital punishment (the death penalty), which has never been proven to save lives and, in the US, disproportionally falls on the poor and the black. Do we then conclude their respect for life is restricted to white, Judao-Christian life from the middle class on up?

It has been suggested that the Schiavo case is one more piece of evidence of the hijacking of the Republican Party by the religious right. John Danforth, a former Senator and a moderate Republican - now there's a phrase that may be rapidly becoming an oxymoron - argued just that in an opinion piece in The New York Times. If so (and I have my doubts that this really does constitute such evidence - not least because some 50 Democrats voted in favor of the DeLay-sponsored bill, and many Roman Catholics, who are not knee-jerk social conservatives, also supported Terri Schiavo's parents), the religious right may have overreached this time: opinion polls indicate that almost 80% of Americans opposed Congress getting involved in this case. Still, there's little doubt that social conservatism is on the rise in the US. Fueled in part by a deep suspicion of scientific advances, especially in biology, a significant number of Americans are expressing doubts about the morality of abortion, stem-cell research, the creation of chimeric animals, and many of the anticipated fruits of the genomics revolution. Evangelical Christians accounted for over a quarter of George Bush's vote in 2004, according to John Green of the University of Akron, and if you include doctrinaire Catholics, then religious conservatives made up over 40% of his total. No administration can ignore such supporters.

But for me, what is most striking about the Schiavo case is that it once again shows the importance of framing the issues properly. An enormous amount of energy, angst and verbiage has gone into a debate about whether or not it is 'right' to end the life of a patient who will never recover cognitive functions. That shouldn't be the issue here at all. Whether or not Terri Schiavo (or any other persistently vegetative patient) ought to have been allowed to die is completely beside the point. The point is, she was dead to begin with.

Someone who will never be able to form a thought, respond to the outside world, and initiate a voluntary movement should never be considered alive by any reasonable definition of the word. But advances in medical technology have allowed us to keep such a person's heart beating for essentially a normal life span. Our ability to sustain some of the outward signs of life has rendered obsolete the legal system's definition of what it means to be alive. Since it is unlikely that this definition will change any time soon, it is incumbent on every individual to make clear exactly what he or she considers being alive to mean.

Many have tried to do so, through the use of 'living wills' -documents that set forth their wishes regarding the use of extraordinary measures to sustain life should something dreadful happen to them. Though such wills have no force in statute, courts and hospitals often take them into account in making judgments about treatment. But one lesson of the Schiavo case is that such language may not be enough, especially in cases where family members, often motivated by sincere efforts to do the best thing for their loved one, fail to agree on what is that best thing. To increase the likelihood of avoiding such conflicts, living wills need to designate a healthcare proxy: someone who is empowered to speak on behalf of the patient when he or she can no longer speak for themselves. It's a good idea for such a person to be as objective as possible, so a close relative might not always be the best choice. Living wills should also spell out, in no uncertain terms, under what conditions a person considers their life to have ended.

Social conservatives have been energized by the Schiavo case, and now seem poised to try to impose their moral values on society through legislation. Our old friends Tom DeLay and Bill Frist are in the vanguard of this movement. "It is not a day we will forget," said DeLay. "We will work as hard as we can to stop this from happening [again]." Right-wing religious groups have vowed to push for new laws restricting when spouses or relatives can end life-sustaining care for an incapacitated person, and for changes in the rules of the Senate that will more easily allow the ruling Republican Party to confirm conservative judicial appointments by the president. Ten US states are also considering legislation that would block termination of life-support measures, unless all legal appeals are exhausted and there is written consent from the patient (a living will).

Just because something is done in the name of God doesn't automatically free it from the possibility of being tyrannous. The dictatorship of the self-anointed morally righteous is still a dictatorship. On one point, however, social conservatives and I agree: life is a thing of great value. In fact, it's far too valuable to allow it to be controlled by a bunch of sanctimonious hypocrites. No one has the right to say what's to be done at the end of my life unless I give them that right. So as soon as I finish this column I'll be updating my living will to name a healthcare proxy. I'm also going to specify under what conditions I believe my life to be over - and that then I wish to be treated accordingly: namely, make me as comfortable as possible and let me go. I will certainly stipulate that I should be considered dead if I am diagnosed by reputable neurologists to be in a persistent vegetative state. And I think I'll add that I should also be considered to be brain dead if I ever start acting like the leadership of the US House and Senate.

Published: 28 April 2005

How may you help me?

Genome Biology 2005, 6:111

The road to hell may be paved with good intentions, but ifyou're looking for the entrance ramp, my current bet is that it was the invention of the self-service gas (petrol) station. Thanks to this exciting development, touted as a boon to thetime-strapped consumer, motorists can come into direct contact with carcinogenic fumes while handling one of the most explosive, flammable materials ever created. Self-service gas stations have also increased the profits of the automotive repair industry, since no one ever checks their oil or tire pressure anymore. The phenomenon has led to a curious linguistic paradox: such gas stations are still referred to as 'service stations', even though service is precisely whatyou can’t get at many of them. Self-service is outlawed at gas stations in New Jersey, however, proving something I've suspected for a long time: that the US would probably be a better country if the Mafia just ran it overtly.

Merging onto the Hades Highway, we next encounter the Automated Teller Machine (ATM), a device ingeniously constructed to make it easier for banks to charge you extra for something they used to do for free, namely giving you your own money. When the only way to withdraw or deposit funds was to enter the bank and talk to a human being (the non-automated teller), such service was provided for free. With the advent of the ATM, banks quickly realized that most people would primarily use such machines to spare themselves the inconvenience of traveling to the bank from wherever they were, so they began charging a fee for using machines that were not actually located at one of their own branches. In other words, as soon as they recognized that remote ATMs were helping consumers, banks started levying a tax on the benefit. It wasn't enough that the bank was already making two or three times more interest on your money than they were paying you for the privilege of letting them use it; they had to take a cut off the top as well. (Please note that both the self-service gas station and the automated teller machine have saved their respective businesses vast amounts of money in personnel costs. In the case of the ATM, the money that banks made by having fewer actualtellers apparently wasn’t enough for them.)

Perhaps the center lane on the tollroad to perdition is the self-service check-out kiosk that many supermarkets - and increasing numbers of other large chain stores - have now introduced. Bad enough that you have to take your groceries off the shelf, put them into your cart, take them out of the cart to be scanned, and when you get them home, unload them again; now you can also have the pleasure of scanning them yourself and, after paying for them, putting them into bags yourself. The grocery stores are saving bundles of money on the checkers and baggers they don’t have to hire (about 2.5 per kiosk), but as far as I can tell this hasn’t translated into lower food prices anywhere.

I see no end to this trend of offloading onto the consumer things that companies used to do for us. Airlines now ask us to check ourselves in at automated kiosks when we get to the airport, and are trying to get us to book our own flights online so they don’t have to hire people to do it for us over the phone. And those maddening telephone menus that ask you a million stupid questions and give you a billion useless options when you call for service or information are simply another way of having the customer replace the person who used to ask those things and make decisions about where to route the call. The number of retail kiosks is expected to grow by over 60% worldwide in the next three years. The fast-food sandwich chain Subway is experimenting with kiosks that take orders and accept payments (they still have human employees to actually make the sandwiches but probably will soon ask us to do that too). Self-service medicine is doubtless next, as governments and insurance companies realize they can cut costs by having us diagnose our own illnesses ("if you have a temperature over 101°F, press 1; if you are comatose, press 2"); perform our own surgery ("please place removed body part in bagging area") and, if we mess up, sue ourselves for malpractice ("to cross-examine yourself, please speak clearly into the microphone").

But what drives me crazy is the sheeplike way consumers are taking this abuse. Surveys show that self-service is generally popular, even though numerous studies have demonstrated that it doesn't save the customer any time (in fact, in some settings, such as supermarkets, it's actually slower than being served by a person, partly because the self-service machines seem to screw up so frequently) and hasn’t led to lower prices. I think people believe that it's faster, or ought to be (and, to be fair, in the case of the ATM it really is more convenient), but I bet one of the main reasons they favor it is the same reason so many believe driving their own car is safer than flying, despite decades of evidence that it’s not: the sense of being in control. Most of us have had so many bad experiences with service personnel over the years that we harbor the illusion that doing things for ourselves is faster and better, even though it's often neither. Of course, as companies reduce staff thanks to us doing their work for them, it becomes even harder to find a service person when you really need one - for example, if you want to do something more complicated than these inflexible machines are programmed to handle. This business of my doing things employees should be doing has gotten so pervasive that it's starting to make me paranoid (OK, more paranoid than usual): I keep imagining that one day soon I will walk into a store and a smiling staffer will greet me with a cheery "Good morning, Sir. How may you help me?"

Still, I was coping reasonably well until a couple of years ago, when I found that the same virus had started to infect my professional life. The first symptom was when genomics journals - ahead of the curve in adopting internet technologies - began demanding that I fill out an online form every time I reviewed a manuscript or even declined to do so. In other words, I was having to enter my information into the editorial database, exactly the job that the editor used to do. Soon, all journals began doing this, leaving me to wonder: so just what is it that editors do now? I suppose they could spend their time reading the reviews and making decisions, but some of the treatment of my own manuscript submissions (not to mention some of the stuff that's gotten published when I said shouldn't be) leads me to wonder if they’re even doing that. Maybe they’re just sitting around congratulating themselves on having gotten the scientists to do so much of their work for them. I've been ignoring as much of this as possible, usually just sending in my reviews or acceptance/decline-to-review by e-mail, although I increasingly feel like I'm trying to stand against a hurricane.

But the last straw as far as I'm concerned has come from the funding agencies. Not only have they started demanding that we submit parts of our grants electronically, thereby saving their administrators the trouble of entering that information into the grants databases; in some cases they have been insisting that we submit the entire grant electronically, as well as sending in paper copies to save them the trouble of preparing those. The US National Science Foundation does this, using an ironically named system called FastLane, which in its early incarnation (it's better now) was so buggy that it took me longer to submit one grant than it did to write it (it was only a short proposal but I’m not exaggerating). And I can't ignore such demands because, well, we're talking about the funding agencies here for goodness' sake, and noone can afford to alienate them. Their gleeful offloading of tasks onto us hasn't stopped with that, either, because now when they ask us to review grants, they don't send those by mail, they simply e-mail us the file and expect us to print it out for ourselves (the journals are starting to do the same with manuscripts for review). I'm sure their printing costs have gone down enormously; my printing costs, on the other hand, have gone up almost threefold over the past two years.

Given that all this seems to be irreversible, how can we keep from ending up doing everybody else's job as well as our own? My solution is to accelerate the trend to the point where it becomes threatening: in other words, we should do even more of the editors' and grants administrators' work. We should reject our own papers regardless of what the referees say, just like they do. We should submit our grants with reviews we prepare ourselves, plus detailed funding decisions including, of course, budget cuts that make it impossible to do half the work we need to do. We should harass ourselves for reviews even when we have been asked to review four manuscripts/grants by the same journal/agency. If we do enough of these things, eventually publishers and the heads of funding agencies will realize that they don’t need any editors or administrators at all, but I'm hoping that before that happens those employees will see the danger coming and reverse this horrible process. And then we can get back to the way things should be. You and I will just do our jobs, and they will just do their jobs. Whatever those are.

Published: 27 May 2005

Eighty years ago

Genome Biology 2005, 6:114

Public acts of the State of Tennessee passed by the sixty - fourth general assembly, 1925. Chapter no. 27, House Bill No. 185 (By Mr. Butler)

AN ACT prohibiting the teaching of the Evolution Theory in all the Universities, Normals and all other public schools of Tennessee, which are supported in whole or in part by the public school funds of the State, and to provide penalties for the violations thereof.

Section 1. Be it enacted by the General Assembly of the State of Tennessee, That it shall be unlawful for any teacher in any of the Universities, Normals and all other public schools of the State which are supported in whole or in part by the public school funds of the State, to teach any theory that denies the story of the Divine Creation of man as taught in the Bible, and to teach instead that man has descended from a lower order of animals.

Section 2. Be it further enacted, That any teacher found guilty of the violation of this Act, Shall be guilty of a misdemeanor and upon conviction, shall be fined not less than One Hundred $ (100.00) Dollars nor more than Five Hundred ($ 500.00) Dollars for each offense.

Section 3. Be it further enacted, That this Act take effect from and after its passage, the public welfare requiring it.

Passed March 13, 1925

Those who were there say it was one of the hottest Julys anyone could remember, and that part of Tennessee can get very warm in mid-summer. It was even hotter in the courthouse - not just because there was no air conditioning (it hadn't been invented in 1925), but also because of the passions burning in the trial lawyers, the witnesses, and the spectators. Forget the O.J. Simpson trial, the Clinton impeachment, and any other claimants - in the US at least, the Scopes Monkey Trial, as the press dubbed it, really was The Trial of the Century.

How could it not be, given the issues involved and, especially, the cast of characters? The question was not whether John Scopes had taught a high-school biology class from a book mentioning evolution, in direct violation of Tennessee House Bill No. 185 - no one disputed that he had. No, the question was whether the law, prohibiting the teaching of anything that denied the biblical story of creation, was against the Law of the Land - the Constitution of the United States. Scopes was the figurehead; it was evolution, and by extension science itself, that was actually on trial. Reporting on that trial in a series of savagely sarcastic dispatches was H.L. Mencken, the brilliant, iconoclastic journalist from the Baltimore Evening Sun. Appearing as consultant for the prosecution was William Jennings Bryan, the greatest orator of his day. Champion of the Populist movement that was spawned in the depression of the 1890s (the most severe economic downturn in the nation's history to that point), he was a man of curious contradictions. Though a religious fundamentalist, he supported women's suffrage. Though conservative, he had backed many of the reforms of the Progressives. Three times he had run for the presidency of the United States, and he had served in high office under President Woodrow Wilson, yet he abandoned his political career to crusade against the teaching of evolution, which he regarded as a menace to the country. Consulting for the defense was Clarence Darrow, certainly the greatest trial lawyer of the time, and arguably the greatest in US history. Deceptively folksy in manner, the agnostic Darrow was famous for having persuaded a judge to sentence Leopold and Loeb, the teenage 'thrill killers' of a young boy, to life in prison instead of to death. He was brought into the trial by the American Civil Liberties Union, which had offered to defend any Tennessee teacher who broke the anti-evolution law. The ACLU and Darrow hoped that the case could be taken all the way to the US Supreme Court, which they were confident would overturn the law on the grounds that it violated the Establishment clause of the Constitution, which prohibits any law establishing a state religion. But things didn't turn out that way.

Almost everything people think they know about the Scopes Monkey Trial is wrong. John Scopes wasn't some crusading high school biology teacher persecuted by bigoted townsfolk. He wasn't a biology teacher at all. He was a general science teacher (hired to teach algebra and physics) and part-time sports coach who occasionally filled in as a biology teacher. He wasn't persecuted, either. He didn't volunteer to be prosecuted for breaking the law, he was drafted, by several Dayton businessmen who saw an anti-evolution trial as a chance to get their little town some free publicity. It's not even clear that he, personally, ever taught evolution, although he used the state's old standard biology textbook, which had evolution in it. And after his conviction, Scopes wasn't run out of town, he was asked to stay on by the Dayton school board, but the 24-year-old now former teacher accepted a scholarship offer from the University of Chicago to study geology instead. He spent the rest of his life as a field geologist and died in 1970.

As for the bigoted townsfolk, no less than Mencken found himself quite taken with Dayton, calling it "a country town full of charm and even beauty", where "Evolutionists and Anti-Evolutionists seem to be on the best of terms". He could detect no hatred in the hearts of its citizens, but no doubts either. There still don't seem to be any: today Dayton, the buckle of what Mencken called "the Bible Belt", has one church for roughly every 200 of its 6,000 residents. Despite its significance, the Scopes Monkey Trial was less a Clash of the Titans and more a Twilight of the Gods. Bryan, though he did not know it, had only days to live. Darrow never participated in another important court case. Mencken grew even more misanthropic, his wit and stylistic genius dulled by drink and bitterness.

Bryan didn't die in the courthouse at the end of the trial while giving a fiery speech against evolution, as plays and movies have sometimes depicted. In fact, his last speech was never given at all. Bryan had written it for use in the closing argument to the jury, but Darrow changed Scopes' plea to guilty at the last minute since the intention all along was to appeal the conviction to Federal courts. Bryan did die in Dayton, though - five days later, in his sleep, of apoplexy. Darrow wasn't treated like a pariah in the town, either - in fact, he and one of the prosecuting attorneys, Ben McKenzie, became close friends. It is true that Darrow and Bryan had once been political allies, when Bryan was President Wilson's Secretary of State, but by the time of the trial Darrow had come to regard Bryan as an ignorant bigot who had to be stopped. That is why, on the seventh day of the trial, in what The New York Times termed "the most amazing court scene in Anglo-Saxon history", Darrow called Bryan to the stand as a witness for the defense, to testify as an expert witness on the biblical view of creation.

Under Darrow's withering examination, Bryan stumbled badly, displaying both ignorance and close-mindedness. The unfavorable publicity resulting from his performance is thought to have set back anti-evolution movements in a number of other states.

One famous speech was given by Darrow on the second day of the trial. It impressed all who heard it, even some of the prosecutors, one of whom said it was the greatest speech he had ever heard. Here is part of it: "If today you can take a thing like evolution and make it a crime to teach it in the public school, tomorrow you can make it a crime to teach it in the private schools, and the next year you can make it a crime to teach it to the hustings or in the church. At the next session you may ban books and the newspapers. Soon you may set Catholic against Protestant and Protestant against Protestant, and try to foist your own religion upon the minds of men. If you can do one you can do the other. Ignorance and fanaticism is ever busy and needs feeding. Always it is feeding and gloating for more. Today it is the public school teachers, tomorrow the private. The next day the preachers and the lectures, the magazines, the books, the newspapers. After while, your honor, it is the setting of man against man and creed against creed until with flying banners and beating drums we are marching backward to the glorious ages of the sixteenth century when bigots lighted fagots to burn the men who dared to bring any intelligence and enlightenment and culture to the human mind."

Yet, equally memorable words were spoken by a relatively unknown attorney for the defense, the ACLU volunteer Dudley Field Malone. Arguing, on day five of the trial, that expert testimony from scientists should be admitted (the judge ruled against this), he said: "There is never a duel with the truth. The truth always wins and we are not afraid of it. The truth is no coward. The truth does not need the law. The truth does not need the force of government. The truth does not need Mr Bryan. The truth is imperishable, eternal and immortal and needs no human agency to support it. We are ready to tell the truth as we understand it and we do not fear all the truth that they can present as facts. We are ready. We are ready. We feel we stand with progress. We feel we stand with science. We feel we stand with intelligence. We feel we stand with fundamental freedom in America. We are not afraid."

The trial certainly garnered plenty of publicity for Dayton, but it wasn't the kind the town had wanted. "It gave Dayton a black eye," says Judge James McKenzie, Ben McKenzie's grandson, who still lives in Dayton and works in the same building where Bryan and Darrow fought each other 80 years ago. "And", he adds, "the case didn't solve anything." John Scopes never paid a dollar of his $100 fine (not an inconsiderable sum for a teacher in those days) because his conviction was overturned on a technicality before ever reaching the federal courts, and the great Constitutional case that Darrow hoped for never happened. It wasn't until 1968, in the case of Epperson vs. Arkansas, that the US Supreme Court ruled that an anti-evolution law was unconstitutional. And then the state was Arkansas, not Tennessee, and the high school biology teacher was Susan Epperson, not John Scopes.

The trial didn't even lead to a triumphant restoration of evolution in the Dayton classrooms: Tennessee's anti-evolution law stayed on the books until 1967. Today Dayton, Tennessee is home to Bryan College, founded by creationists in 1930 to commemorate their legal victory over science. It has 600 students whose studies are "based upon unequivocal acceptance of the inerrancy and authority of the Scriptures". (It's a funny thing, this inerrancy and authority of the Scriptures. A number of other religions have their inerrant and authoritative texts too (the Koran, for example). Since their teachings differ, they can't all be the word of God. They can't all be inerrant. So who decides which is the right one, making all the others wrong? This sort of question comes up in the movie version of the Scopes trial, and the screenwriters have Spencer Tracy, playing Henry Drummond (the Clarence Darrow figure), say: "The Bible is a book. It's a great book. But it's not the only book.") The students at Bryan College would disagree. In science classes they are taught that God created the world and everything in it about 6,000 years ago; that the Grand Canyon was carved out by water in about three weeks, and that, in the words of one of their geology professors, "Scripture trumps interpretations of physical data."

I have a problem with the consistency of those who argue that everything in the Bible must be taken as literal truth. When Christ calls himself "the Lamb of God", even the most ardent fundamentalists don't actually believe he is telling us that he is a baby sheep. Why then do they have trouble accepting the idea that other things in the Bible, like the creation story in Genesis, might also be metaphoric? From the wellspring of this insistence on a literal interpretation of Scripture has flowed a river of ignorance, prejudice and persecution. It has retarded human progress and plunged families, tribes, and nations into bitter and sometimes bloody conflict. Interestingly, the title of the famous play and movie based on the Scopes trial, Inherit the Wind, is taken from the Bible, from the Book of Proverbs [11:29]: "He that troubleth his own house shall inherit the wind." But the most significant lines are next: "And the fool shall be servant to the wise of heart."

In 1965, 40 years after his trial, John Scopes wrote, "I believe that the Dayton trial marked the beginning of the decline of fundamentalism. Each year - as the result of someone's efforts to better interpret what the defense was trying to do - more and more people are reached. This, in conjunction with the labor of scientists, educators, ministers and with the dissemination of the results of their efforts through books and news media, has retarded the spread of fundamentalism. But most importantly, I feel that restrictive legislation on academic freedom is forever a thing of the past, that religion and science may now address one another in an atmosphere of mutual respect and of a common quest for truth. I like to think that the Dayton trial had some part in bringing to birth this new era."

Forty more years have passed, and sadly, it is clear that Scopes was wrong. The new era looks depressingly like the old era. Fundamentalism, it seems, was only sleeping and has now risen as powerful as before. Restrictive legislation on academic freedom is a thing of the present. Driven in part by fear of the consequences of advances in medical technology and genomics, the public in many states, such as Kansas, are considering passage of laws that, if they don't actually prohibit the teaching of evolution, mandate the teaching alongside Darwinism of alternatives such as 'Intelligent Design' - which tries to find evidence of a guiding hand (most of its proponents don't use the word 'God', at least not officially) in nature, and which, despite the claim of some of its proponents that it has no theology in it, mixes, as a Nature editorial puts it, "the supernatural with scientific doctrine".

Intelligent Design, like Creationism, is metaphysics, not science. It is perfectly appropriate as subject matter for religion class and probably for philosophy class, but not for biology, or geology, or any other science class. Attorney Malone articulated these sentiments on day 4 of the Scopes Trial: "The broad purpose of the defense will be to prove that the Bible is a work of religious aspiration and rules of conduct which must be kept in the field of theology. The defense maintains that there is no more justification for imposing the conflicting views of the Bible on courses of biology than there would be for imposing the views of biologists on courses of comparative religion. We maintain that science and religion embrace two separate and distinct fields of thought and learning."

The following things are not opinion, they are fact. The earth is several billion years old. Life on earth began several billion years ago with simple single-celled organisms. Over a period of billions of years, life evolved from that primitive beginning to complex multicellular organisms, including humans, by a process consisting of random genetic changes and natural selection. Although some of the fine details of the process are still uncertain (for example, the relative contributions of gradual change versus 'punctuated' or sudden bursts of change), the general features are not, and are completely consistent with all available evidence.

Evolution is not called a 'theory' because it is just an opinion. It is called a theory because in science a theory is an explanation for observations. The theory of evolution is as solid in biology as the theory of relativity is in physics. I've said it before but I think it bears repeating: if there is a God, evolution is how He/She/It works. To deny that is to be the fool that Proverbs refers to. Much of the appeal of Intelligent Design stems from the need many people have for a view of the world that doesn't conflict with their religious beliefs. Scientists could probably do a better job explaining that the truth about the way the world has evolved does not have to be a threat to people's faith. For me, the best words associated with the Scopes Monkey Trial don't appear in the official transcript. They don't appear because nobody at the trial ever said them. They were the invention of the writers of Inherit the Wind. I offer them for consideration, as today we continue to wrestle with the issues debated by Bryan and Darrow 80 years ago. I especially offer them as a question for those who believe that evolution is incompatible with divine revelation. How do you know that God didn't speak to Charles Darwin?

Published: 30 June 2005

The life aquatic

Genome Biology 2005, 6:116

I don't normally find myself agreeing with George W. Bush on virtually anything, but I have to admit he might have a point about going to Mars. On 14 January 2004, in a speech at the headquarters of the US National Aeronautics and Space Administration (NASA), he outlined a number of goals for the future of that agency. Here's what he said about one of them: "With the experience and knowledge gained on the moon, we will then be ready to take the next steps of space exploration: human missions to Mars and to worlds beyond. Robotic missions will serve as trailblazers - the advanced guard to the unknown. Probes, landers and other vehicles of this kind continue to prove their worth, sending spectacular images and vast amounts of data back to Earth. Yet the human thirst for knowledge ultimately cannot be satisfied by even the most vivid pictures, or the most detailed measurements. We need to see and examine and touch for ourselves. And only human beings are capable of adapting to the inevitable uncertainties posed by space travel."

Not that I agree with him completely. I think he said the right thing, but not necessarily for the right reasons. I don't know if, given the enormous costs and risks associated with manned space flight, especially over interplanetary distances, satisfying some nebulous thirst to see and touch for ourselves is enough justification for huge expenditures of public money when we have so many unmet social needs on earth. I do think it might be a reason for spending private money, but that's another matter. And I think he has it completely backwards about humans being capable of adapting to the inevitable uncertainties posed by space travel: experience suggests that, when it comes to manned space flight, uncertainties are frequently fatal. Robots are expendable, people are not (unless, of course, the President had in mind sending liberals - the way his administration treats them suggests he may believe they are expendable). But I think there is a justification that does make sense, on both societal and scientific grounds (President Bush, who doesn't seem to know or care much about science, didn't mention it). I think if we want to know for sure whether there was, or still is, life on Mars, we have to send people there.

We've been sending robots, without much luck. Of course, the amount and type of terrain that a robot can explore is limited. So are its preprogrammed options for finding evidence for the presence of life. Although the experiments built into the early Mars landers were clever, they were based on a restricted, conventional view of what chemical activities a living organism ought to perform. Two Viking landers that reached Mars in 1976 carried out four basic experiments to search for evidence of life. First, gas metabolism: look for changes in the atmosphere inside a test chamber induced by metabolism in the Martian soil. Second, labeled release: Look for release of radioactive carbon dioxide by metabolism from organic material labeled by radioactive carbon. Third, pyrolytic release: search for radioactive compounds in soil by heating soil exposed to radioactive carbon dioxide. And fourth, mass spectrometry: search directly in Martian soil for organic compounds known to be essential to Earth life.

All these experiments were designed around the hypothesis that if there were life on Mars it would have a similar metabolism to life on Earth, and that it would have a similar biochemistry that was based on the same sort of organic compounds essential for life on Earth. The results of these experiments were ambiguous. The first three gave positive results, but the complete absence of any organic compounds in the Martian soil according to the mass spectrometry experiment suggested that the positive results for the first three were not evidence for life, but rather evidence for some sort of complex inorganic chemistry in the Martian soil. At a press conference to discuss these results, a NASA spokesperson proclaimed, "Viking not only found no life on Mars, it showed why there is no life there.... the extreme dryness, the pervasive short-wavelength ultraviolet radiation... Viking found that Mars is even dryer than had previously been thought... The dryness alone would suffice to guarantee a lifeless Mars; combined with the planet's radiation flux, Mars becomes almost moon-like in its hostility to life." True? Perhaps, but even if true, true only for the thinnest surface layer of the planet, in only two locations, which was all the robots could explore. And true only for the kind of life we could easily imagine.

My argument is that life as we know it now, thirty years later (in large part as a result of microbial genomics), has turned out to be so diverse in its survival strategies, so unpredictable in its morphologies, so subtle in its manifestations, that only a human observer, on the spot, has a realistic chance of recognizing it when he or she stumbles across it. I'm saying, if you'll pardon the analogy, that life is like US Supreme Court Justice Potter Stewart's famous remark about pornography: it's hard to define but we probably will know it when we see it. I'm further arguing that actual life, not the traces of life long dead, is what we should be looking for. Not just because that would be so much more exciting to find, but because it's what we're likely to find.

If there ever was life on Mars, then I think the probability is quite high that there still is. The ability of life to adapt to supposedly hostile conditions, given enough time, is astounding. This is true to some extent of eukaryotes, even metazoans, but it is overwhelmingly true for microorganisms. The complete genome sequence of the bacterium Deinococcus radiodurans provides a dramatic illustration. This little microbe, which was first discovered as a contaminant of irradiated canned meat, has been isolated worldwide from soil, animal feces, and processed meats, as well as from dry, nutrient-poor environments, including weathered granite in a dry Antarctic valley, room dust, and irradiated medical instruments. It can survive radiation doses 1,000 times greater than those that were thought to be lethal to all forms of life. After acute exposures to ionizing radiation, early stationary phase D. radiodurans cells can reassemble their entire 3.285 megabase-pair genome, which consists of four haploid genomic copies per cell, from the hundreds of radiation-induced DNA double-strand broken fragments, without lethality or mutagenesis. And this is despite the fact that the number of genes in this bacterium devoted to DNA repair is actually smaller than that found in Escherichia coli. Microbiologists believe that the extraordinary resistance of D. radiodurans to DNA damage arose not as an adaptation to high levels of radiation, but rather as a response to desiccation. In an arid environment, dormant D. radiodurans cells would gradually accumulate DNA lesions of all kinds, including strand breaks, leading to the requirement for a full complement of repair capabilities.

Thus, if life similar in generation time and genetic plasticity to our earthly bacteria once existed on a Mars that was warmer and wetter than it is now, unless that particular environment disappeared literally overnight it is reasonable to suspect that such microbial life had enough time to adapt to the changing conditions. So far, our robotics missions haven't seemed to make much use of this reasoning in their attempts to find evidence for life there. We've either looked for indirect evidence that life existed once, or we've looked for existing life that has certain metabolic or other characteristics similar to mesophilic and, especially, thermophilic organisms on earth. The former is just too dicey - our own fossil record is woefully incomplete, plus it's not easy to be sure that what looks like a fossilized microorganism really is one - and the latter seems to me to be a classic example of the drunkard looking for his lost car keys under the lamppost, not because he dropped them there but because that's where the light is.

In this case, the lamppost is genomics. Ever since the US National Science Foundation launched its program for the study of 'extremophiles', microorganisms that live in extreme conditions of temperature and pressure, genome sequences of these extraordinary creatures have been piling up faster than they can be analyzed. Unfortunately, nearly all of them are sequences of thermophiles - bacteria and archaea that grow at temperatures above about 50°C. There are several reasons for this, including the utility of such organisms or their thermostable proteins in industrial processes, not to mention our curiosity as to just how that thermal stability is achieved.

At first glance, extreme thermophiles would seem to be ideal model organisms for life on other planets. They tend to have stripped-down genomes, perhaps because they don't need so many enzyme catalysts - a number of chemical reactions proceed pretty well on their own at high temperatures. Many of them are anaerobic and can survive nicely in the absence of an oxygen atmosphere; some even grow on methane, which is found in abundance in some planetary atmospheres. Thermophilic archaea, in particular, are thought to be the best examples we have of some of the earliest single-celled organisms in the evolution of life on earth. And if we were looking for evidence of ancient life on Mars, they would also be the best examples we have for what that might look like, assuming of course that it looked anything like something we know. But if we're looking for life that's still there today, they're probably not such good examples at all.

Mars might have had a hot surface once, but it certainly doesn't have one now. Early life on Mars may well have been - probably was - adapted to high temperatures, but any life there today must of needs be adapted to extreme cold; to an absence of molecular oxygen in the atmosphere; to scarcity, if not outright absence, of liquid water in the immediate environment; and to dangerously high levels of certain types of radiation. D. radiodurans proves that adapting to radiation is no problem. Neither is living without oxygen, the ultimate electron acceptor in eukaryotic metabolism. But the enormous range of solutions to the problem of deriving energy found among anaerobic bacteria - some of which utilize metal ions, others sulfur, still others nitrates or arsenates and so on in place of O_2 - suggests that it would be difficult, if not impossible, to program a robot to anticipate even the strategies we know about. (My favorite example of this sort of thing is the bacterium Sulfolobus acidocaldarius, which inhabits hot (+85°C) and sulfurous thermal springs: it lives in boiling sulphuric acid. S. acidocaldarius is a chemoautotroph, utilizing CO_2 as a source of carbon and hydrogen sulfide as a source of energy (electrons), in a process similar to anoxygenic photosynthesis.)

Then there's the problem of adaptation to low, as opposed to high, temperatures. Most evolutionary microbiologists believe that the earliest organisms were thermophiles: the early earth was hot, and primitive enzymes wouldn't need to have been very efficient in a thermophile because elevated temperatures would help push reactions along. The early history of life on earth therefore was probably largely governed by the need to adapt to reduced temperatures as the planet cooled, which required the evolution of better catalysts. Some organisms never had to do this, of course, because they remained in a hot environment, like the thermophilic bacteria and archaea found in hot springs or the volcanic ocean vents - and indeed, most of their enzymes, when assayed at room temperature, have relatively low catalytic activity compared with their homologs from mesophiles (organisms that grow best at 20-50°C, like E. coli or us). And a few organisms, such as those on the Antarctic continent or those existing far underground, would have had to adapt not just to reduced temperatures but to temperatures close to or below 0°C.

There is genome sequence information for a few psychrophiles, bacteria whose optimum growth temperature is below 20°C, but in general adaptation to sub-zero conditions has received little attention. Such adaptation might have consisted of biosynthesizing anti-freeze compounds that depress the freezing point of water (some Arctic fish make anti-freeze proteins for this purpose; some insect larvae biosynthesize glycerol in the winter to keep their body fluids liquid). Some psychrophiles are adapted for life in very cold environments, close to the freezing point of water; an example is Polaromonas vacuolata, which lives in antarctic sea ice. This organism reproduces best at temperatures of 4°C; above 13°C, it cannot reproduce at all. Not all psychrophiles are bacteria; there are some eukaryotes, and even some multicellular organisms. In 1997, colonies of tubeworms were discovered living in methane hydrate deposits (a combination of natural gas and ice), 1,800 feet down on the bottom of the Gulf of Mexico. These ice worms are believed to get their food via symbiosis with colonies of chemoautotrophic bacteria living within them.

More work is urgently needed, both to discover and to characterize such organisms, because the nighttime temperatures on the surface of Mars are low enough to freeze the liquid that is inside any of the organisms we have characterized thus far. Obvious places to look for extreme psychrophiles are the two polar regions, Siberia (which has a town called Oymyakon that is the coldest permanently inhabited place on earth, where the temperature can fall as low as -96°F (-71°C)), and of course Boston in mid-winter, San Francisco in mid-summer, or the interior of any English home any time.

Equally interesting is the problem of adaptation to low-water environments. Life as we know it can exist without molecular oxygen, without elevated temperatures, without sunlight. It can probably even, if our speculations about the primordial RNA world are correct, exist without DNA or proteins. But it can't exist without liquid water. There's nothing else like H_2O in the universe as far as we know. Very few simple substances are liquid at temperatures likely to support life. Most of them are either too reactive, like acetic acid, or too nonpolar, like liquid methane, to serve as the basis of an intracellular medium in which polar substances can be dissolved without decomposing. Only water, the 'universal solvent' of alchemical lore, has just the right amount of chemical reactivity plus suitable physical properties. Einstein, in a famous remark, said that when he retired he wanted to devote the rest of his life to thinking about light. I think that when I retire I'd like to think about water, and I suspect many biochemists would feel the same way. No computer model successfully predicts all of its remarkable properties - in other words, we still don't really know the details of the structure of arguably the most important chemical substance of them all. What we do know is that life without it seems to be impossible. A human being can go without food for two months and live. He can't last a week without water. Microbial life is equally dependent on liquid water, with one amazing exception: some bacteria and fungi, when dessicated, form spores and in that state they can exist for many years without external water, even when frozen solid.

Sporulation is my candidate for the model system to look at if we want to understand what we may find on Mars. No one knows exactly how long spores can survive dessication and still be able to germinate, but fungal spores found inside Egyptian tombs were still able to grow when rehydrated, after presumably several thousand years of drought. Extreme cold is also no problem for at least some bacterial spores, which can be cooled close to absolute zero without impairing their ability to germinate when warmed back up. Thus, spores are known to survive precisely those conditions that exist on Mars today. Spores are probably the closest thing we know of to true suspended animation - if indeed they are suspended. For the remarkable thing is that, with the exception of some pioneering work by Shelly Chu, Pat Brown, and the late Ira Herskowitz on genome-wide changes in gene expression during sporulation induced by nitrogen starvation in yeast, we know very little about what goes on, or does not go on, inside a spore. Bacterium-like creatures on a warm, wet Mars millions of years ago may, as the climate slowly changed into one of cold and dryness, not have been able to adapt fast enough still to be able to proliferate. But if they could sporulate, there's a chance that those spores are still there, waiting for a little liquid water - with, probably, the right nutrients in it - to wake them up. What those nutrients are I don't know. Where the spores are I don't know either. But I do know that if I'm right, NASA and other government science agencies should be funding a lot more microbiology and genomics on spore-forming, arid-surviving and extreme psychrophilic bacteria. And also, of course, bacteria that exist considerably below the surface of the earth, because it is deep in the Martian soil that we are most likely to find organisms, or their spores, that learned how to deal with the hostility of the planet's surface. I can't imagine a robot finding, or recognizing, such spores or such microbes, much less figuring out what to do with them. But I think a trained microbiologist walking around on the surface of the planet, and digging into it in the right places, might.

So, until we have a better idea just what the universal hallmarks of life really are - if, of course, there are any - I don't see any alternative to human exploration of other planets and their moons (at least those where conditions that might conceivably support life either seem to exist or are likely to have existed in the past). Answering the question, "Is there life on other worlds?" requires the flexibility and imagination of the human mind, with input from the human eye, guiding the human hand. That's assuming we think the question is so important that it's worth the risk to human life to be certain of the answer. But are there many, if any, scientific questions that are more important? Life elsewhere in our own solar system would virtually guarantee life - and probably intelligent life - elsewhere in the universe. Certainty of that would change so many things: our view of our place in the cosmos, our philosophies, perhaps some of our religious beliefs, our very sense of what is possible. And right now, of all the places in the solar system that we just might be able to send a human being to, there is only one that has a realistic chance of giving a "Yes" answer. If Mars ever had life, then the odds are it still does. I'd love to know if that's true before my own life is over. Wouldn't you?

Published: 28 July 2005

Trinity

Genome Biology 2005, 6:118

"The whole world lit up." That's how Jack Aeby, who took the only color photograph of the event, remembers the explosion of the first atomic bomb, at Alamogordo, New Mexico, 60 years ago, at 5:30 in the morning, on Monday, 16 July 1945 (you can see the historic picture at http://www.npr.org).

Another observer had a similar thought. J. Robert Oppenheimer, the scientific head of the Manhattan Project that created the bomb and a student of Sanskrit literature, was suddenly reminded of a verse from the Bhagavad Gita:

If the radiance of a thousand suns

Were to burst at once into the sky

That would be like the splendor of the Mighty One.

Richard Feynman, standing twenty miles from Trinity, as the site of detonation was called, was nearly blinded by the flash. One and a half minutes later, the sound of the explosion reached his ears.

It was at about that moment that Oppenheimer, stationed far forward, recalled a second verse from the Gita:

I am become Death,

The shatterer of worlds.

Kenneth Bainbridge, the Harvard physicist who also worked on developing the atomic bomb, shared this sentiment but expressed it more prosaically. As Oppenheimer went around congratulating the assembled physicists on their success, Bainbridge shook his hand and looked him in the eye. "Now", he said, "we're all sons-of-bitches."

It was Bainbridge who selected Alamogordo as the site for the test blast. He did not know that the place he had chosen was haunted ground. The Spanish settlers had a different name for it, commemorating a long-forgotten tragedy. Bernardo Gruber, a German peddler who traveled El Camino Real up from Mexico City to the Spanish outposts along the Rio Grande, had a run-in there with the Spanish Inquisition in 1669 over the selling of magical charms. Gruber was imprisoned on a rancho near Sandia Pueblo (later Albuquerque) for two years. Somehow, he managed to escape, only to be killed by Apaches while fleeing back to Sonora. The lonely and desolate place on the trail south of Socorro where Gruber's body was found came to be known as 'Jornado del Muerte' (The Dead Man's Route). That was the spot that Bainbridge had chosen, and that Oppenheimer code-named Trinity.

The Allied atomic bomb project came about, as everybody knows, because Albert Einstein wrote a letter to US President Franklin Delano Roosevelt, warning him of rumored German efforts to develop a nuclear weapon, and urging that the US begin a crash program to do the same. Einstein actually only signed the letter, which was written by two Hungarian physicists, Eugene Wigner and Leo Szilard. In fact, the atomic age really began, as so much else in physics did, with Szilard, a nomadic theoretician with an engineer's instinct for the practical. Six years earlier, as he crossed a London street, in a flash of insight he had realized that a self-sustaining nuclear chain reaction unleashing untold amounts of energy could be created from the right fissionable materials. Richard Rhodes, in his magnificent book, 'The Making of the Atomic Bomb' (New York: Simon and Schuster; 1988), describes the moment: "In London, where Southampton Row passes Russell Square, across from the British Museum in Bloomsbury, Leo Szilard waited irritably one gray Depression morning for the stoplight to change. A trace of rain had fallen during the night; Tuesday, 12 September 1933, dawned cool, humid and dull. Drizzling rain would begin again in early afternoon. When Szilard told the story later he never mentioned his destination that morning. He may have had none; he often walked to think. In any case another destination intervened. The stoplight changed to green. Szilard stepped off the curb. As he crossed the street time cracked open before him and he saw a way to the future, death into the world and all our woe, the shape of things to come."

In the summer of 1939, Szilard and Wigner, alarmed by reports that Germany was about to embark on a project to produce just such a chain reaction, decided to visit Einstein, who was spending that July at a friend's house on Long Island. They succeeded in attracting his interest, but he would only agree to write to the Belgian ambassador, whom he knew. Later in the month, convinced that the letter must go to Roosevelt, they drafted it and decided to drive back out to Long Island. But Wigner was unable to make the trip and Szilard did not know how to drive a car, so they enlisted fellow Hungarian physicist Edward Teller to act as Szilard's chauffeur.

It was foggy that night, Szilard did not remember the way, and they became lost in a maze of streets on Long Island. Finally, Szilard said, "Maybe it's not meant to be. Maybe we should go home." Just then, they saw a young girl about 10 years of age, walking down the street. "Do you know where Dr Einstein is staying?", they asked her. "Sure", she said. "Do you want me to take you to him?" Einstein served them tea and then signed the letter Szilard had prepared.

Wigner, who told me this story when I was a student at Princeton almost forty years ago, said it was appropriate that a child, a messenger of the future, as he put it, had played so instrumental a role in ushering in the Atomic Age. I saw it differently. It seemed to me that the child, if she symbolized anything, symbolized innocence, and that the moment Wigner described was the last time physics would ever have that virtue.

It's been said by more than one person that because of the atomic bomb physicists have known original sin. What's meant by that, of course, is just this loss of innocence, a knowledge of not only good but evil. I think it's instructive, 60 years after Trinity, for biology, as we leave the Atomic Age and enter the Age of Genomics, to ask why that is so. The same thing has never been said of chemists, despite nerve gas and Bhopal and a long catalog of chemical horrors. My guess is that this is because chemistry has always had one foot firmly planted in the worlds of commerce and the military. It's always been seen as a practical science. Physics, especially atomic physics, was a 'pure' science, where the pursuit of knowledge for its own sake was the entire raison d'etre. The employment of that science for the making of weapons of mass destruction gave atomic physicists enormous political influence and access to almost limitless research funding, but the price was that purity of mission. When, three weeks after Trinity, the two bombs were dropped on Hiroshima and Nagasaki, at least a quarter of a million people lost their lives to nuclear physics, and neither the world, nor physics, was ever the same again. Leaving aside the question of whether or not those bombs should ever have been dropped (and I'm of the opinion, reluctantly, that Truman's decision to do so saved hundreds of thousands, perhaps millions, of Japanese lives as well as Allied lives), it was suddenly, powerfully clear that Oppenheimer and Bainbridge were right about what physicists had become.

Biology now stands where physics stood in the days before Trinity. Like physics, it has long been thought of as a 'pure' science, whose applications, if any, were to the advancement of human health. But the spectre of bioterrorism and the ethical dilemmas posed by advances in genomics, reproductive biology, human genetics and genetic engineering maybe presenting it with the Faustian bargain of influence and money in exchange for innocence and purity of purpose. I am not advocating abandoning these discoveries or the technologies they are creating. But if the lesson of Trinity is that the mistake the atomic physicists made was in not considering the full implications of what they were doing before undertaking it, so that the ethical dilemma caught them unawares, then I think there is something we should do.

My opinion of bioethics as a discipline is ambivalent, to say the least. On the one hand, many of its practitioners seem to me to be neo-Luddites whose lack of understanding of science is coupled with a socially conservative agenda. But a number are thoughtful, concerned people who raise important questions and realize the danger of simplistic answers. Every biology graduate program in the US that receives Federal funds is required to put its graduate students and postdocs through a course on the responsible conduct of research. Unfortunately, these courses, which tend to be taught by bored faculty and attended by even more bored students, usually focus on such subjects as plagarism, intellectual property, and conflicts of interest. I think the requirement should be extended to cover basic elements of bioethics, such as the following. What subjects, if any, should be excluded from free inquiry? What duties does a researcher owe to the society that funds his or her science? What, if anything, should never be published because it might be too dangerous in the wrong hands? How does a scientist balance the obligations of self with those of the public? Who should make decisions about bioethical matters and on what grounds?

Many other topics could be covered, but you get the idea. To those who would argue that most students would find such material as boring as the plagarism and intellectual property lectures, my response is that I have no interest in what they think. Anyone who finds these questions of no interest is never going to be a leader or opinion-shaper in the area of science and public policy anyway. But I'm hoping that a small number of young scientists will be interested enough to continue to think about these questions, to talk about them with their peers, and to play a role in shaping the way biology deals with the future that stretches before it. If they don't, such matters will be left entirely in the hands of politicians, religious leaders, and activists, and personally I don't trust any of them.

Oppenheimer looked at Trinity and thought that he had become Death. Bainbridge saw the same spectacle and had a similar, less poetic thought. They were right. They were right because nuclear physicists, in part because they were at war but largely because the challenge was so seductive, thought more about what they could do than what would happen if they did it. It may be that such reflection would have changed little - that's my guess, actually - but one thing I think would have changed: the role of physics in the nuclear age would have been more than just to service the appetite of the weapons industry it created. I want our bright young biologists to start thinking now about the ethical issues of what we can do and will be able to do in the future. I want them to participate in the dialogue with the politicians and the activists and the general public. I don't want them to bury their heads in the sand and pretend that this is not their concern. Because if they don't engage, and some day in the future, because of something we do, the whole world, figuratively, lights up, what then will we have become?

Published: 30 August 2005

Half right

Genome Biology 2005, 6:120

There's a wonderful moment in the equally wonderful 1973 film 'Sleeper', in which doctors in the year 2173 are discussing their new patient, Miles Monroe (played by the film's director, Woody Allen), who has just been awakened, like Rip van Winkle, from a 200-year hibernation (the result of a botched operation). "This morning," says one of the physicians of the future, "for breakfast, uh, he requested something called wheat germ, organic honey, and tiger's milk." To which another doctor remarks, "Oh yes. Those are the charmed substances that some years ago were thought to contain life preserving properties." "You mean," says the first doctor, "there was no deep fat? No steak, or cream pies, or hot fudge?" "Those were thought to be unhealthy," replies the other, "precisely the opposite of what we now know to be true."

Woody Allen would not be surprised at a thesis put forward by John Ioannidis, a Professor of Epidemiology who divides his time between University of Ioannina School of Medicinein Greece and Tufts University in the US, and neither, I suspect, would most Americans today. In an Essay just published in the Public Library of Science's journal PLoS Medicine, entitled "Why Most Published Research Findings Are False", (PLoS Medicine 2005, 2: e124), Ioannidis asserts that "there is increasing concern that in modern research, false findings may be the majority or even the vast majority of published research claims. However, this should not be surprising. It can be proven that most claimed research findings are false." He goes on to give a few reasons why, arguing that claimed research findings may often simply reflect the prevailing bias, or be influenced by financial and other interests.

I won't summarize the statistical arguments he goes through to try to prove his point. They depend on models for bias and testing by several independent teams, and on my reading have a certain ad hoc character that makes me somewhat suspicious of them, but let's assume they may be valid. They lead him to some interesting corollaries, as follows. First, the smaller the studies, the less likely the research findings are to be true. Second, the smaller the effect sizes, the less likely the research findings are to be true. Third, the greater the number and the lesser the selection of tested relationships, the less likely the research findings are to be true. Fourth, the greater the flexibility in designs, definitions, outcomes and analytical modes, the less likely the research findings are to be true. Fifth, the greater the financial and other interests and prejudices, the less likely the research findings are to be true. And sixth, the 'hotter' a scientific field, the less likely the findings are to be true.

I think items one through four should be subject to debate, but five and six sound logical to me, given human nature. Anyway, after six pages of basically arguing that every factor one could think of contributes to findings being false, Ioannidis never actually gives a final figure for what percentage of published results are wrong. In previous publications and interviews, however, the figure of somewhat over 50% gets bandied about, so let's be generous to ourselves and assume it's about half. That's what most science writers did when they wrote stories about this article - and did they ever write stories about it. Almost every important newspaper in the US carried reports with headlines screaming that half of all scientific research is false, many of them on the front page.

And it does seem as though every week there's a new report that contradicts a previous report. Fat is bad for you. No, it's not. Yes, it is. No, not all fat is, only certain fats. No, you need some of all fats. No, you don't. And so on. The yo-yoing in the popular press over the benefits versus the risks of birth control pills and hormone replacement therapy alone must have caused many women to run screaming to their doctors, who probably were just as confused as their patients. And given that the issues in most of the articles I’m talking about can be expressed as yes or no questions, the figure of 50% wrong sort of makes sense.

But is that really the case? Looking at the essay in moredetail, I don't see how it can be. First of all, the title of the paper, "Why Most Published Research Findings Are False", gets my vote for the stupidest, most misleading title of theyear. Nearly all of the examples are taken not from scientific research in general but from medical research in particular, and most of them concern clinical trials of drugs or reportson the health benefits of various foods and diets. These do tend to be reported in 'yes or no' terms, so it's understandable why one might guess that half of them are false. And such studies suffer from a number of other factors that make them grist for the Ioannidis mill. They are frequently funded by organizations that have a vested interest in the outcome, so charges of bias are easier to make (though perhaps not to prove). They are often relatively small studies with a large number of variables. And they are being performed with the most difficult, pernicious, inhomogeneous experimental subjects in all of science: people. Finally, their results are usually reported in statistical terms, and many reporters, not to mention scientists, have only a rudimentary grasp, at best, of statistical concepts and pitfalls.

Few if any of these factors apply to many other areas of science. Hardly any of them apply to most branches of physics and chemistry or to basic research in general. Drug trials and tests of nutrients and environmental factors on human health are examples of highly targeted research with relatively absolute end-points. Basic research is not only more openended, it is a continuum. Studies tend to evolve rather than end, and intermediate results are publishable. Data are usually reproducible. Conclusions may be overturned as new data become available, but that doesn't make the research false, because the data are often right. I can’t count the number of times I have gone back to the older literature and extracted enormously valuable data from a paper whose conclusions are no longer believed to be true. Classifying research papers as true or false belittles and grossly oversimplifies the way most fields work.

Besides, I wonder if it has occurred to the author of the essay that, if most published research findings are false, then his work is also more likely to be false than true, which would mean that most published research findings are true, which would mean that his are also likely to be true, which would mean that most published research findings are false, whichwould mean... what?

I can't help thinking we wouldn't be in this mess if so many scientists, especially in medical research, didn't feel it necessary to trumpet their findings in newspapers and popular magazines even when the real impact of the work is minimal. I have gotten so jaded with breathless statements of increased risk of dying from this or that which turn out to have only a 5-10% increase in the odds ratio that I have made it a policy not to get concerned unless the risk changes by at least a factor of two.

Of course, even that rule of thumb has to be applied carefully. It works most of the time because the odds of getting most diseases are pretty low if one is in good overall health,so a change of 10% in a probability of 1 chance in 500, say, really doesn't amount to much. But there are situations where the risk is large enough that small changes in it matter. Neurodegenerative diseases like Alzheimer's and Parkinson's have risk factors that increase exponentially with age after one turns 60, and become quite high by the time one approaches 90, so things that modify those risks even by small amounts are worth attention. Polymorphisms in oncogenes and tumor-suppressor genes may also confer moderately increased risks of cancer in certain populations - an example is the I1307K single-nucleotide polymorphism in the APC gene, which is carried by about 1 in 20 Ashkenazi Jews and almost doubles their risk of colon cancer. I've become a big advocate for personalized medicine because things like that have important consequences: knowing one carries that mutation, for example, would seem to dictate earlier and more frequent colonoscopies than are usually recommended. As for claims for this vitamin or that type of diet, I've decided that most of those studies do nothing except increase by about 33% my chance of losing my lunch. Few fields are so beset with overinflated claims, misapplied statistics, and employment of scare tactics. Ioannidis is right about those papers, I bet. But his conclusions don't apply to other fields. And he shouldn't have implied that they do.

So let's see if I've got this right. Half of all medical research isright, and half is wrong, as long as this paper claiming that half of all medical research is wrong is right, but since there's an equal probability it's wrong, that would mean that the half of all medical research that was wrong might be right after all, unless of course all medical research is wrong, which would also be consistent with this paper being right. Right? Of course, I could be wrong.

Published: 30 September 2005

H5N1

Genome Biology 2005, 6:121

The year 2005 might just go down in history as The Year Nature Struck Back. Earthquakes kill more than 50,000 in Pakistan and Kashmir (proving how stupid it is for people to fight one another when sooner or later they will need each other). More than 1,000 die in hurricane-spawned floods in Mississippi and Louisiana (exposing the sorry state of both the infrastructure and the emergency response system in the US). Eight straight days of rain dump a foot of water on New England, weakening ancient dams (there's that infrastructure problem again) and threatening numerous towns with severe flooding. And as I write this the 21st tropical storm of the Atlantic season, Wilma, is churning up the waters of the Caribbean, with a projected path towards Florida via the battered Gulf of Mexico. Wilma is also the 12th hurricane of this season, tying a record set in 1969 (the 21 tropical storms also tie a record, set in 1933).

How bad has it been this year? Well, we're about to run out of letters of the alphabet: tropical storms are named alphabetically each year, with boy's and girl's names alternating (it used to be only girl's names until someone suggested that this seemed a tad misogynist, as in fact it was). For some reason the letters Q, U, X, Y and Z are not used (no hurricane Quasimodo, Ursula, Xavier, Yves or tropical storm Zorro), so if more than 21 storms occur - and they might well; the storm season doesn't officially end until November 30 - the Greek alphabet will be used, starting with Alpha. That hasn't happened since they started keeping records in 1851.

But of all the natural disasters, actual or potential, that beset us this year, the one that seems to terrify people the most is the possibility of a flu pandemic. The H5N1 influenza strain, first identified in Asia (where it has killed 65 of the 117 people known to have been infected by it since 2003, 44 of them in Vietnam), has now turned up in dead birds in Turkey and Romania, and probably in Greece as well, although that hadn't been confirmed when this article was being written. These latest findings lay to rest a long-standing argument about whether influenza outbreaks that start in domestic poultry can become a pandemic by the agency of migratory birds. Obviously, they can. And that is something to be very concerned about, as I'll explain in a minute. Normally, I don't get too worked up over widely publicized threats. The fact that everybody is worried about something makes it much less likely, in my experience, that things will turn out as badly as feared (remember the 'Y2K' computer bug?). It's the unexpected that usually produces the greatest consequences. So, since everybody is so worried about the possibility of a pandemic of influenza, doesn't that mean, ipso facto, that I'm not that worried? Unfortunately, it doesn't. Not in this case. I'm afraid an influenza pandemic is very much something to worry about.

The term pandemic refers to an outbreak of a disease that spreads over huge areas. Fortunately, there have been relatively few in recent history, largely because increased scientific understanding of the causes of disease has led to improved public health policies. But funding for public health is in decline in most countries, including the US, and it is worth recalling that there have been a number of pandemics in the past 100 years (starting with the great influenza pandemic of 1918), and nearly all have been outbreaks of flu. Major flu strains are named for the particular alleles of the two major viral coat proteins they contain. The outer shell of the membrane-enveloped influenza virus is studded with spikes of a sugar-binding protein called hemagglutinin (the 'H' in the strain designation) that is involved in target-cell recognition and fusion of the viral membrane with that of the cell, and a sugar-hydrolyzing enzyme called neuraminidase (the 'N'). Hemagglutinin seems to tolerate more mutational variability than does neuraminidase: there are about 15 different strain types of hemagglutinin and 9 of neuraminidase, making at least 135 potential major viral strains. Some infect birds; others infect pigs; still others, people, and so on. H5N1, which has hemagglutinin type 5 combined with neuraminidase type 1, is primarily an avian virus. It is particularly virulent for poultry, and has a high capacity for genetic change, both by single mutations and by recombination with the genetic material of other flu strains.

The history of the H5N1 strain tells us a lot about the way flu works. It also tells us a lot about the responses of people and governments to it. The strain was known as a purely bird flu for decades, but in 1997 it passed from chickens to humans in Hong Kong, causing the death of 6 people out of 18 infected and leading to the destruction of some million chickens. That radical action squelched the epidemic, and it also taught scientists that the high avian virulence of H5N1 also applied to humans. Late in 2003 and early in 2004, outbreaks of H5N1 occurred in poultry farms in Cambodia, China, Indonesia, Japan, Laos, South Korea, Thailand and Vietnam. In February 2004, the strain was detected in pigs in Vietnam, showing that it had acquired the ability to infect non-human mammals. Fresh outbreaks occurred in China in July of that same year and in Malaysia in August. Ominously, also in August the first cases of human infection were reported in Vietnam and Thailand. These were almost exclusively poultry farmers. As had been the case in the 1997 Hong Kong outbreak, the mortality rate among infected humans was very high. In January of this year a major outbreak occurred among poultry in Vietnam: 33 of the 64 cities and provinces were affected. In an attempt to contain the epidemic, 1.2 million poultry were slaughtered. It is estimated that over 100 million birds died of the disease.

In May, it became clear that H5N1 had started to spread beyond southeast Asia. Migratory waterfowl began dying from the disease at Quinghai Lake Nature Reserve in Western China. Storks, geese and gulls are known reservoirs of avian flu virus but they rarely become ill from it. This variant of H5N1 was apparently even more virulent than usual. Public health officials became alarmed, because in the fall there are mass bird migrations from Asia to Africa, by way of Russia and Turkey. In July, the first human fatality in Indonesia was reported. In August, the virus was confirmed in birds in Mongolia and Kazakhstan; by the end of the month, it had spread to south-western Russia. In September, the United Nations health representative who would coordinate a worldwide response to a pandemic, David Nabarro, estimated that a pandemic among humans could kill up to 150 million people worldwide. And last month, analysis of dead birds in Turkey and Romania confirmed that H5N1 had reached continental Europe.

Simultaneously, a team from The Institute for Genome Research (TIGR) reported the complete sequence of 207 H3N2 isolates and two H1N2 isolates, giving the first comprehensive picture of influenza virus evolution (Ghedin et al.: Nature 2005, 437:1162-1166). They observed point mutations, deletions and segmental exchanges. Their most dramatic finding is the discovery of an epidemiologically significant reassortment that explains the appearance, during the 2003-2004 season, of the 'Fujian/411/2002'-like strain, for which existing vaccines had limited effectiveness. They conclude "not only that the influenza virus population contains multiple lineages at any given time, but also that alternate, minor lineages can contribute genetic variation to the dominant lineage, resulting in epidemiologically significant, antigenically novel strains."

The best example of what an "antigenically novel strain" can do to the world is the great 'Spanish flu' pandemic of 1918. No one knows exactly how many people died that year, worldwide, but the estimates range from 20 to 50 million, making the 1918 flu the deadliest single epidemic in world history. (More people may have died from the Black Death of the 13th century, but that was actually a series of epidemics stretching over decades. It killed a third of Europe, but spared most of the rest of the world. The 1918 'Spanish' flu hit almost every continent.)

It's funny about that 1918 pandemic. When I was a boy no one talked about it, even though there were plenty of people alive who had been through it. No books or newspaper articles were written about it, and every flu season didn't begin with panicky reminders of that devastating autumn. The 1918 flu spread around the globe in just a few months - in an era before regular airplane travel. It killed more young people than old people. On one day alone, October 10, it killed 342 people in New York and 514 in Philadelphia. It killed so many people in Boston that they ran out of coffins. It killed with alarming quickness, a trait not seen before in influenza epidemics. Religious folk thought the world was coming to an end. It was followed by an even more mysterious disease, an epidemic of sleeping sickness, encephalitis lethargica. Over a fifteen year period, 5 million people around the world came down with this malady. A third died quickly; one third never recovered, remaining virtually comatose for the rest of their lives. A bright young British pianist, Philip Leather, age 13, came down with encephalitic lethargica in 1933 and was admitted to the Royal London Hospital in Whitechapel. He never left, dying there on December 15, 2002, age 82, the last known survivor of the strangest epidemic in history. He, the disease that destroyed his life, and the flu pandemic that preceded it were all but forgotten until recent years. They've been rediscovered now, in part because scare stories about emerging diseases sell books and newspapers, and there's an appetite among the reading public for history that seems relevant to our times.

And there's another reason it makes a lot of sense to be thinking about the 1918 pandemic these days. In a remarkable feat of forensic genomics, teams of scientists have succeeded in genome sequencing (Taubenberger et al.: Nature 2005, 437:889-893), and then reconstructing (Tumpey et al.: Science 2005, 310:77-80) the influenza virus strain that caused the 'Spanish' flu. Their work shows that it was unquestionably an avian virus. But it wasn't, as people thought for years, the strain called H1N1. It appears to have been a variant of H5N1. The 1918 pandemic virus genome was reassembled from fragments recovered from preserved tissues from 1918 victims. The reconstructed virus is as lethal as feared; it kills mice more quickly than any other human flu virus known. Three genes appear to be the chief contributors to its virulence: the hemagglutinin is unusually potent in latching onto the surface of cells; the virus doesn't need to rely on its host cells for the protease trypsin to cleave and activate the hemagglutinin - the neuraminidase appears to do that. (This may be why the 1918 virus, like some highly virulent bird flu strains, can grow in any cell type, not just trypsin-containing lung cells.) And finally, the 1918 strain has polymerase genes that allow it to replicate very efficiently in human bronchial cells. The polymerase genes are similar to those found in bird flu, including H5N1 in Asia, so the researchers conclude that the 1918 flu probably arose directly from a bird virus without combining with a flu strain already adapted to humans, unlike the strains that caused the much less lethal 1957 and 1968 flu pandemics. For example, there are only 10 amino acid positions (out of 2,232 total codons) that consistently distinguish the 1918 polymerase proteins (and those of other strains that infect humans) from their avian influenza counterparts. The present H5N1 strain making its way out of Asia already has some of the mutations it needs to look a lot like the 1918 strain. The rest could accumulate over time, but it would probably take quite a while. What is worrying public health officials is the possibility that, since influenza can also evolve through genetic rearrangement, time may be about to run out.

Currently, in humans, H5N1 has an extremely high mortality rate but a very low rate of bird-to-human infectivity and, as far as is known, a zero rate of human-to-human transmission - yet. It's the 'yet' that has everyone in a sweat, because the way avian flu strains were thought to acquire that capability is when they infect a mammal (a pig, say, or a person) that is also infected with a more human-like flu virus, and the two strains exchange genetic material, just the sort of recombination event the TIGR team describes. So the current efforts of public health officials to contain the virus are focused on culling flocks that contain infected fowl so that the probability of human infection is kept extremely low. That strategy will probably work in Europe, and maybe even in the Middle East, but the migratory birds that are now spreading this disease aren't planning to spend the winter in Nice, as attractive as that location may be: they're heading for East Africa. That's right, the same East Africa that is so beset by famine and war that two things seem certain: one, that no one there is going to kill domestic fowl herds en masse - food sources are just too valuable; and two, the local public health infrastructure is not likely to be able to prevent simultaneous infection of mammals with both avian and human viruses.

That's one reason there is such a fuss about the flu drugs oseltamivir (Tamiflu, by Roche) and zanimivir (Relenza, by GlaxoSmithKline). These are a new class of antiviral compounds that work by inhibiting the neuraminidase. They are also among the first structure-based pharmaceuticals ever developed. They are the brainchild of an Australian named Graeme Laver, who works at the John Curtin National University in Canberra, Australia. He was one of the scientists who showed that the 1968 pandemic was caused by a virus that arose through genetic reassortment. Realizing that the best target for an antiviral drug should be an enzyme, he set out to determine the crystal structure of the neuraminidase in 1978. He couldn't get any major pharmaceutical company interested in his crystals so he took them to a young protein crystallographer at CSIRO in Melbourne named Peter Colman. Colman solved the structure in 1982. It made the cover of Nature. The structure immediately revealed a highly conserved cavity in the active site, a perfect target for drug development. Starting with a compound developed years before by two Viennese chemists that was a weak inhibitor, Colman and Laver began to use a series of neuraminidase-inhibitor crystal structures to produce an improved binder. They did this through a small company they formed called Biota, with the aid of chemist Mark von Itzstein. Once they had their drug, they tried shopping it to big pharma again, and again no one seemed interested. Finally Colman persuaded Glaxo to take a chance, and Relenza (Glaxo's name for zanimivir) was born. Once one major drug company decided that influenza drugs were a good idea, the rest of the pharmaceutical industry, with that creativity and daring that characterizes it, jumped right in. Next past the post was Roche, with a compound they called Tamiflu (oseltamivir, originally designed by a small company, Gilead).

Tamiflu is the major focus of drug stockpiling now, because it can be given orally (Relenza must be taken as a powder in inhaled form). In 1994, Fred Hayden of the University of Virginia was the first person to give a neuraminidase inhibitor (Relenza) to a human being. The clinical trial data show that these drugs shortened the recovery time of infected individuals by a couple of days, reduced the risk of complications, and when taken prophylactically seemed to protect against infection in many cases. Since they hit a highly conserved target, there is every reason to believe that they will work against most strains, including H5N1 variants, but to date their effectiveness against the reconstructed 1918 strain has not been established as far as I know, and there is too little experience with them in the field to know if resistance to them can develop rapidly. Certainly it can develop: a variant of H5N1 resistant to Tamiflu has just been discovered in Vietnam (Le et al.: Nature 2005, 437:1108). Vaccine development for flu, as well as for other viral scourges, is still lagging way behind where it needs to be, making the neuraminidase inhibitors the front line defense against an H5N1 outbreak in a human population center. So, the fact that people now seem to be buying and hoarding these drugs in a panicky response to the scare stories about H5N1 is very troubling. Indiscriminate use of the drugs by ordinary people could be a disaster: 100 million people around the world get 'ordinary' flu every year, and all it might take would be a few years of Tamiflu and Relenza use for such relatively harmless flu cases to produce a reservoir of resistant human virus. Resistant, and just waiting for a bird flu to exchange genes with.

So, for now the best thing for us to do is to wait, too. Wait, and hope that the H5N1 virus doesn't make it to East Africa. Because if it does, we may look back on the events of 2005 wistfully. Which reminds me of a story: two businessmen are sitting at lunch, bemoaning their lot. "What a time I've had," groans the first one. "Two years ago I lost $50,000; last year I lost $100,000, and this year I lost $200,000." "That's nothing," says the second. "I spent a fortune sending my son to medical school. When he finished, he decided he didn't want to be a doctor; he wanted to be a lawyer. So I spent another fortune sending him to law school. Now that he's finished that, he says he doesn't want to be a lawyer. He wants to be a painter. What could be worse than that?" And the first man says, "Next year."

Published: 1 November 2005

Who steals my identity steals trash

Genome Biology 2005, 6:122

"'Who steals my purse steals trash,"' said my mother, a lifelong Bardophile, using a favorite quote from Othello to make a point to her then-10-year-old son, "but if someone steals your good name..."

"Shouldn't that be, 'Who steals my purse steals cash?"' I said brightly, thereby earning myself yet another in my seemingly endless childhood trips to the woodshed. (Yes, I was a smart-aleck even then.) But her point stuck. I know that one's good name is among the most precious of possessions. I also know that identity theft is no joke, and that those people to whom it has happened have often found it to be a prolonged nightmare. Nevertheless...

I've been thinking about this lately because, as the holiday season once again descends upon us with all the subtlety of a mudslide (in the US the Christmas shopping period now apparently starts in July, treating us to rather alarming pictures of Santa Claus in full winter regalia while the outside temperature has plunged to a frigid 94°F), I've been doing a lot of shopping online. It's convenient, rapid, offers a wide range of choices, and seems natural since I spend about 23 hours a day at the computer terminal anyway. And of course, every online merchant has plastered the store website with reassurances of how secure the transaction is. "Don't worry," they say, just as I'm about to enter an increasingly worrisome amount of personal information, which doesn't yet include sexual history but wait until next year, "this transaction is completely secure." That's supposed to alleviate all my anxieties.

You'll note that they don't tell you how it's secure (except for some occasional techno-gobbledygook about WEP or LEAP encryption systems) - possibly because if they did, it would make it much easier for nefarious persons to breach that security, but equally possibly because they don't know. But one thing seems clear: the more secure they try to make it seem, the more personal information they demand. Not just your name, address, telephone number and e-mail address (which they swear on their father's grave they will never divulge to anyone else, but where the hell is all that spam mail coming from then?), but also your favorite pet's name (ostensibly in case you forget the password they also make you create, but possibly so that they can send that pet spam e-mail, as several companies now do to my dog) and of course your credit card number, the expiration date - I accidentally entered 2108 one time and the system just took it, never batted an eyelash - and lately, that mysterious, magical "security" number on the back of the card. I don't consider myself a stupid person, but I really don't understand this escalation of numbers. I mean, why is adding a third identifying number any better than just having the first two? If the identity thief has your credit card, he or she has that number too. And if the thief intercepts the transaction, he or she will also have intercepted that number. Yes, I realize that the additional number was probably introduced to foil people who steal credit card information from receipts at restaurants and other stores, where only the front of the card is copied. But I also realize that nearly everyone shreds such receipts these days, and that the receipts lack all the other personal information that the thief will need to make online purchases, which is the only place where the pesky third number is required anyway. Eventually the credit card companies and the online retailers must realize this too. No doubt they will respond by adding a fourth identifying number, presumably on the edge of the card.

But I digress (as usual). The point I'm trying to make is that I've thought about this identity theft issue, and I've decided not to worry about it. My cavalier attitude is not because I believe what the merchants tell me about security. (I never believe anything any merchant tells me, including "Going Out of Business Sale". One oriental rug company in my neighborhood has been going out of business for twenty-two years. They just expanded their store last month.) No, my blasé feelings come from careful consideration of the consequences, not to me, but to the thief, of anyone who steals the identity of an academic scientist.

The first thing our thief will probably try to do is use my credit card to charge some outrageous number of expensive purchases. Of course, like all academic scientists, I'm constantly hovering around the credit limit of my card, which, as soon as the credit card company stopped laughing when I disclosed my salary to them, they set at $11.50. So our first picture is of our thief, dazedly emerging from some posh retail outlet, holding the cut-up fragments of the credit card in his dishonest hands.

Now let's suppose the thief has decided to use the purloined information not just to steal my identity but to assume it - something that apparently happens more frequently than one might think. Armed with my background information, reputation and credentials, he is easily able to secure a low-paying job at a research university. In the first week, he has fifteen interminable committee meetings to attend, plus five hour-long classes and two evening recitation sections to teach. As he sits in his closet of an office, trying to ignore the inoperable climate control system while desperately writing lesson plans at his postage-stamp-sized desk, there's a knock on the door.

Identity Thief: "Come in."

Student: "Professor Petsko?"

IT: "No. I mean, yes. What do you want?"

Student: "I need these medical school recommendations filled out." (Deposits pile of fifty envelopes on desk).

IT: "Good god. Uh, when are these due?"

Student: "They're due tomorrow. Sorry for the short notice. Got to go to class. Thank you so much." (Students always say "thank you so much" now. "Thank you very much" seems to have gone the way of "roll" in rock-and-roll. Someday I must find out where old expressions go when they die.)

As our thief is sitting there, looking stunned at the mountain of papers, two more students enter in succession, each with even larger piles of envelopes, each with the same request.

An hour or so later, the identity thief is jerked out of his state of shock by the arrival of the day's mail, which brings with it two bits of news. The first is a letter from the editor of 'Nature Gerbil', stating that, regretfully, they are unable to publish Dr Petsko's submitted manuscript on the complete genome sequence of the common gerbil, because one of the six referees they have had review the paper dislikes the typeface that was used in the manuscript. The letter ends by saying that, as is their invariant policy, no appeal against this decision is possible.

The second letter is from a grants administrator at NIGMS - the National Institute of Gerbil Medical Sciences - stating that, regretfully, they will be unable to fund Dr Petsko's submitted application, 'Functional Gerbil Genomics', because it was only found to be in the top 3% of all submitted applications and this year the cutoff for funding is the 2% line. Reading the critique, the thief is stunned to find that the major criticism is that the application failed to give adequate details about how a particular set of experiments would be carried out. Because the identity thief has had to familiarize himself with my publications, he realizes that the technique in question was invented by me, fifteen years previously.

As he collapses back in his chair, the telephone rings, and an angry voice at the other end asks the thief why he has not yet submitted his required activity report. As soon as he hangs up, it rings again, and an even angrier voice demands to know why he is late with the referee's report he promised to write for that manuscript that was sent to him last week. Just then, a cheery 'You Have Mail' message pops up on his computer screen, announcing the arrival of a still angrier e-mail insisting that his overdue review article for 'Gerbil Cell' be submitted immediately.

So, I think we can all probably go about our holiday shopping with an easy mind. Because if someone wants to steal the identity of any academic, my response is: good luck to them. Inside of a week, I'm betting they'll be here, on their knees, begging us to take it back.

Published: 2 December 2005

Foxes and hounds

Genome Biology 2005, 6:124

I hadn't planned to write another column about the dog genome, but they insisted. Not my editors - their helpful suggestions usually take the form of "You're writing about WHAT?". It was Mink and Clifford, the two dogs who generously allow me to share their house in return for food, regular walks, throwing of tennis balls, and a copious supply of doggie treats. Ever since my column on the 1.5× draft dog genome sequence (Genome Biol 2003, 4:120), they have been trying to convince me that the most important part of the story had been overlooked by most of the pundits. Now that the new 7.5× sequence has been released (Lindblad-Toh et al.: Nature 2005, 438:803-818), they've been pestering me constantly. So I decided to revisit the topic, not only to keep them happy (though I do a lot of things for that reason alone), but also because I must admit they have a point.

Much of the excitement over the original 1.5× dog genome sequence, which was from Celera and covered about 75% of the 2.4 billion base pairs that comprise the 39 chromosomes of Canis familiaris (albeit with gaps in many genes), concerned the implications that a better understanding of canine biology would have for human biology. The extraordinary phenotypic diversity of the more than 500 different breeds of dogs (of which about 150 may qualify as distinct subspecies since they are reported not to exchange genes) has arisen in less than 50,000 years (although the exact time of domestication of the Asian grey wolf, the ancestor of all modern dogs, is uncertain). And since each pure breed - for example, Mink is a chocolate Labrador Retriever - is an isolated genetic population, their distinct morphological (for example, brown fur, big nose, drools a lot) and behavioral (lazy, big-hearted, always hungry) phenotypes can in principle be linked to specific genetic changes. The new science of behavioral genomics should get an enormous boost from the new, essentially complete (99% coverage) dog genome sequence. So should evolutionary and developmental biology. And much has already been written about the implications for human health: like most inbred strains, pure dog breeds are susceptible to specific illnesses (hereditary kidney cancer, for example, occurs only in German Shepherds, and epilepsy is found in certain other breeds), making the identification of disease genes relatively easy. Veterinarians have already found over 500 canine diseases that are similar to human hereditary diseases, and have used the dog to identify 25 associated genes. (Hybrid vigor is just one of many things that lead Clifford, a mixture of Cocker Spaniel and French Poodle, to believe that he is superior to his step-brother. Evidence suggests that, if this is true physically, it is certainly not true mentally.)

But that isn't what Mink and Clifford wanted me to write about. What fascinates them is that with the completion of the dog genome sequence the first step has been taken in understanding one of the most remarkable, and mysterious, phenomena in biology: domestication.

It would be hard to overemphasize the importance of domestication of wild animals in human progress. Jared Diamond devotes a huge section of his fascinating book, 'Guns, Germs and Steel', to the role that domestic animals played in the development of civilization. Until the invention of the steam engine, for over 100,000 years no human could travel faster than a horse could carry him or her, or haul a load greater than an ox could pull. Domestic animals made farming possible, which in turn allowed previously nomadic people to become settled, which in turn led to the creation of cities and permitted the rise of a leisure class that could focus its attention on philosophy, the arts, and scientific research. Diamond argues persuasively that the mere presence of domestic animals, and the consequent exposure of their human companions to the milder forms of infectious diseases that they carried (cowpox versus smallpox, for example), gave cultures with such animals an enormous competitive advantage over cultures that lacked them.

The dog was the first animal to be domesticated, and its single ancestor, the wolf, is still available in essentially original form as a basis for detailed comparison. Since the first 1.5× draft dog genome sequence was that of a poodle while the latest one comes from a boxer, we already have two different breeds to compare in some detail. About ten other breeds have had enough partial sequencing done (about 6%) to allow a large compendium of single-nucleotide polymorphisms (SNPs) to be derived. This information already gives some clues about the domestication process that led to Canis familiaris. Linkage disequilibrium within breeds extends over distances of several megabases, while across breeds the distance is typically tens of kilobases. Lindblad-Toh et al. interpret this as evidence for two principal genetic bottlenecks in dog history: one due to domestication and the other due to more recent breed creation from single sires. Interestingly, the Labrador Retriever, which is one of the most popular dog breeds (150,000 new puppies registered annually, but then Mink always did like big families) has not undergone a severe recent bottleneck because of much greater long-term diversity in breeding (we have long suspected that there might be some bloodhound in Mink's family tree, for example). Hybrid vigor has led to mixed breeds becoming increasingly popular, so in the future dogs like Clifford may become the norm - a frightening thought.

Arguments about domestication usually focus on anthropomorphic issues of 'choice'. Did some animals 'choose' to become domesticated, accepting a reliable source of food and protection in return for giving up control of their lives, or did primitive humans select certain species for a conscious program of domestication? Sociobiologists have championed both viewpoints. But the dog genome sequence suggests a much more interesting, and more answerable, question.

Exactly what morphological and physiological changes occurred as Canis lupis evolved into Canis familiaris, and what changes in its genome accompanied the process? We don't yet know, because the wolf genome sequence hasn't been done. In a News and Views piece accompanying the dog genome article (Ellegren: Nature 2005, 438:745-746), Hans Ellegren writes that the large genetic diversity seen among dogs is at odds with the hypothesis that only a few wild ancestors contributed to the domestic gene pool, and that it implies back-crossing with wild relatives continued long after the domestication process had begun. Maybe, but Mink and Clifford favor the hypothesis that there was a small number of ancestors, and they point out that one of the most intriguing, and in their opinion, underappreciated experiments in modern biology supports that view.

Forty-five years ago a Russian geneticist, Dmitry K. Belyaev, decided to test the hypothesis that the key property that natural selection operated on in domestication was not size or reproduction but behavior - specifically, a lack of anxiety and aggression that he called tamability. Belyaev believed that individual animals possessing this trait were most fit for survival in a human society, and that therefore the process of domestication would slowly select for it. Since behavioral changes are linked to hormonal changes, which in turn affect development, he further predicted that specific morphological traits might also follow. He chose as the subject of his experiment an animal that is close to the dog but has never been successfully domesticated, in fact, one thought it could not be domesticated: Vulpes vulpes, the silver fox. Starting with a breeding pair selected as being the calmest out of a population of 130 foxes from a commercial fur farm in Estonia, he kept culling and interbreeding those individuals who seemed to possess this behavior to the greatest extent (typically about 5% of male offspring and 20% of female offspring, and yes, I know what you're thinking). A series of tests were developed to identify those pups that seem most calm and friendly around humans. By the sixth generation, the tamest of the foxes would whimper to attract attention and sniff or lick experimenters like dogs, behavior unheard of in wild foxes. By the tenth generation 18% of the pups behaved this way; by the 20th 35% did.

Belyaev died in 1985 but twenty years later his experiment continues at the center he founded - the Institute of Cytology and Genetics of the Siberian Division of the Russian Academy of Sciences http://www.bionet.nsc.ru/indexEngl.html. Through genetic selection, the team of researchers there, now headed by Belyaev's former student Lyudmila Trut, has created a colony of tame foxes that differ not only in behavior (more than 80% of the pups now display the characteristics described above) but also in many physical characteristics from their progenitors. It took just 45,000 foxes and about 35 generations of selection to produce these docile, eager-to-please animals. The few that have escaped from their 'captivity' have always returned.

These domesticated pups respond to auditory stimuli two days earlier, on average, than wild fox pups, and their eyes open a day earlier. They develop a fear response weeks later than wild foxes, just about at the same time after birth (approximately 10 weeks) that it develops in dogs. They have less pigment in their coats. Their ears are floppier (more like those of a dog than a fox). Their legs and tails are, on average, shorter than normal. Their skulls are taller and narrower, and their snouts are shorter and wider. Most interesting of all are their reproductive patterns: the domesticated foxes reach sexual maturity a month earlier on average, and give birth to litters that are one pup larger. They also have a longer mating season. Not all of the domesticated foxes show these traits - in fact, most don't - but the presence in the population of some that do skews the averages. The estimate is that these physiological changes occur at least an order of magnitude less frequently in the wild. The mating behavior is unprecedented; fur farmers in Siberia have tried to breed such traits for over a century, without success. But they were attempting to select for that while the Belyaev team selected for something else, a behavior, and the rest just went along for the ride.

The most recent data from this wonderful experiment shows that, although the foxes were not specifically selected during breeding to be more skillful at solving social problems, they are in fact just as skillful as domestic dogs at reading human social cues (Hare et al: Curr Biol 2005, 15:226-230). It would seem that social intelligence can increase simply as a result of an animal becoming less fearful and aggressive towards potential social partners.

The experiments were designed to prevent inbreeding, and some of the new traits are controlled by dominant genes, which rules out a variety of trivial explanations. The most likely explanation is that there are specific genetic changes that can lead to increased tamability under selection for that trait, and that the same pathways influence morphology as well as physiology. One of the reasons why this is likely is because other types of animals, domesticated by different peoples in different parts of the world at different periods of history, all tend to show similar characteristics.

The anthropologist Darcy Morey and others have pointed out that domestic animals tend to be pedomorphic, that is they retain in the adult traits that are usually lost in wild animals when the juvenile matures. Young wolves whine for attention and are submissive; adult wolves do neither, but adult dogs do. Morey believes that other common features such as earlier sexual maturity and smaller body size would also be advantageous in colonizing a niche already occupied by another animal (that is, Homo sapiens). If that is true, there should be a common set of changes in genes involved in hormone-dependent signal transduction pathways that can explain all these developmental effects. Given the striking progress in only 35 generations in the Russian fox experiment, the number of genetic events may be relatively small.

In a study published last month, a group of Norwegian researchers have provided evidence for just that (Lindberg et al.: Curr Biol 2005, 15:R915-R916). Using some of the Russian lab foxes, which they imported in 1996, the Norwegian scientists compared gene expression for three brain regions in domesticated foxes with nondomesticated ones using cross-species hybridizations of pools of fox mRNA to human microarrays. Cross-species hybridizations are useful when the genome of the species under study is poorly known, and the method is sufficiently sensitive for identification of some genes with large expression differences. Only 40 clones showed mRNA expression differences attributable to domestication.

So Mink and Clifford would argue that a high priority ought to be a complete genome sequence of the grey wolf, plus a few of its closest non-domestic relatives (the coyote, the jackal and the African wild dog) to give a good baseline. They'd also like to see sequences for the wild fox and for one of the domesticated foxes done as soon as possible. I think they're right.

Some of the abilities of dogs are truly extraordinary: among my favorite charities are the various rescue dog associations (for example, see the Search Dog Foundation http://www.searchdogfoundation.org/98/html/index.html), which take unwanted dogs from shelters and train them to locate, by smell, humans trapped under rubble in disaster sites. These dogs can distinguish live humans from corpses and have saved hundreds of lives, most recently in earthquake-ravaged Iran. Other dogs have been able to identify early-stage human bladder cancers in urine samples, so successfully that when a number of the dogs persistently misidentified a control sample as being cancerous, the person providing the control was retested, whereupon he was found to have a previously undiagnosed transitional carcinoma of the right kidney (Willis et al.: BMJ 2004, 329:712). Humans have benefited from these and other canine traits for tens of thousands of years; in fact, we may owe our survival as a species to the dog. It's not hard to imagine that there may have been more than one moment in early human history where our few endangered ancestors, huddled around a Pleistocene fire, were warned of imminent danger by the far keener senses of their newly acquired wolf companions. And if there are more loyal, unconditionally loving friends to be had, I would like to meet them. One of the truest things ever said was: "I'd like to be the kind of person my dog thinks I am." Domestication is one of the few really complex biological processes that might be possible to understand at the molecular level with the kind of information genomics can provide right now.

And it may have other implications. Before Clifford came along, Mink paid no attention to police or ambulance sirens. The first time Clifford heard one, he lifted up his head and began to howl like, well, a wolf. Mink immediately did the same. Fifty thousand years of domestication notwithstanding, the call of the pack is still there. We might remember that this holiday season. The holidays throw into dramatic contrast the better and baser sides of our human nature. Great generosity lives side-by-side with the kind of savagery that daily headlines from Iraq remind us of. Studies of domestication may help us understand why, despite tens of thousands of years of 'civilization', our own wolf is still there, somewhere under the fur.

Published: 3 January 2006

Let's get our priorities straight

Genome Biology 2006, 7:101

Periodically, I like to amuse myself by making little lists. The Christmas holidays sometimes remind me of one I started making as a boy, back in Washington, D.C. It's a list dividing the presents I receive into categories based on my reactions to them. The top category contains 'things I never would have asked for but now wouldn't give up if my life depended on it'. High on this list is my copy of The Complete Sherlock Holmes, an omnibus edition of all of Conan Doyle's stories about the greatest detective of all time. My Aunt Ethel gave me that book when I was nine. I had never heard of Sherlock Holmes or Dr. Watson or 221B Baker Street before that Christmas morning. I settled down with the book in my favorite living room chair that afternoon and didn't budge for three days. My mother even brought my meals to me there, but I wasn't really in the house. I was in a magic country of the mind, where the fog rolls in off the Thames and the game is afoot and it is forever 1885. I still own that book. It's on a shelf flanked by Koufax, the autobiography of the great baseball pitcher, and my autographed copy of The Lord of the Rings by J.R.R. Tolkien, whom I knew during my student days at Oxford. They all fall into the same category of surprise delights. These are the three books I would first save from a fire.

Another category is 'things I really wanted and am glad I got'. My first bicycle is at the head of that list. I like cars, and I can say without boasting that I have driven, and owned, some truly exciting automobiles, but none of them meant as much to me as that first bike. It was a magic carpet that freed me from the boundaries of my own yard, and started me off on a lifetime of wanderlust. My first chemistry set is somewhere on this list too, as is every dog or cat I ever had, plus my first personal computer (a Mac, of course). I bought that last one as a gift for myself, and I must say I admire my taste.

Category three consists of 'things I really wanted and wish I hadn't'. This category seems to have a lot more adult items, which may mean my judgment has gotten shakier with age. For example, I really wanted another African-American judge on the US Supreme Court - to replace Thurgood Marshall, a great justice and great human being. I got Clarence Thomas. (I forgot to specify such additional qualities as intelligence and compassion.) I really wanted a new direction for structural biology as the field matured. I got Structural Genomics. (I forgot to specify that I didn't want the direction to be downhill.) Several ex-girlfriends are on this list, but good manners - not to mention fear - prevents me from naming names.

But the category that I want to discuss here isn't any of these. It's the one that gets my blood boiling every time I think about it: 'things I really didn't want any part of but got anyway'. George W Bush. Reality TV. The war in Iraq. Male pattern baldness. And of course, supplementary material.

I hate supplementary material. It's one of the worst ideas in the history of bad ideas. It's the scientific publishing equivalent of fighting a land war in Asia. Oh, I understand that publishers love it because by shortening papers it allows them to publish more articles per issue at a lower cost, but I really hate it. And I have lots of good reasons.

First, I despise the name. Supplementary implies something extra. A dietary supplement is added to the normal intake of food. But the supplementary material in a scientific paper isn't extra; it's just the stuff the editors made the author take out of the body of the article to reduce the number of printed pages. Or it's the stuff the authors really don't want you to look at too closely. The point is, it isn't extra, it's just deemed to be less important, like the credits at the end of a movie that go by so fast they're Doppler-shifted. A more accurate term for supplementary material would be 'inferior material' - at least that's how it's treated.

Second, nobody reads it. When was the last time you even downloaded the supplementary material in a paper, much less read it? It's hard enough to find time to download, print and read the actual papers; dealing with the S&M, as I like to call it, adds several extra steps. Much of the scientific literature is rarely read anyway, but S&M is like whatever they keep in the basement of the British Museum: only a few people ever get to see it, and you sort of wonder about them.

But the main reason I hate supplementary material is that it sends exactly the wrong message about our priorities. What typically gets put into S&M? The details of the experimental methods and often, especially for papers in genomics, tables and figures containing at least some of the primary data. The main paper gets summary figures and cartoons of models based on the data. The stuff my students and postdocs most often need to read - the methods section - is treated like an afterthought. What does that say to young scientists about the value of careful and creative experimental design, the need for good controls, and the importance of making sure that anyone can repeat what you've done? If the journals are emphasizing eye-catching, pithy stuff at the expense of the substantive, doesn't that imply that the first priority is how you sell your work? Doesn't it elevate our conclusions, colored as they are by our assumptions and self-interest, ahead of our observations? If the one thing we as scientists have going for us, our insistence on letting nature speak to us, is relegated to a supplement, then what's fundamental? The background? The conclusions? Only those portions of the results we choose to display prominently?

I understand that genomics experiments in particular produce reams of data. I've seen microarray or genome sequencing papers where the primary results would fill several issues of most journals. There's no cost-effective way to put that amount of material into a published document - short of a book - and I'm not insisting that we even try. Some sort of archive (usually web-based) is necessary for the results of such projects. But this consideration certainly doesn't apply to the methods. How the data were obtained should never be a supplement in any paper. The tendency to marginalize the methods is threatening to turn papers in journals like Nature and Science into glorified press releases.

I always thought that the most important thing in any scientific paper was supposed to be the data and how they were obtained. Everything else is window-dressing, because it's filtered through the lens of subjectivity. The background, the discussion - these are somebody's opinions. If the experiments have been done carefully and analyzed thoroughly, the data are the only facts in the paper, the only thing that can be trusted. They're what I want to read and understand. The people who obtained the data have the right to tell me what they think it all means, and I often find their opinions useful, but I also have the right to decide for myself. Yes, I can still do that if I dig out the supplementary material, but I shouldn't have to dig. If our priorities are straight, the methods and the data should be the centerpiece. And in the modern era, there's no reason not to put them there.

All online versions of papers should have no supplementary material, period. When I download a paper, I want all the relevant information in one place. If publishers insist on shorter printed documents, how about leaving out the discussion section (it would still be in the online version)? That would send a clear message about what really matters in science.

For me, Supplementary Material has all the charm of the safari jacket someone insisted on buying me back in the 1970s. (The American philosopher Thoreau said that if a man does not seem to be in step with his fellows, perhaps it is because he hears a different drummer. In my case, apparently they thought I was listening to jungle drums.) And so I say to all scientific publishers what I would like to say to everybody who contributed items on this particular list: I did not ask for this. Please take it back.

Published: 1 February 2006

Sweden has the right idea

Genome Biology 2006, 7:103

Of the many tasks that I do that are not directly connected with teaching, research or column-writing (including reviewing manuscripts and grant applications, sitting on various advisory boards, miscellaneous administrative chores and so on), the one that has given me the most satisfaction in recent years is one I do for the Swedish Foundation for Strategic Research. It involves reviewing applications for their Senior Individual Grants. I don't know anything quite like this grant program anywhere else, but I know a lot of places, including the USA, that could sure use one.

The first Senior Individual Grants competition was announced in 2003. Its stated purpose was to enable senior scientists with a strong track record to take up new challenges. Applicants had to be working in Sweden, in the research areas supported by the foundation (natural science, engineering and medicine). The goal was to enable these established investigators, in their 50's and 60's, to renew their research and explore new ideas, preferably of a cross-disciplinary, integrative nature. There was also an understanding that the proposed research should be of some clear benefit to industry and society in Sweden.

The competition had two phases. In the first phase, 18 grants, each of approximately €165,000 or $192,000 would be awarded for a period of one year, to enable the grantee to be relieved from ongoing tasks and assignments and to develop, primarily through time spent working at another institution, an entirely new research direction. In other words, the grant was essentially a fully funded sabbatical with that mission.

Phase two kicked in a year later, when the foundation announced a number of additional grants, each worth approximately €660,000 or $770,000, for further research activities over three years. Only those 18 grantees from the first stage were eligible to apply. The purpose of the second grant was, of course, to make it possible to turn the ideas developed during the previous year into a completely new research program. Twelve awards were eventually made at this stage, meaning that a senior scientist who passed the first phase of the competition had a 67% chance of getting the additional three years of support. The combination of a generous amount of money plus excellent odds of receiving it ensured that the program would attract the attention of a large number of senior scientists.

Applications were reviewed by both internal and external referees. I was one of the external group, and the foundation allowed me to follow the process all the way through - that is, the applicants whom I had reviewed in phase 1 and who were awarded one of the 18 planning grants were also sent to me for review for the phase 2 competition (along with a few I hadn't seen before). Thus, I got to see exactly how these scientists used their year of rethinking their research, and what projects they now intended would come out of it.

Talk about fascinating. The subject matter ranged from systems biology to nanotechnology. Nearly all of the applicants I reviewed at the first stage were distinguished scientists with international reputations, but it had to be said that most of them seemed to be on what I would call the downward part of their careers. They were still publishing, but generally doing things very similar to what they had been doing for more than 20 years. They mostly weren't working at the cutting edge any more because the cutting edge had moved away into other areas. In short, they were at the stage of their scientific lives when many researchers find themselves unable to sustain the level of excellence they once displayed, and tend either to keep repeating themselves or slowly wind down into irrelevance. Yet, given the chance to come up with something new, a significant number of them managed to find - through time spent in other labs, usually in other countries - creative and important new ideas to work on. In most cases this amounted to a significant change in scientific direction, and in many it represented a shift to a whole new field. Some of the ideas were mundane, but most were not, and many were highly imaginative.

Why hadn't these researchers done this before? The answer, I think, lies in the way science is supported. Once you have established yourself as a young scientist, the conservative funding system, which tends to prefer giving money to things that seem likely to work rather than to things that are innovative and therefore risky, rewards those with a track record so long as they continue to do the things they have a track record in. Try working in a new area and you will often be discounted as overly ambitious (read, 'naive') or unfocused (read, 'straying too far from your own turf'). Anyone with a new idea faces these problems, of course, but they're particularly acute for the middle-aged scientist. Science is seen as a young person's game, and there is an unspoken expectation that senior researchers - and often the fields they work in - should slowly be put out to pasture, leaving the racetrack for the colts and fillies.

I think the notion that science belongs to the young has a lot of truth in it, but I also don't think it's the whole story. Studies of the aging brain have shown that, while younger minds consistently trump their elders in situations that call for fast reactions and cleverness, older people do better in tasks that require wisdom and experience. Since creativity often involves many of these skills, it isn't reserved exclusively to one generation. Certain types of creativity (poetry, for example) do seem to be fueled best in the fires of youth, but musical composition doesn't show the same burn-out with age, and neither does philosophy. Mathematics and theoretical physics clearly are the provinces of young scientists (why is not clear), but biologists on average do their best work in their forties and fifties, and many have done very important work well past that. Genomics is too new a science to judge how it will stack up in this regard, but given that at its highest levels it seems to require both imagination and a broad view of biology, I might predict that significant contributions could be made by scientists of a wide range of ages.

It seems particularly silly to make it difficult for senior scientists to change fields when the history of science in general, and biology in particular, is filled with examples of breakthroughs made by researchers who came into a field from outside, bringing with them a different perspective - and sometimes new techniques - without the burden of the prejudices and unchallenged assumptions that often bedevil those who have long labored in it. Senior scientists would seem to be among the best equipped to do just that, but how are they to change research directions when they are forever type-cast to be what they have been? In the USA, some private foundations such as the Ellison Medical Foundation and the McKnight Endowment for Neuroscience do award research funds largely on the basis of the novelty of the idea and the overall track record of the applicant, without requiring a previous history in the specific field, and anyone fortunate enough to obtain support from the Howard Hughes Medical Institutes can switch directions easily, but these are exceptions. The rule is that once you have established yourself in a field it is hard to break out of it, and the older you are the harder it gets. Many senior scientists are indeed winding down, and it is crucial to make way for bright young talent, but my experience with the Swedish Senior Individual Grants program leads me to believe that we may be wasting a significant number of middle-aged scientists who could be making significant contributions in new areas if only they were given the chance.

If the Swedes do have the right idea, how hard would it be to implement such a program elsewhere? It should be highly competitive, so even in a large country we're not talking about more than a few dozen awards. Let's say, in the USA, 50. I like the Senior Individual Grants model and it has seemed to work, so why not copy it? The first year, the award would be $200,000 to cover salary and expenses for the year of planning the new research program. Only scientists 50 years of age and older would be eligible. That's $10 million for the first year of the program, not a large sum. Then out of those, pick the 30 best proposed programs after the year is up, and fund them for three years at $333,000 per year. Repeat the program every four years. The steady-state cost would be $10 million yearly. If the results after 12 years suggest that there is indeed a significant untapped resource in the pool of senior scientists, then we could consider expanding the program, but for now, why not start small and see what happens? The amount of money involved is modest enough that a foundation could do it if the government doesn't have the will.

As I said, reviewing the Senior Individual Grants proposals, watching these middle-aged scientists get excited about their new directions, and seeing the clever things they have come up with, has been one of the most gratifying things I've done. To think that it's possible to renew your career at a time when conventional wisdom might doubt that makes me more optimistic about the fate of the aging scientist. All that might be needed for many is the chance to show what they can still do. And oh yes, in case you're wondering: I'm 57.

Published: 1 March 2006

The system is broken

Genome Biology 2006, 7:105

It's not true that things have never been this bad before. They were about the same in the early 1970s. But it is true that they have never been worse. When a scientist doing work in genomics, or cell biology, or biochemistry, or immunology submits a grant proposal to the US National Institutes of Health (NIH), the largest supporter of life science research in the world, his or her chance of it being funded are at historic lows. And this situation is threatening to destroy the jewel in the crown of US science, the system of competitive peer review of research applications.

In contrast to the hierarchical system in many other countries, where research funds are often distributed to heads of departments or centers, who then dole them out to their component research groups, in the United States most university research faculty are independent entrepreneurs, who compete with one another for funding on the basis of the quality of their proposals. The competition is judged by the applicant's peers - scientists in the same general area of research. This Darwinian selection system has, for over half a century, largely guaranteed that merit, not cronyism, determines what science is supported by the federal government. The procedure is straightforward, and until now has worked remarkably well.

But I think the procedure has stopped working well because of the perception that financial support for science in the US is drying up. Thanks to the war in Iraq and tax cuts mostly for the richest Americans, federal funding for life science research, which doubled over a seven year period not long ago, has remained flat in real dollars and declined in inflation-adjusted dollars during the last few years. To make matters worse, scientists from all disciplines flocked to the NIH for support like pigs to a trough during the budget-doubling period, resulting in a huge increase in the number of submitted research proposals. And NIH administrators didn't help matters either. They seem to have assumed that the big increases in their budget would go on forever, and rather than engineer a soft landing for when the inevitable crash came, they spent like sailors on shore leave, mostly for big new programs that benefited only a small number of investigators (Hello, Structural Genomics Initiative). And since new programs are like living creatures and fight for survival with the ferocity of a cornered wolverine, the chance that we could rid ourselves of these white elephants when budgets got tight has, of course, turned out to be zero.

With chance for support dwindling, individual investigators, the lifeblood of creative scientific research, are beginning to flee the field. I personally know of many young research students who are either going into industry or leaving science altogether because they believe that they have little possibility of being able to obtain funding were they to set up their own laboratory. And I know of an equal number of senior scientists who are going into administration or taking early retirement, not because they want to, but because they have become discouraged about the prospects for continued support.

The Bush administration and our own greed are to blame for this situation, but the immediate cause of the problem from the perspective of the individual investigator is what I see as a breakdown of the peer-review system. Unless that can be fixed, the likelihood of a turnaround, even if budget levels improve, is not good.

Peer review of applications submitted to NIH takes place in two steps. Applications for support from the NIH are evaluated initially by peer-review groups of scientists who are assigned grants to review on the basis of their expertise. The objective of this initial peer review is to determine the scientific and technical merit of the proposed research project. If the project represents a continuation of one funded previously, the productivity during that period is also considered in evaluating the competing renewal. The panels that review the proposals are called Scientific Review Groups and are managed by Scientific Review Administrators, employees of the Center for Scientific Review, one of the approximately 27 institutes and centers that are the components of the NIH. Approximately half of the proposals considered at a particular Scientific Review Group meeting will be triaged as being not competitive for funding at all. The top half are discussed in detail and are assigned priority scores: numerical ratings of scientific merit from 100 (best) to 500 (worst). The scores are converted into percentile rankings that indicate, for example, whether a grant is in the top 20% of all grants scored by that group (the 20th percentile). After the conclusion of the meeting, the Scientific Review Administrator prepares a summary statement for each discussed proposal that includes the reviewers' written comments, recommendations of the group and the priority score and percentile ranking. The summary statement is sent to the program staff of the awarding institute and to the applicant. (The second level of peer review is carried out by the NIH National Advisory Councils. These councils are composed of scientists from the extramural research community and public representatives. They are meant to ensure that the NIH receives advice from a cross-section of the US population in the process of its deliberation and decisions. Councils don't usually overturn the funding decisions of the Science Review Groups, but they do have that power.)

There is some confusion about the meaning of the percentile score awarded by Science Review Groups as compared with the success rate for a grant being funded. The success rate is the total number of grant applications that are funded in a given fiscal year divided by the number of grant applications that were peer-reviewed. The percentile is a ranking that shows the relative position of each application's priority score among all scores assigned by that particular Scientific Review Group at its last three meetings.

For a given NIH Institute, the success rate usually differs from the percentile ranks. The percentile ranks are calculated using all applications reviewed by that initial Review Group, which includes applications assigned to other NIH institutes and centers. If grants assigned to one institute tend to receive better priority scores than the NIH average, then that year more than, say, 10 percent of its grant applications will rank better than the 10th percentile. Applications that are amended and resubmitted during the same fiscal year are also only counted once in the success-rate calculations, whereas all applications, both original and amended versions, are included when the percentiles are calculated. Therefore, funding all applications with ranks better than, say, the 20th percentile will result in a success rate greater than 20 percent when revised versions of some projects are removed from the success-rate base.

For 2006 the percentile cut-off for a grant to be funded by the National Institute of Allergy and Infectious Diseases is the 14th percentile. It's the 10.5th percentile in the National Institute of Aging, the 11th percentile for the National Cancer Institute, and the 12th percentile for the National Institute of Neurologic Diseases and Stroke. These translate into success rates in the order of slightly above 20% for most institutes, which can be compared with success rates close to 40% 7-10 years ago. (Most institutes try to give young investigators a break by setting the 'payline' about 2-5 percentile points higher for their proposals, resulting in a slightly higher success rate for first-timers.)

A drop in success rate of 50% is nothing to be happy about. But the number that really matters for peer reviewers is the percentile ranking, because this is what the Scientific Review Group members are aware of when they review a proposal. If they know that the payline is around the 10th percentile, as it is now, then they also know that out of 100 proposals that might be reviewed at that meeting, only about 10 will get funded. And that knowledge is the problem.

Ten years ago, when grants scoring better than the 25th or sometimes even the 30th percentile were being funded, reviewers knew that most good proposals would be supported, and that if they made a mistake about a grant at the margin, they were not making a mistake about the very best science. Consequently, the tone in review-group discussions was that of constructive criticism. Reviewers tried hard to find reasons to support work, particularly by young investigators, and their comments were often encouraging and guiding. No one was afraid that if someone else were funded, it would hurt their own chances of being funded; the pie was large enough that everyone felt they had a fair chance at a slice.

Not any more. When the percentile cut-off is around 10%, reviewers are being asked to do the impossible. They have to make choices from among research proposals that they themselves have evaluated as being better than 90% of all other grants in the field. No human being can make objective distinctions between grants at that level of quality. Because, since they must, subjectivity inevitably creeps in. Now Scientific Review Group members must try to find reasons not to fund proposals. The tone of reviewing is one of nit-picking. Increasingly silly criteria are being used to distinguish between applications: one of my proposals lost points because I did not give enough detail about how I was planning to carry out a particular experimental technique. Forgive me if I was a trifle starry-eyed about it, but I really didn't think I needed to demonstrate my competence in using a method that I had invented some fifteen years before.

Of course, when funds are this tight, generosity of spirit is in danger of being replaced by unenlightened self-interest. Every funded proposal now is a direct threat to one's own grants being funded. This mentality inevitably leads to turf protection, as reviewers in a subfield look after one another's applications, even if these are not of the best quality. To the credit of most reviewers, I haven't seen too much of this, but I've sure seen more than I saw a few years ago.

And if good grants are not funded simply because they just miss the cut-off, for whatever reason, including pure bad luck, it's not likely that there are many, if any, substantive criticisms that the investigators can address in a resubmission. Imagine how discouraging it must be to write a good proposal and see it not funded, and not to have any idea how to improve it because there's really nothing to improve. Who wants to roll the dice again with those odds?

But I think it's equally discouraging for the reviewers. If you're given 20 proposals to evaluate out of a crop of, say, 100, and you determine that 6 are of excellent quality, but you know that the probability that more than 2 of these will actually get funded is nil, how can you feel good about what you're doing? Or about your own prospects for getting funded? Or about the future of your profession? Also, with a payline this low there's a significant chance that nothing you review will get funded, making the whole, time-consuming exercise one of futility. Good people won't serve on study sections under these circumstances.

When the payline hovers around the 10th percentile, when fewer than a quarter of submitted grants are funded, and when the process of peer review has become one of trying to make judgments among things of equal quality, the system is broken. But I don't think it's broken beyond repair, at least not yet. Next month, I'll tell you how I think it can be fixed.

Published: 30 March 2006

Instructions for repair

Genome Biology 2006, 7:106

Last month I wrote about the sharp decline in the success rate for scientific research proposals submitted to the US National Institutes of Health (NIH) and other agencies. That column provoked numerous responses from both administrators of the funding organizations and life scientists. The administrators, while not denying some of the problems I discussed, argued that things aren't quite as bad as they seem, and that a large part of the difficulty stems from sizeable increases in the number of grant applications and the amounts requested, rather than from poor choices in managing the doubling of the NIH budget that took place not long ago. The scientists, on the other hand, all said that things were even worse than I had claimed.

Care has to be taken in drawing conclusions from either of these sources. I'm sure that people who have experienced difficulty in obtaining funding are more likely to respond to that column than those who've had success. And administrators probably feel the need to defend themselves, and their agencies, from what they might, with some justification, see as an attack by someone who doesn't know the whole story the way they do.

Nevertheless, although I think both sets of comments are useful, I also think both largely missed the point. People who wrote to me were all concerned, in one way or another, with the amount of money available for research and how it is being allocated. That's what seems to be on everybody's minds, and it's certainly worth talking about. Whether or not we're allocating the available funding sensibly is something that ought to be engaging officials as well as researchers in an ongoing dialog about priorities in science. (But that dialog isn't taking place. Somehow it just seems easier to keep asking for more money.) Yet, that wasn't the main point of the column. What concerns me is that, whether there really is a crisis in scientific funding or not, the perception that there is - and believe me, that is the perception on the part of just about every researcher I have talked to - has crippled the peer-review system.

Peer review is the foundation of quality in science. It prevents widespread cronyism and slowly weeds out unproductive lines of inquiry. But it requires that reviewers be both fair and wise. When the perception is that there's not nearly enough money to fund even all of the highest-quality proposals, a defensive turf-protection replaces a spirit of curiosity and egalitarianism. When it seems as if the primary job of a reviewer is to eliminate most proposals rather than to fight for the good ones, nit-picking replaces generosity. When the feeling is that every dollar counts so much that no risks dare be taken, conservatism and incremental advances get rewarded at the expense of bold new ideas. And when all of these things happen - and I believe they are happening, now, in the US - then the system is broken.

Societies based on scarcity tend to become hierarchical, with a well-fed elite and starving masses. As can be seen from publicly available data http://grants1.nih.gov/grants/financial/QA_Doubling_Period.doc, during the recent doubling of the NIH budget over a seven-year period, the number of investigators getting funded changed very little. Where did the money go? Besides a very large increase in the funding for NIH's own intramural research program, it seems to have gone to large increases in funding for established investigators who renewed their grants successfully during this period, or wrote additional ones. Instead of bringing lots of new people into the system, we ended up with more money for roughly the same set of grant holders. Now that funding is tight, those bloated operations are under tremendous pressure to at least maintain their size, which makes it even more difficult for new investigators - or new ideas - to enter the system. The average age at which a scientist receives his or her first NIH grant in the US is currently 42 for PhDs (even older for MDs), and in this time of perceived scarcity a broken peer-review system is not likely to change that.

What's the best way to fix things? It could be argued that the problem is temporary, and that when funding loosens up again, as it always has in past boom-bust cycles, peer review will recover along with everything else. After all, that's what happened in the 1970s. No need to tamper with the system. Time will take care of the problem.

I have my doubts. There's one big difference between peer review in 1975 and peer review today: the number of senior investigators participating in the process. Back then most review panels had a preponderance of such scientists, who provided the system with institutional memory of the way things were supposed to work. Nowadays, most established investigators feel they are too busy to put in the considerable time required to deal with the glut of proposals that every panel faces. The result is that less experienced scientists, with no history of a different gestalt, are being fed into a system where fault-finding and conservatism are the norm, so when the funding situation improves, there's no guarantee that the peer-review system will improve with it. (If you doubt this, consider the former Soviet Union. When it collapsed in 1989, newer Soviet-block countries like Poland and Hungary and Czechoslovakia, where there was a generation of people who still had a memory of how a market-based economy should work, did much better than Russia, where no one alive had experienced any system but communism.) In addition, the insistence that the composition of the panels must satisfy a requirement for geographic and institutional balance means that it's hard to have a large number of top scientists on any panel, even if they wanted to serve.

So my first repair instruction is simple: Do away with the misguided concept of balance, and require that all holders of research grants serve at least one year on a reviewing panel for every five years of funding they receive, regardless of seniority. Renewal of funding would be contingent on fulfillment of this service. If there is a surplus of available talent, then grants administrators could forgive the obligation for any given five-year cycle, but the requirement would kick in again when a grant was renewed. There would need to be a mechanism to deal with people who hold multiple grants - perhaps they would only incur a single one year debt for every five years of total funding, or the length of service could scale with the total budget; these details can be worked out. The important point is to create a pool of the best researchers, and to make sure that they represent the majority on all peer-review panels. As a dyed-in-the-wool advocate of personal freedom, the coercive aspects of this suggestion do trouble me somewhat, but it isn't really all that different from the way things work in the other main form of peer review - the jury system.

My second idea for how fix things is meant to address the problem of reviewer morale. When someone is given twelve grants to review, and knows that there is only a small probability that even the best one is actually going to be funded, he or she rapidly becomes discouraged. It's even more depressing when some less knowledgeable reviewer nit-picks one's best proposals, and depression is not the best mindset from which to make judgments. I suspect the program officers at the funding agencies must feel equally demoralized: it's no fun having to say "no" all the time, and to watch conservative study sections pass over the most exciting new ideas in favor of more of the usual. The solution, I think, is to give the program officers more autonomy in funding decisions. Some NIH institutes and centers claim that they do this, but in practice I have found that program officers rarely go against the recommendations of the reviewing panels. I suggest taking at least 10% of the budget of each institute or center and allowing the program officers to use it to fund grants that they believe to be exciting but that would otherwise miss the payline cut-off. They would need to justify each decision to the council, of course, but this suggestion would empower them to rectify some of the worst mistakes of the panels. In my experience, funding officials tend to be bright, committed individuals with a good broad knowledge of their field; I have no hesitation in giving them more autonomy. This is the way things actually work at the National Science Foundation, a funding agency that many believe has a better long-term history of supporting innovative research than does the NIH.

There also needs to be a way to improve the judgments coming out of the panels. Having more experienced reviewers would help, but it's hard to deal thoroughly and fairly with each proposal when the number being reviewed has increased so greatly. The way to solve the problem of proposal overload is to reduce proposal size. NIH proposals now are limited to 25 pages for the scientific description (that includes background and significance, progress during the past budget period, and the plan for future research). I think that should be shortened to 15 pages. If you can't describe clearly in 15 pages what you've already done, what you intend to do, and why it's important, you probably can't do it in 50.

But I think the proposals should be structured differently for different investigators. Scientists submitting their first proposal need to spend more space detailing how they are planning to carry out the work than established investigators should. In fact, I would argue that established investigators shouldn't have to describe their proposed methods in any detail at all, except if these are novel. To ask someone who has demonstrated for years that they can deliver the goods to prove that they know what they're doing is silly and borders on insulting. It also provides the nit-pickers with extra ammunition. People who tout stocks are constantly warning investors that past performance is no guarantee of future returns. But there is one area where it is: scientific research. The best predictor I know of as to whether a project will work is the track record of the principal investigator. Someone who has been consistently successful is not likely to fail, even when doing something risky. We need to stop pretending that isn't true. Most organizations that award pre- and post-doctoral fellowships spend very little time picking over the details of the applicant's research proposal, because they know that these young people haven't had any experience writing proposals and anyway usually end up doing something different, or in a very different way, from what they propose. Instead, fellowship reviewers tend to consider the qualities of the individual to be the most important factor on which to base their judgments. I think that makes sense at all levels of science. We need to be much less concerned with the details of projects, and put our bets on people and ideas.

While we're waiting for funding levels to improve, we need additional mechanisms to get young people started. The observation that, while investigator funding went way up during the NIH budget doubling, the number of investigators changed very little, suggests that we should consider putting a cap on the size of each award so as to make more money available for funding new projects and people. This is a serious matter, because it potentially has an impact on current employees, so if we implement a cap we will need to phase it in gradually. I am not proposing that we limit the total amount of funding that an individual can have - I think if someone can justify the need for millions of dollars to do first-rate science they should be able to obtain it. But I do think that we should exercise more scrutiny in such cases, and one way to do that is to force someone who claims to need, say, a million dollars to support a project to submit two or three proposals instead of one. I also think we will do better science, as a community, if we have more individual investigator-initiated projects and fewer mega-sized 'me-too' programs. Most innovation comes from small projects by relatively new people.

Two final ideas pertain to the machinery of the reviewing process itself. Turf protection is one of the biggest problems in peer review: as fields try to survive in a time of scarce resources, they often fight to fund their own mediocre science at the expense of quality in other areas. This largely stems from the personal and professional relationships that develop among members of a particular discipline. It's less of a problem when there's more money to go around, but right now we need to fight it. Here's a heretical and possibly crazy idea: I think we should consider not allowing people to review grants in their own field. Instead, they should only be allowed to comment on any questions of technical feasibility that come up during the review. This may seem absurd, but I'm not sure it is. If we follow my suggestion to bet on people rather than projects, detailed technical expertise isn't so important. And if we have the best, most experienced people back on our review panels, they usually will have a pretty broad knowledge of genomics, or biology, or whatever the main subject is. That will allow them to assess the importance of the proposed research and the impact of the applicant's previous contributions, which I maintain are the only two criteria that really should matter. Reviewing outside one's primary area of technical expertise happens all the time on fellowship panels, and they usually make pretty good decisions. After all, you don't have to be able to lay an egg in order to tell a good one - or to smell a bad one.

Box 1

Repair instructions

Do away with the misguided concept of balance, and require that all holders of research grants serve at least one year on a reviewing panel for every five years of funding they receive, regardless of seniority.

Give the program officers more autonomy in funding decisions.

Take at least 10% of the budget of each institute or center and allow the program officers to use it to fund grants that they believe to be exciting but that would otherwise miss the payline cut-off.

Solve the problem of proposal overload by reducing proposal size.

The scientific description (that includes background and significance, progress during the past budget period, and the plan for future research) should be limited to 15 pages.

Established investigators shouldn’t have to describe their proposed methods in any detail at all, except if these are novel.

Be much less concerned with the details of projects, and put our bets on people and ideas.

We should consider, as a community, the advisability of putting a cap on the size of each award so as to make more money available for funding new projects and people.

We should also consider trying the idea of not allowing people to review grants in their own field. Instead, they should only be allowed to comment on any questions of technical feasibility that come up during the review.

Guarantee the quality of the peer-review process by reviewing the reviewers.

The second procedural change we should consider is aimed at addressing the issue of possible bias in the system. In times of scarce dollars, reviewers worried about their own chances of obtaining funding have an incentive to prevent others from being funded. Even if we assume such a thing rarely happens, we should want to ensure that proposals are reviewed wisely as well as fairly. I think the best way to guarantee the quality of the peer-review process is to review the reviewers. The data to do so exist, because there is a record of how every member of a panel has voted on every grant. Since most panelists only read their assigned proposals in detail, we need only be concerned with how a reviewer's scoring of such applications compares with the average score awarded to those same applications by the other assigned reviewers. Abnormally high or low scores would not be damning in and of themselves (there's plenty of room for legitimate differences of opinion in science) but a consistent pattern of low or high scores could indicate either poor judgment or bias. You may wonder how to be sure about such an evaluation, but it's actually easy, because we can compare each reviewer with him or herself. Bias or territoriality should be relatively easy to detect by examining how a suspect reviewer treats the same grants when they are resubmitted after revision. Since unsuccessful applicants try hard to answer the criticisms raised by the previous review, the scores of resubmitted grant proposals should improve, on average. If a reviewer's scoring on such resubmissions remains abnormally low compared with other reviewers who are also seeing the proposal for a second time, then there is reason to question the impartiality, or the judgment, of that reviewer, and they can be eased off the panel. There might even be no need to evaluate every reviewer all the time: random checking might be all that is needed to discourage trying to rig the game.

When fear and discouragement drive peer-review decisions, then the system is broken. But it's not broken beyond repair. The suggestions I've offered here can help mend it; at the very least, I hope they will start a dialog about what should be done. The worst thing we can do as a community is to throw up our hands in despair or pretend that everything will right itself magically when more money becomes available. Peer review is too important to give up on, or be left to chance. If we're serious about funding the best science and making our profession attractive to the brightest, most creative young minds, then we need to fix the system so that it once again serves those ends. Let's get to work.

Published: 28 April 2006

The next epidemic

Genome Biology 2006, 7:108

In about 50 years, more than a quarter of the world will be over 65 years of age. It's even worse for some countries: the projections are that at that time, Japan and Germany could have 50% of their population in that category. The figure for the US is estimated to be about one-third. The fastest growing demographic segment in most developed nations is people 85 and older. We are witnessing something utterly unprecedented in human history: an explosion of people well past their reproductive years.

Evolution ceases to care about an organism when it has done its job of passing its genes to the next generation. As far as we know, natural selection does not increase the fitness of an individual for later life; indeed, there is some reason to think that longevity may be harmful in an evolutionary sense. Older, non-reproducing organisms consume resources that might better serve their younger, breeding brethren. And chief among these resources is medical care, because old age is a risk factor for just about everything bad that can happen physically.

Cancer (most types, anyway) and heart disease are just two of the conditions that afflict the elderly much more frequently than the young. Osteoporosis, pneumonia and other potentially fatal infectious diseases are amongst the others; and the list is a long one. But in almost no case is the deleterious effect of aging more dramatic than in the case of neurologic diseases. With the exception of a few rarer ones such as amyotropic lateral sclerosis (Lou Gehrig's disease) and Huntington's disease, which do their damage earlier, the incidences of Alzheimer's disease and other dementias and of Parkinson's disease and other movement disorders increase exponentially starting at about age 60, such that by the time a person reaches their mid-80s, their chance of showing symptoms of at least one of these conditions approaches 50%. The prevalence of Alzheimer's alone doubles every 5 years past age 60. Right now, in the US, there are about 1 million people with Parkinson's disease and about 5 million with Alzheimer's disease (the corresponding figures for the UK are just under a million Alzheimer's cases and about 200,000 Parkinson's cases). Exact figures are impossible to get because there is overlap in symptoms between cognitive and movement disorders in many patients and definitive diagnosis is often not possible until autopsy. But what is clear is that the major neurologic diseases cost the US about a third of a trillion dollars a year, out of a gross domestic product of $12.7 trillion. If you think that's a lot, and it is, then brace yourself: in fifty years, unless something is done, all of these figures will at least triple. There will be 15 million US Alzheimer's patients, 3 million with Parkinson's disease, and the annual cost will be over 1 trillion dollars. Every other western nation will experience similar increases. No economy can survive that.

One reason the future looks so bleak is that there is at present not a single effective treatment for any of the major neurologic disorders. Promising ones are claimed to be in the pipeline for the big killers like stroke and Alzheimer's, but then, we've been hearing those promises for at least three decades. And the 'lesser' scourges such as Parkinson's disease and other movement disorders are considered to have prevalence too low for most major pharmaceutical companies to be interested in developing therapeutics for them. So bloated, and debt-laden, have some drug companies become after the recent round of mergers that a disease offering only a million patients is considered unlikely to generate the return on investment needed.

This would appear to leave a clear field for biotechnology companies, but they haven't exactly been leaping into the breach either. Many appear to be scared off by the difficulty in doing clinical trials for diseases like Parkinson's (to be fair, big drug companies are worried about the same thing). Neurodegenerative diseases are typically slowly progressing with variable rates of decline and complex symptomology. Picking a suitable clinical end-point is hard enough, but when you add to it the likely time required for a trial for a disease like Parkinson's, which typically has a 20-year progression, it's understandable that even the major pharmaceutical companies are wary.

Governments often need to step in when the private sector is reluctant, and to some extent they have, but much of the innovative research in neurodegenerative diseases is funded, at least initially, by private foundations set up by patient advocacy and support groups. Thanks to them, there has been progress, but things are still moving very slowly.

Ironically, neurologic diseases may be a lot easier to treat than disorders like cancer. If you want to cure cancer, you had better be perfect, because if you let even one rogue cell escape, that may, in theory at least, be enough to start a fatal metastasis. I don't know about you, but I'm far from perfect - just ask my research group. But if you want to 'cure' Alzheimer's or Parkinson's disease, which are typically late onset and slowly progressing, you don't have to be perfect. Delay the average age of onset by a decade or two and the problem becomes much less serious. Slow the rate of progression by just one order of magnitude and a fatal disease may no longer be a significant problem for most people. In other words, for neurodegenerative disorders, all that may be required is to buy enough time.

Increasing evidence suggests that genomics should be a significant contributor to doing just that. Because the most common forms of the major neurologic diseases are sporadic and idiopathic, it was long thought that genetic factors played a relatively minor role in susceptibility (compared with, say, environmental factors and diet). But recent twin studies in Scandinavia and elsewhere paint a very different picture. Monozygotic twins show a high correlation in incidence of Alzheimer's disease compared with nonidentical twins, where the correlation is low. The best current guess is that more than 75% of the susceptibility to sporadic Alzheimer's disease may be due to genetic factors. The figure for Parkinson's disease is estimated to be lower, below 50%, but still substantial. Since most neurologic disorders don't present with symptoms until a sizeable fraction of the relevant neurons have already died off, many neurologists have felt that preventative measures were a better long-term strategy than trying to arrest the progress of the disease. The problems are: how do you measure efficacy of prevention for a sporadic disease, and how do you avoid having to give the preventative drug to the entire elderly population? The recent sad story of Vioxx, an arthritis painkiller that had to be withdrawn from the market after it was linked to increased incidences of heart attacks and strokes, shows what can happen when a drug is administered to a larger population than absolutely need it.

But if the tools of genomics allow us to identify genetic risk factors for the sporadic disease, then preventative measures can focus on reducing the risks for that population only, down to 'normal' levels, which in fact may be very small. The recent discovery that Ashkenazi Jews who are carriers for Gaucher disease are at increased risk of developing Parkinson's disease represents, I think, just the beginning of what should be a massive effort to identify the haplotypes that predispose individuals to a high risk of neurodegenerative disease.

Meanwhile, the incipient epidemic still needs to be checked. The best hope short-term probably lies with drugs that slow or arrest the neuronal decay. Finding them requires that the clinical trials problem be solved, but I don't think that may be as daunting as it seems. All of the major neurologic diseases have rarer, closely related conditions that are much more rapid in their progression and that have death as a clinical end-point. For example, although Parkinson's disease progresses very slowly, multiple system atrophy, which has similar pathology and appears to involve many if not most of the same molecular players, is usually fatal within about five years of diagnosis. Using these faster diseases as surrogates for the slower may be a way to design clinical trials with a clear outcome (survival) and an acceptable duration. But that requires accurate and early diagnosis of these conditions, which currently is very difficult to do, as they all resemble one another in many of their symptoms. Microarray analysis of gene expression and other genomics tools may help overcome this problem, which right now represents the major obstacle to progress.

The hope then is that genomics will make it feasible for biotechnology companies and large pharmaceutical firms to expand the scope of their efforts in neurologic diseases. If they don't, we could be looking at a future in which the human life span is continually extended but the quality of that later life is horrible. I don't know about the H5N1 virus and the avian flu; as I've written previously in my column (Genome Biology 2005, 6:121), the prospects for that epidemic are uncertain. But the coming neurologic crisis is an epidemic that is as sure as anything I know of. And this one won't be confined to a third world country, or to some place safely remote. The clock is ticking for all of us.

Published: 31 May 2006

The ninth wave

Genome Biology 2006, 7:109

Surfboard riders, borrowing an old sailor's expression, often speak of a 'ninth wave'. It means a single wave larger than all the others. Colossal, unexpected - ninth waves are the stuff of legend. It is said that nothing can withstand their power. I'm fascinated by all-pervading technologies that seem to spring up overnight. They are the ninth waves that wash over our culture with sudden, transforming power. The personal computer is most assuredly not one: it seemed to take forever before it made its way from business offices into most homes. But video rental is a great example of one. Didn't we all wake up one morning and find a video rental store in every shopping center, looking as though it had been there forever? In biology, the polymerase chain reaction most assuredly fits the definition: because of PCR, almost overnight, cloning went from something that was hard even for experts to something anyone could do, so everyone started doing it. Email is not one. It took years for email to replace telephone calls and regular mail as the main form of personal correspondence in business and academia, and it still hasn't done so outside of those venues.

We could argue whether the internet is a ninth wave (my personal opinion is that it isn't, since I'm old enough to remember that for a long time it was just a useful, but cumbersome, data-exchange mechanism that was restricted to government labs, the military, and a few universities). But surfing the web definitely is. Even before Google, which works so well that it has become a verb, just like Xerox (another example), the invention of the web browser changed the way we think about information, and did so with astonishing speed. For thousands of years, information was the property of a privileged elite, whose value depended on the fact that data were hard to come by, and they had access. Once, these high priests of knowledge were priests in fact: monasteries were the repository of learning for centuries. In the modern world, it is money that has tended to define who has access. As a luxury item, information - and the education needed to understand it and the technology required to obtain it - has tended to be found primarily in the developed world. If people in developing nations wanted access, they usually had to emigrate to a developed country for education, and once there, they most often stayed. A taste for information, once acquired, is not easily forsaken.

Surfing the web has changed all that, and changed it in a heartbeat. With so much information so easy to come by, and with most of it available free of charge, information has suddenly become a commodity. No longer can it be hoarded. And the barriers to entry into the world of information have, equally suddenly, become very low. All that is needed is a computer, and they are relatively cheap. To meet the demand for access from those without their own computers, the internet café has sprung up almost as rapidly, and spread as widely, as the video rental store once did. Young people all over the world are now accustomed to virtually unlimited access to a virtually unlimited store of knowledge.

The social consequences of this have been profound, no less so in science than in other aspects of life. Because the ability to access information became widely available at the same time that the genomics revolution was producing a flood of data (the ninth wave of biology, at least for this generation), people who could organize and make sense of the data had enormous value. And such people could not only come from anywhere; they could work anywhere.

I haven't seen any statistics to support my contention, but I believe that, once their training is completed, graduate students and postdocs today return to their own countries much more often than they used to. Partly this is because other countries are investing more in science and technology, so facilities and opportunities are better. But a large part of it is access to information. Remember how often we in the developed nations used to gather up our old journals and send them off to less-developed countries where they had none? I haven't had a request like that in quite some time. Internet surfing, combined with the rapid rise of open access publishing, has made many scientific articles accessible anywhere in the world. I think this is a very healthy trend. Countries like India and China have not had the infrastructure to compete with the West scientifically, but they've never lacked for brainpower. Thanks to the widespread availability of information, that brainpower can now be used to tackle many of the questions that genomics, in particular, has raised.

But this trend also presents a great danger. A PubMed search for the term 'bioinformatics' produces 12,657 scientific articles, not one of which is older than 1993. In fact, over 12,000 of these articles - more than 95% - were published since 1999. This explosive growth is fueled by a number of factors: widespread data access thanks to the internet; an armada of computationally savvy people thanks to a decade of surfing that same internet; the relatively low cost of setting up the research program of a newly hired faculty member in bioinformatics; and above all, a desperate need on the part of biologists to make sense of the flood of data produced by genomics. And it is this demand for analysis, combined with the reciprocal demand from bioinformatics for more data to analyze, that constitutes the danger, because heavy demand is rarely associated with high quality.

People often complain that there is nothing good on television. That is simply nonsense. There are many first-rate programs. But there are many more bad ones. The reason is simple: with the advent of hundreds of cable channels there is an insatiable demand for content to fill the enormous number of programming hours, and there aren't enough quality offerings to make much of a dent in that huge demand. Quality programming, like quality research, is a pretty fixed, relatively rare quantity, and its frequency is largely independent of demand. Increased demand does bring some additional high-level offerings, but mostly the extra slots just get filled with mediocrity.

Bioinformatics and genomics are creating a huge demand for data and data analysis, neither of which should be confused with greater understanding of how the world works. To analyze something is not de facto to understand it. In my experience, correlations are interesting but causality can only be proven by carefully designed experiments. Yet analysis is cheap and seems useful, data gathering is popular and easy to justify because it produces reams of tangible results - and there seems to be less and less room for hypothesis-driven, experimental research. Properly designed, clever experiments are hard to do and don't always yield clear-cut answers. Computational analysis of someone else's data, on the other hand, always produces results, and all too often no one but the cognoscenti can tell if these results mean anything.

Funding agencies feel the need to learn something from the mass of information their genomics and genomics-enabled projects are generating. Given the choice between lengthy, difficult, expensive individual-investigator-initiated experiments and inexpensive, flashy computational studies that are guaranteed to produce something quickly, it seems pretty obvious which they are likely to prefer. The fact that such studies can be done anywhere in the world only adds to their popularity. And while I have learned a lot from some bioinformatics papers, I still much prefer, and have been taught much more about the world by, a good experimental study - which, I fear, may be in danger of going the way of the dodo.

It isn't as bleak as it seems, though. Hidden in the results of genomics and proteomics and structural genomics and metabolomics and transcriptomics and god-knows-what-other-omics studies are a wealth of hypotheses waiting to be formulated and tested experimentally. Bioinformatics can help find them. We need to demand that it do that, and, if it doesn't, we need to harness its tools ourselves and use them to do that. Some biologists are already taking that approach. If more did, we might all be able to ride this wave together.

There's a painting by the 19th century Russian artist Ivan Aivazovsky called 'The Ninth Wave'. (You can read about him at http://center.rusmuseum.ru/inetbook/gaivazan_pict_eng.htm.) It depicts a huge wave about to crash down on the survivors of a shipwreck, who are desperately clinging to the broken mast. The question for all of us, as biology - driven by the combined forces of genomics and bioinformatics - seems about to become an information science, is whether hypothesis-driven, individual-investigator-initiated experimentation is about to suffer the fate of the people in the painting. If it does, we will all be poorer for it. Or is it possible that, like surfers who actually wait for the ninth wave, hypothesis-driven research will somehow manage to climb to the crest of this trend and use its enormous energy? One thing seems clear: if that happens, it will be a heck of a ride.

Published: 30 June 2006

Facts and figures

Genome Biology 2006, 7:111

I spend far too much time flipping through a slim volume that arrives in my mailbox at the start of every summer. No, it isn't a travel brochure for island get-aways. It's the Pocket World in Figures, published by The Economist magazine. (I realize I am committing something of a faux pas by referring to The Economist as a magazine. With a haughtiness they perhaps have earned, since they've been in business since September 1843, they always refer to themselves as "this newspaper". It's sort of like David Beckham referring to himself in the third person, I guess.) I've been a subscriber for over 30 years, and along with the only decent news coverage of the world outside the United States, one of the other benefits I get is this yearly little book.

You can learn all kinds of amazing things just from opening it at random. For example, the United States has the second highest divorce rate in the world: 4.8 divorces per 1,000 population (the UK is 14th, at 3.0; Canada is 29th at 2.3). The country with the highest rate is Aruba (5.3). Aruba? What on earth is it about Aruba that puts such a strain on marriages? It can't be the tourists: no other Caribbean nation makes the top 40. Certainly can't be the weather. Aruba touts itself as a very friendly place; maybe the people there are too friendly. Anyway, whatever the reason, there's something about Aruba that's apparently incompatible with marital longevity. The country with the lowest rate is Colombia, with only 0.2 divorces per 1,000 people. The fact that it's a Catholic country is certainly part of the reason, but so might be the fact that, owing to a rather serious crime problem, a large segment of the population is armed to the teeth. You might think twice about divorcing your spouse if you know that he - or she - regularly packs some serious firepower.

Particularly interesting are the statistics about health and disease. Swaziland has the highest death rate, 31.2 per 1,000 people. Places 2 through 18 on the list are also held by African countries where AIDS, malaria and/or tribal wars are endemic. The lowest death rate, 1.3 per 1,000, is in the United Arab Emirates. Places 2 through 10 from the lowest death rate are occupied by other oil-rich, Middle-Eastern countries, suggesting a correlation between wealth and health. But it can't be that: Mexico is 13th and the Philippines is 16th from the top. Neither the US nor the UK even cracks the top 25. The disease figures are equally fascinating. The countries with the highest death rates from breast cancer are all Northern European. The diets and lifestyles are so different, it makes one wonder if there's a gene in there somewhere. Hungary has a lung cancer death rate almost 20% higher than any other country on earth. And the US spends more on health care, as a percentage of Gross Domestic Product, than any other country by a large margin, yet it is tied with Portugal for 40th on the table of life-expectancy. Japan, where people live on average 5 years longer, is not even in the top 30 in health care spending. In fact, a plot of health care expenditure against either life expectancy or death rate is a scatter plot, with no apparent correlation whatsoever.

We could argue forever about what some of these facts mean, but I doubt there is a single scientist who wouldn't find the data interesting. Most of us become scientists because we are fascinated by the causes of things, and the causes of death and disease affect us all. Deducing these causes from a morass of figures is the work of one of my favorite sciences, and one that I think should be the closest ally of genomics: epidemiology. Epidemiology is the study of the factors involved in the health and illness of individuals and populations. It's the cornerstone of both public health and preventative medicine. Epidemiologists try to establish statistical relationships between disease agents, both infectious and non-infectious, and human illness: for example, they were the first to establish a link between lung cancer and cigarette smoking. Although human beings have probably speculated about such connections since the Stone Age, the science of epidemiology is only about 150 years old. It begins, as so much of our modern world does, with the Victorians.

The summer of 1854 saw the worst cholera epidemic in the history of London. Over 10,000 people died. It flared up, seemingly at random, in various spots throughout the crowded, unsanitary city. As the summer drew to a close, Soho, which had been spared up to that point, was suddenly hit hardest of all. The majority of those who died became ill on the night of 31 August and were dead within days. It is said that 75% of the population of the city left town that week out of fear of becoming ill. One who didn't leave, however, was London's most famous physician, Dr John Snow.

John Snow was born in 1813, the eldest son of a Yorkshire farmer. Apprenticed to a surgeon at 14, he graduated from the University of London with his medical doctorate on 20 December, 1844. He had long been fascinated by the mode of transmission of cholera, and as a young surgeon had actually written a paper, which was largely ignored, proposing that contaminated water supply might be the mechanism. In 1846, he became interested in reports from America about the properties of ether as an anaesthetizing agent. (The history of anesthesia is one of the most remarkable of all medical stories, and one that I plan to write about in the near future.) Experimenting largely on himself, Snow developed improved methods of administering the drug and demonstrated its effectiveness in the dental out-patient clinic at St George's Hospital. You might think that, as the man who introduced the use of ether into English surgery, Snow would have had a vested interest in the continued use of this drug. But he had a true scientist's mentality, and when data began to reach him that chloroform had advantages, he unhesitatingly championed its use. Anesthesia was scorned for use in child-birth by the (entirely male) medical establishment of that time, not because of suspicion of its effectiveness, but because it was thought to be contrary to the biblical injunction to Eve, "in sorrow thou shalt bring forth children (Genesis 3:16)". All that changed, forever, on the 7 April, 1853, when Snow persuaded Queen Victoria to use chloroform anesthesia for the birth of Prince Leopold, her eighth child. This, then, was the doctor who turned his attention to the cholera epidemic raging through London at the end of August 1854.

Medical wisdom at that time held that cholera was spread by 'miasma in the atmosphere' (I don't know quite what that means, but it sure sounds bad, doesn't it?). Because of that belief, nothing was done to contain an epidemic when it broke out. Snow, however, had already formed the opinion that contaminated water might be responsible, and the Soho epidemic gave him his chance. At that time he was living on Frith Street, right in the heart of the district. He started to patrol the district. He interviewed the families of victims, and began to plot on a map of that part of London the deaths from cholera. He found that nearly all of the deaths had taken place within a short distance of a water pump on the corner of Broad and Cambridge Streets. The well was nine meters deep, but a sewer only seven meters below ground was just above it. Snow took his findings to the Board of Guardians of St James's Parish, where the pump was located, and persuaded them to remove the pump handle so no one could obtain water there. The cholera outbreak stopped almost immediately.

Although the Victorian medical establishment continued to express skepticism about Snow's theory of cholera transmission, this remarkable demonstration of the power of data analysis led eventually to improvements in London's sanitation, including the construction of a proper sewerage system in the 1880s. John Snow is widely credited with the invention of the science of epidemiology. The site of the Broad Street pump, now the corner of Broadwick and Lexington Streets in Soho, is the location of a pub, aptly called The John Snow. A water pump with no handle sits outside. It was erected there on 28 July, 1992. A picture of the good doctor is on the pub's signboard. There's a room at the back on the second floor housing an exhibit dedicated to his life and work; if you ask, you'll be allowed to go see it. It's a good pub, too - a favorite hang-out of mine when I'm in London. You just might see me there when you visit. Ironically, you would never see John Snow there: he was a teetotaler. There's a society dedicated to promote knowledge of the life of John Snow and of his works, to encourage communication and collaboration between specialists of the many disciplines that have benefited from Snow's work, and to ensure that John Snow's memory continues to be celebrated in the pub bearing his name. I'm a member. Since March 2001, the John Snow Society has been based in the Royal Institute of Public Health, Portland Place, London. In 2003, John Snow was voted the greatest doctor of all time in a poll of physicians by the journal Hospital Doctor. Hippocrates finished second.

The science of epidemiology that Snow created remains, in my view, one of the most fascinating, and important, of the medical sciences. As for why I think it ought to be the closest allay of genomics, consider the following connections. Both sciences are data rich. Both depend on finding unexpected connections within data. Both aim to get at the underlying causes of things. And where genomics has been sold - I would claim, oversold for the present - as a key to personalized medicine, epidemiology is where the first glimmerings that such medicine might even be possible came to light.

If we could collect and mine enough epidemiological data, it would tell us where to look for the genes most important to human health. For example, several human genes that, when overexpressed, are associated with various cancers have the property that their deletion or loss of function is associated with neurodegenerative conditions like Parkinson's Disease. (Though surprising, the finding makes sense because cancer involves cells living that ought to die because of genomic instability or damage, while neurodegeneration involves the death of cells that ought to live: they are two sides of what might be the same coin.) This connection was discovered by the fact that cancer researchers doing proteomics found upregulation of genes in tumors that neurologists had found using human genetics and the genome sequence to be mutated in rare, autosomal recessive, familial Parkinson's Disease. Yet epidemiologists had already suspected that there was such a connection, because Parkinson's patients tend to have lower than normal incidence of certain cancers. I think one of the best places to look for new cancer genes is in the genetic neurologic disorders, and if we want to determine the pathways to neurodegeneration, we might want to look closely at genes that are important for tumor survival.

Similarly, consider the enormous number (hundreds) of inborn errors of metabolism. Most are recessive, and in many cases the carriers are asymptomatic. Considering that many of these conditions have carrier frequencies of 1 in 200 or even greater, the number of carriers in the general population is quite high. An obvious question, given the importance of most of the affected proteins, is whether being a carrier puts the individual at risk for anything else? Epidemiological evidence is mounting that it does. Gaucher Disease, the most common genetic disorder among Ashkenazi Jews, has a carrier frequency in the general population that is estimated to be as large as 1 in 100. Gaucher carriers show no symptoms of Gaucher Disease, but epidemiological data indicate that they may have as much as a 10-fold higher risk of sporadic, idiopathic Parkinson's Disease than non-carriers. I suspect that haploinsufficiency of important metabolic enzymes may underlie many of the 'sporadic' diseases. The right marriage of genomic and epidemiological data should find these connections, and with them, uncover the pathways to disease.

We need to think as broadly as possible about questions like this. We need the barriers between disciplines to be as low as possible. We need data from sciences like genomics and epidemiology to be freely available in forms that can be understood widely and transferred from one discipline to another easily. It may be that we need genomics and epidemiology to become one science. If we had genome sequence information for whole populations coupled with epidemiologic information about health and disease and lifestyle, imagine what a new generation of John Snows could do with such data. And imagine what a book of figures that would make!

Published: 28 July 2006

Senior moments

Genome Biology 2006, 7:113

Almost thirty years ago, I was sitting in my basement office (they always used to put X-ray crystallography labs in the basement in those days - either because they were afraid the heavy equipment would crash through the floor or because they thought the radiation would contaminate people below - I never figured out which) at Unnamed Eastern University, trying to write a grant. I had only joined the UEU faculty a few days before, and the prospect of finding funds to support my scientific ideas - not to mention students to carry them out - was seeming particularly daunting that day. All the science buildings at UEU were connected by a rabbit-warren of underground tunnels, which included the corridor outside my office. Because UEU had never bothered to design its science buildings with any foresight, these tunnels were often used as storage rooms for the files, equipment and other paraphernalia that wouldn't fit in the labs upstairs. My office was located near the junction of the tunnel under the Chemistry building and that under the Earth and Planetary Sciences building, and right around the corner from my door were dozens of old wooden cabinets filled with geological specimens: meteorites, quartz crystals, petrified wood, stromatolites, fool's gold, trilobites, and hundreds of others. It was fun to go and look at them for a while on those long days early in my career when no one called, no mail came, and I was sick of writing.

But that day I was writing when suddenly a whole troop of very young undergraduates stormed into my office. They were all holding large pieces of paper and pencils. I had heard that, to help familiarize them with the geography of their new surroundings, UEU held a scavenger hunt for incoming freshmen, who had to go around campus marking the locations of various odd objects; apparently, these students were on such a mission. "Excuse us, Professor," one of them said, "could you tell us where we could find the fossils?"

"Well," I replied - and by my answer earned instant notoriety in the UEU community - "most of the senior faculty are on the third and fourth floors." Something - it doesn't matter what - reminded me of this episode a few weeks ago. I laughed thinking about it - at first. Then I realized that, if the same thing happened today, I would be one of the senior faculty I so cavalierly referred to. How did this happen? I don't think of myself as 'senior faculty'. Like most people, my mental picture of myself is rather different from my chronological age. If I think about it objectively, I would say that I usually imagine myself to be about as I was 10 to 15 years earlier, and that this has been true for much of my adult life. By no stretch of the imagination should a 43 year-old scientist be considered 'senior' in the sense I meant the term back at UEU.

But, of course, I'm not 43. I'm 58. Somehow, without my realizing it, I have become what I beheld. I'm suddenly past my prime, an object of pity or derision for my younger colleagues, old scientifically as well as physically. It isn't exactly like Gregor Samsa waking up one morning to find that he has metamorphosed into a giant insect, but it's close. All of which has led me to compiling a list designed to help those of you who may be in a similar situation. So that you will not one day be shocked to find that you have become senior faculty, here is a set of signs that will allow you to recognize the abyss as you approach it.

You are senior faculty if you can actually remember when more than 10% of submitted grants got funded.

You are senior faculty if you can remember when there was only one Nature.

You are senior faculty if you still get a lot of invitations to meetings, but they're all to deliver after-dinner talks.

You are senior faculty if students sometimes ask you if you ever heard Franklin in person, and they mean Benjamin, not Aretha.

You are senior faculty if a junior colleague wants to know what it was like before computers, and you can tell her.

You are senior faculty when the second joint on the little finger of your left hand is the only joint that isn't stiff at the end of a long seminar.

You are senior faculty if you sleep through most of those long seminars.

You are senior faculty if you visit the Museum of Natural History, and the dummies in the exhibit of Stone Age man all remind you of people you went to school with.

You are senior faculty if you find yourself saying "Back in my day" or "When I was your age" at least twice a week.

You are senior faculty if you actually know what investigator-initiated, hypothesis-driven research means.

You are senior faculty if you occasionally think that maybe you should attend a faculty meeting once in a while.

You are senior faculty when your CV includes papers you can't remember writing.

The problem, of course, with being senior faculty is not the inevitable lack of respect you get from your younger colleagues. That's as it should be: science is a young person's game. (They may even come to admire your wisdom, which is really nothing but experience, and ask you to read their papers and grants. Hopefully, they'll ignore your advice.) No, the problem with reaching senior status is the feeling that you have nothing much to contribute except experience. I was feeling that way myself until I read about the Neanderthal Genome Project.

A project to sequence the genome of Homo neanderthalensis, the last representative of which died more than 35,000 years ago, sounds like science fiction, but it isn't. Jonathan Rothberg and Michael Egholm, who work at 454 Life Sciences, a high-throughput sequencing company in Branford, Connecticut, USA, are doing exactly that, in collaboration with Svante Pääbo of the Max Planck Institute in Leipzig, Germany. The project, which was launched on 20 July of this year, takes advantage of the whole-genome shotgun-sequencing technique developed by Craig Venter for the human genome sequencing project. In that method, the genome is broken up randomly into fragments about 100-200 base pairs long, which can be sequenced rapidly by machine. The final sequence is assembled from the fragments computationally, by using the overlaps between them. In the case of the Neanderthal genome, time has already broken the DNA up into fragments of just about that average length. The genetic material is being extracted from the right arm of a 40,000 year-old skeleton found in a cave in the eponymous Neander Valley in Germany. And 454 Life Sciences has novel technology for chip-based sequencing using emulsions to separate fragments so that each well on the chip has only one piece of DNA. (Disclosure: I have no connection with either 454 Life Sciences or its parent corporation, CuraGen.) The other hallmark of 454 Life Sciences' technology is the PicoTiterPlate, which allows a single instrument using patented light-emitting sequencing chemistries to produce, they claim, over 20 million nucleotide bases per 5 hour run, more than 60 times the capacity of instruments using the current macro-scale technology. Pääbo is an expert in, among other things, dealing with the problems of microbial DNA contamination of ancient samples.

Over the next two years, the Neanderthal sequencing team will reconstruct a draft of the 3 billion bases that made up the genome of Neanderthals. For their work, they will probably use samples from several Neanderthal individuals, including that specimen found in 1856 in Neander Valley and a particularly well-preserved Neanderthal from Croatia. The Max Planck Society's decision to fund the project is based on a preliminary analysis of approximately one million base pairs of nuclear Neanderthal DNA from a 45,000-year-old Croatian fossil, already sequenced by 454 Life Sciences. The Neanderthal genome sequence, which is expected to differ from that of the chimpanzee by about 4% overall, should shed considerable light on the evolution of Homo sapiens. Because the specimens being sequenced come from relatively late individuals in the history of H. neanderthalensis, they may also answer the long-standing question of whether the two humanoid species ever interbred.

If they succeed - and I'm betting they will - then the obvious next challenge would be to sequence the DNA of something even older. And that is where I have something to contribute. Since I am now senior faculty, I can contribute my DNA. After all, why stop at a Neanderthal when you can sequence a dinosaur?

Published: 1 September 2006

Fly's time

Genome Biology 2006, 7:115

Genome sequences are coming so thick and fast these days that it's easy to forget when any new one guaranteed a cover article in Nature or Science - and occasionally, as in the case of the human genome, in both. I used to do a column about each new eukaryotic sequence as soon as it came out; I haven't felt the need to do that in quite a while. Soon there will be hundreds of bacterial genomes sequenced and dozens of eukaryotes, so I guess a certain jaded attitude is understandable. Still, it wasn't that long ago that any new one, especially from an important model organism, was considered so important that sometimes there were races between competing scientific teams to produce them.

Of all these races, those between teams from the public and private sector were the fiercest, involved the most colorful characters, and raised the most compelling issues. We remember the epic contest between Francis Collins' government-funded group and the rival band from Craig Venter's Celera Corporation to sequence the human genome, which led to a brokered announcement of a "tie", heralded by pictures of the team leaders posing uneasily with one another and President Clinton. We tend to forget, however, that these same battle-lines were drawn earlier, and not over the genome of Homo sapiens or any other mammal. They were drawn over the humble fruit fly, Drosophila melanogaster.

It is this struggle between, well, if not exactly God and mammon, then at least public mammon and private mammon, to sequence the fly genome, that is the subject of Michael Ashburner's new book, Won for All: How the Drosophila Genome Was Sequenced (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2006, ISBN 0-87969-802-0). Mike (we aren't on a first-name basis, but you'll see in a minute why I call him that; as a matter of disclosure, I do know many of the participants in the story very well) is a well-known fly geneticist who has spent much of the past decade making significant advances in bioinformatics. He's one of the people responsible for the Gene Ontology (GO) database, which attempts to link the known functions or attributes of genes and their protein products to well-defined pathways and processes in the cell. Because he moves easily between the worlds of genetics and computational biology, he was at the center of much of the action that took place between the summer of 1998, when Venter announced that he was going to sequence the fly genome as a warm-up for his whole-genome shotgun sequencing of the human genome, and November of 1999, when the Drosophila sequence, produced in record time by combining the results from Celera's shotgun data with the partial sequence information from the publicly-funded effort that had been going on for a number of years, was annotated in a frenetic two-week 'jamboree'.

The book isn't meant to be a detailed history of that period; rather, it's a very personal account of Mike's perceptions of, and interactions with, the other principals. We meet Gerry Rubin, the brilliant geneticist who had put together the public effort, which involved labs in both the U.S. (chiefly at Berkeley) and Europe (chiefly at the Sanger Center). Essential to the very idea of a publicly funded sequencing program was the immediate release of data to the whole community without restriction. We meet Gerry's private sector counterpart, the equally brilliant Craig Venter. Driven out of the National Institutes of Health by their refusal to back his program for sequencing expressed sequence tags (ESTs), Craig had founded first The Institute for Genome Research (TIGR), which had done the first genome sequence (Haemophilus influenzae) in 1995 by the same shotgun sequencing method, and then Celera, whose mission - totally antithetical to that of the public effort - was to make money by selling sequence information. We meet Suzi, Phil, Jim and a host of other characters. We frequently have no idea who they are when we meet them, because Mike nearly always calls them only by their first names, even when they are introduced into the story for the first time. To be fair, he does add their family names and a bit of bare-bones background information in footnotes. He loves footnotes. Oh god, does he love footnotes. I thought Oliver Sacks loved footnotes more than any writer I had ever encountered, but Mike puts him to shame. Won for All is 74 pages long. It has 161 footnotes. On many pages, the word count in footnotes is greater than that of the text. It really breaks the flow of the narrative to have to keep referring to them, but if you don't, you often have no idea what is going on. I wish Mike had just integrated most of that information into the story; lots of good writers manage to do that without losing the casualness of the style.

And this style is about as casual and breezy as you could ask for. Mike says he wrote this piece a number of years ago as a kind of therapy (only deciding to publish it now), and it does have something of the same stream-of-consciousness air as might come from an analyst's couch. Although this makes the book confusing at times, it doesn't make it uninteresting. One gets to know quite a lot about Mike as a person: he hates the airlines (who doesn't?), has a similar attitude toward Marriott hotels (again, makes sense to me), believes absolutely in openness in science, and in general seems the kind of chap it would be fun to hang out with. We learn how Gerry Rubin (the hero of the story, in many ways) immediately realized that the sensible thing to do in order to get the job done was to join forces with Craig Venter rather than to compete with him - I wonder how many people who had as much invested in their own program could have subordinated their own egos to the good of the cause so readily. We learn about the negotiations that went on between the fly genetics community and the corporation, which led to the sequence being available without restrictions as soon as it was complete. We learn about the skepticism in the sequencing community about the possibility of using the whole-genome shotgun approach on so large a genome; Craig was right about its power, as he was about ESTs and a number of other things. For me, the anxiety about the partnership with private enterprise seemed a bit silly at the time, and certainly does now; there was never a possibility that the fly sequence could have made the kind of money that Celera was ultimately looking for, so there was no incentive for them to try to keep it to themselves. The part of the book that I like the best is the description of the annotation jamboree. I always wondered what it was like in the heady few days when these first really important genome sequences were completed, and Mike really makes you feel like you were there.

Won for All concludes with two very good appendages: an Epliogue, by Scott Howley, and an Afterward, by Ethan Bier. The Epilogue is the best concise history of fly genetics I have ever read, and the Afterward is an excellent summary of what having a genome sequence can do for a field. Both of these short essays should be widely read. I hope Cold Spring Harbor Laboratory Press allows some organ with a large circulation to reprint them.

It's been my experience that nearly every nonfiction book I have ever read is at least twice as long as it need be. These days, authors seem to equate density, either of style or of pages or both, with profundity and erudition. The result is usually neither, but rather tedious repetition. Frequently, one only needs to read the first and last chapters to have a very good idea of the entire argument. My little complaints about style notwithstanding, Michael Ashburner's book does not suffer from this problem. Won for All tells an engaging, historically important story in a generally entertaining fashion. By showing the results of open access to the Drosophila genome sequence, he makes, without preaching, the strongest case I have ever read for unfettered sharing of scientific results. I was rather sorry when it ended; I sort of wish it had been twice as long. I read it in one sitting, and it went very fast. But then, when you have a well-told tale with a happy ending, I guess time flies.

Published: 29 September 2006

Transformation

Genome Biology 2006, 7:117

Well, this year's Nobel Prizes have been announced and once again no monthly columnist was awarded the Prize in Literature. I put this down to a long-standing and unreasonable prejudice in favor of serious writers. The science prizes were, as they often are, somewhat controversial, not because the winners didn't deserve to win - I certainly think they all did - but because there are others who seem to be equally deserving, and who therefore perhaps should have shared the awards. In general, I think the various Nobel Committees do a pretty good job of selecting worthy recipients, but often err on the side of too few awardees for any given discovery or advance. To be sure, it's hard to get it right, especially with the limit, set by Nobel's will, of three winners per prize, but given the collaborative - and competitive - style of modern science, one or even two winners would seem to be too few most of the time.

The disappointment for those who might have - or should have - been included must be acute. Awarding a prize in a given field often means no more prizes will be given in that area. If one's whole career has been devoted to winning a Nobel, the sense of injustice, perhaps of failure, could be overwhelming. But it needn't be. It wasn't for the man who did the greatest experiment in the history of biology with his own hands, and never won the Nobel Prize, even though he lived on for more than half a century after the experiment changed biology forever. His name was Maclyn McCarty, and he was the junior member of the team of Avery, MacLeod and McCarty that proved that genes are molecules of DNA.

I only knew Mac, as everybody called him, for the last few years of his life (he died 2 January 2005 at 93 years of age). He was one of the happiest people I ever met, and also one of the nicest. (The two often seem to go hand-in-hand - perhaps if we are to be nice to others, we must first be nice to ourselves.) In any case, Mac McCarty was totally comfortable with who he was. He never volunteered to talk about the extraordinary work that he had been a part of, back in the 1940s - he was far too modest a man to do that - but he could be cajoled into it, and I never tired of sitting with him, listening to his marvelous anecdotes about that exciting time.

In 1928, Frederick Griffith, an English army doctor, wanted to make a vaccine against a Streptococcus pneumoniae, which caused bacterial pneumonia. Though he failed in making the vaccine, he stumbled on a demonstration of the transmission of genetic information by a substance that was to be called the "transforming principle". He found that the bacterium had two forms when grown on agar plates, a smooth (S) and a rough (R) form (see Figure 1). The R bacteria were harmless, but the S bacteria were lethal when injected into mice. Heat-killed S cells were also harmless, but when live R cells were mixed with killed S cells and injected into mice, the mice died, and the bacteria re-isolated from those mice had been 'transformed' into the S type. This experiment strongly implied that genetic material had been transferred from the dead to the live bacterial cells. It was hard to be certain of this, or to know exactly what genetic material was transferred and was responsible for the transformation process, but a small number of scientists eventually realized that in understanding this experiment lay the key to understanding the molecular basis of heredity.

At Rockefeller University in the mid 1930s, Oswald T. Avery and Colin MacLeod carried out a more elegant experiment: they showed that simply putting dead, lethal encapsulated S pneumococcus Type III in a Petri dish with a live, unencapsulated and harmless R strain would cause the live strain to become virulent. They then began to isolate the substance responsible for transferring virulence. In 1940, McCarty - who had just finished his residency in pediatrics at Johns Hopkins - joined Avery's lab and also began working on the problem. By this time Avery's team was already homing in on DNA as the most likely transforming principle. Mac's special skill as a biochemist was not only useful in preparing highly purified DNA; it also led him to carry out the definitive control experiments, which showed that the transforming principle was destroyed by the enzyme DNase but was untouched by proteases, glycosidases, or enzymes that digested RNA. In 1944, Avery, MacLeod and McCarty published, in the Journal of Experimental Medicine, the paper on transformation that transformed biology forever. It showed - conclusively to anyone with the wit to see it - that DNA was the genetic material.

Figure 1

Rough and smooth bacteria. Rough colonies on blood agar (right) and smooth colonies on bicarbonate agar (left) of cultured Bacillus anthracis. Picture CDC/Dr. James Feeley.

Despite the powerful evidence in the paper, this conclusion was not accepted by many influential scientists. Chief among these was Avery's Rockefeller colleague Alfred Mirsky, a biochemist, who lobbied for years to deny Avery and his team the recognition their work deserved. Mirsky was convinced that proteins had to comprise the genetic material and believed Avery's DNA samples had to be contaminated with them. He seems to have persuaded the Nobel Committee, because although Avery and his associates were nominated repeatedly in the years following their discovery, they never won the Nobel Prize. Avery died in 1955, age 76 (which, by the way, means he was 65 when he published the discovery of the century - that's for those of you who think that older biologists are over the hill). The assertion that he didn't live long enough for his work to be appreciated is nonsense: by 1952 it was generally accepted that genes were composed of DNA and that the Avery paper was the work that had proven it. (To be fair, Avery himself did not help matters. He had a quiet and self-effacing personality, presented his work in a low key manner, and was averse to any sort of speculation. His presentations were few, and when invited to speak at international meetings he usually sent his younger collaborators.)

Nobel Prizes may not be awarded posthumously, so that was it for Avery, but Mac McCarty lived another 50 years after Avery's death; the Committee had ample time to rectify their mistake in his case. They never did. MacLeod harbored some bitterness over that slight, but Mac didn't seem to. He was modest, happy, spoke well of others, and generally seemed to be having a very good time nearly all the time. If you met him, you would never have known that he might have suffered the greatest injustice in the history of biology.

People often make themselves miserable chasing recognition. When they don't get it, they often become bitter; when they do get it, they sometimes become either insufferable because they have it or depressed because it doesn't really nourish them the way they'd hoped. Mac never got the recognition he deserved: he, Avery and McCloud should have won a Nobel Prize, and it's to the everlasting shame of the prize-givers that they didn't. I know of scientists who have brooded over lesser slights the way Gollum brooded over the loss of the One Ring. If Mac ever did, he never showed it. Here's what he said about Mirsky in his book, 'The Transforming Principle: Discovering That Genes Are Made of DNA' (New York: WW Norton & Co.; 1985):

"As far as I was concerned, I was in the position of being on the same faculty with Mirsky for the remainder of his life, and it made no sense to continue to behave as though we did not know each other. In the end, we arrived at a congenial relationship, even though one could hardly say that we were close friends."

It may have seemed sensible to Mac to be cordial to Mirsky, but I wonder how many of the rest of us could have done it.

The good news is that he did eventually get a lot of attention, especially toward the end of his life, when his importance to history as the only survivor of that period was appreciated. After all, he had carried out, with his own hands, the greatest experiment ever done in biology. I know of scientists who have thought of themselves as minor deities because they had done something far less important. Mac never seemed to think of himself as anything but an ordinary human being. One of my graduate students went to New York once to be interviewed for the Helen Hay Whitney postdoctoral fellowship competition. He came back to my lab and told me that his interviewer was a very pleasant elderly scientist and that they had spent a delightful couple of hours together. I asked who he was, and he said, "McCarty, I think - he told me to call him Mac." I asked if he knew who he had just been talking to. He had no idea. I wonder how many other people could have sat for two hours with a young scientist and never bothered to tell them that they were in the presence of one of the men who had proven that genes were made of DNA.

That was the great irony of Mac McCarty's life and career. He found the universal principle of transformation, and yet he himself was not transformed in any way by the discovery. He carried out the greatest experiment in biology, yet he never acted like someone who had done anything very special. I don't know if you could say that he discovered the secret of life - Watson and Crick laid claim, with some justification and their customary sense of self-importance, to that title - but I do think he might have discovered one secret of a happy life.

Wouldn't it be great if there was some way to rectify injustices like the one that he and his colleagues suffered? I think there is. It may be impossible to award Nobel Prizes posthumously, but there is no provision in Alfred Nobel's will that would prohibit the various Nobel Committees from recognizing neglected scientists in some other fashion. I propose that, every year, at the same time the Nobel Prizes are given out, the Committees designate scientists as 'Nobel Committee Honorees'. The only requirements for such distinction are that the scientists in question be deceased and that their work be of seminal importance and not previously awarded a Nobel Prize. There's no Hall of Fame for science, and it's probably just as well that there isn't (I'm not a fan of places of pilgrimage), but the Nobel Foundation has a pretty terrific web site http://www.nobelprize.org where these scientists could receive a little of the honor that was their due. Having the Nobel cachet attached to it will give it the stature they are entitled to. I'm not in favor of limiting the number of honorees in any year, but if there must be a limit it should be set high, like at least five.

Such a simple gesture might do a little to ease some of the hurt that comes along every October. Unlike some people, I'm not a believer in abolishing awards like the Nobels; I think our profession is too little recognized in general, and the huge publicity these prizes engender is good for all of us. But I do think there's a lot of unfairness, unintentional for the most part, that goes along with the Nobel Prizes, and my suggestion may help remedy that. At the very least, someone who missed out in a year when their field was recognized could cling to the hope that some day they might still receive something of their due.

So here are my nominations for the 2007 Nobel Honorees. In Chemistry, I suggest Josiah Willard Gibbs and Ludwig Boltzmann for their pioneering contributions to the theory of chemical thermodynamics. In Physics, I would propose Lise Meitner, J Robert Oppenheimer and Leo Szilard for their seminal contributions to the harnessing of atomic energy. And finally, for their landmark discoveries on the nature of the genetic material, I nominate, for the 2007 Nobel Honors in Medicine or Physiology, Rosalind Franklin, Oswald Avery, Colin MacLeod, and Maclyn McCarty.

Published: 1 November 2006

Do the math

Genome Biology 2006, 7:119

It looks like the tenuous cease-fire is not going to hold. Already there are signs of renewed hostilities. Both sides are marshalling their forces, hurling derogatory slurs at one another, and preparing for open warfare. I am not referring to Darfur, or to the Middle East. I am talking about something much more intrinsically fraught with ominous possibilities. I am talking about the teaching of mathematics in American schools.

The average American student can do many things that his or her parents cannot dream of doing: program a video cassette recorder; get a high score in any video game; download almost anything, legally or illegally, to his or her iPod, and multitask to an extent that makes one wonder how many brains are really in there. But when it comes to doing math, that same student displays the approximate level of intelligence of a paramecium.

At least, that's what both national and international tests seem to show. American 8th grade students trailed those from Japan, South Korea, Singapore, Taiwan, Hong Kong, and many European countries in the recent Trends in International Mathematics and Science Study. In the state of Washington, this year only about half the 10th grade students passed the basic math proficiency part of the state education test. A website, http://www.nychold.com/, has been set up so that concerned parents can find links to information about battles over math education in their home states. A reading and math tutoring system focusing on basic skills that originated in Japan, Kumon, now has franchises in many states and a global clientele of more than 4 million children in 43 countries.

Perhaps in response to all this, in September of this year, the National Council of Teachers of Mathematics issued a report recommending that schools focus more on teaching basic math skills and stop trying to teach dozens of different mathematical topics in each grade. This is the same National Council that, in 1989, issued a report that said exactly the opposite, so you'll forgive me for viewing their current statement with the same degree of unease that I might greet, say, an announcement by President Bush that we were going to do the whole Iraq thing all over again but this time get it right.

That earlier report, and about ten years of experimentation in math education that preceded it, produced a curriculum that emphasized letting children find their own ways to solve math problems and use calculators to perform elementary operations. The movement had a number of names, including 'fuzzy' math and 'new' math, and it was imposed on an entire generation of students over, in many cases, the objections of their parents. California abandoned this idea a half dozen years ago, and the scores of California students on standardized tests went up sharply as a result, but math educators in many states have resisted the call to 'return to basics'. A New York Times article on November 14 quotes R James Milgram, a math professor at Stanford University, saying that "the math situation in the United States is a complete disaster."

The self-esteem movement, which hit the US school system at just about the same time 'fuzzy' math did, hasn't helped. By emphasizing that the student's own idea of how to attack a problem, or even the student's own answer, was good even if it was wrong because it was the product of the student's creativity, the drive to increase self-esteem fed perfectly into a system of mathematics instruction that focuses on the student's own approaches. The same New York Times article recounts the story of a Seattle mother who was aghast to find that her stellar 6th grade student had no idea how to do long division. When she confronted his teacher, she was told, "We don't teach long division. It stifles their creativity."

Personally, I think the best route to self-esteem is getting the right answer, and having confidence that you know how to get the right answer. And I think when it comes to getting the right answer, there is no substitute for being taught a reliable method. But I think there's more to our problems with math education than a well-intentioned, but muddleheaded, educational philosophy. I think our failure to train people properly in mathematics reflects our lack of appreciation for just how unusual a field it is.

There's something about mathematics. It isn't like any other subject. Most of us are familiar with the generalization that the average philosopher or social scientist tends to do his or her best work relatively late in life; biologists do it in their 40s and 50s; chemists in their 40s; physicists in their 30s and 40s; and mathematicians in their 20s to early 30s (there are, of course, many exceptions, though seemingly fewer for math than for the other subjects). But it isn't just that the best work is done very early in the case of mathematicians. It's that it's often their only important work, period. In every other subject I know of, even after the peak of one's career, the typical practitioner still can make significant contributions. And with age, even if one's mastery of the field may not increase much, it usually doesn't decline much either. But mathematicians often seem to regress relative to their field once they are past their prime. A number of them have told me that after their major work was completed, they knew it was time to devote themselves primarily to teaching others, because they simply wouldn't be able to do cutting-edge stuff any more.

The peculiar nature of mathematics is most apparent, I think, to a teacher of other subjects. I regularly teach freshman chemistry, a subject that most people in class don't want to be taking, and the distribution of backgrounds and abilities among my students is about as broad as it gets. But with very few exceptions, any of them can improve their understanding of the subject if they keep working at it. Progress can be frustratingly slow in some cases, but it's nearly always there. It was that way for me, too, when I was a student: some things were harder for me than others, and in some instances I didn't spend enough years working on them to experience that magical moment - I call it the pedagogical moment - when the learning curve turns sharply upward and everything suddenly starts to make intuitive sense. But I always felt like I was making at least some incremental progress when I put additional time and effort in.

Except in mathematics. I think that, unless you are one of the few who are going to be professional mathematicians or who have an intuitive grasp of the subject, when you study mathematics at some point you hit a wall. It's in a different place for each person (geometry for some, algebra for others, calculus for many), but once you hit it, there's almost no chance you will go past it. This wall makes it literally impossible to teach fundamental mathematical concepts to a broad collection of students. But that, of course, is exactly what the 'new' mathematics curriculum has been trying - and failing - to do, for over 20 years.

If I'm right about this, and I believe I am, then the 'new' math goal of having all students understand what they are doing rather than memorizing methods and regurgitating answers is simply unattainable. True, the old approach produced many people who disliked math as a subject and believed they couldn't understand it. But what if that belief was right? Mathematicians may wish that everybody understood and loved their subject, but it looks to me as though that desire is producing generations of students who can't use mathematics, and isn't being able to use it what the real objective ought to be, for most people? My mother disliked math and certainly didn't understand it in depth, but she was trained in doing it so well that she made her living as a bookkeeper for many years.

All this, of course, has enormous implications for biology in the age of genomics. Data gathering is useless without data analysis. Genomics has led to mountains of data, requiring increasingly sophisticated analysis, yet biology has always attracted scientists who wish to avoid the mathematics in physics and chemistry. Such biologists are at the mercy of those who claim to have extracted important insights from genomics data by complex analytical methods. The ranks of bioinformatics are largely drawn from people with a background in math or computer science; it seems to be easier for those scientists to learn some biology than it is for biologists to learn the other subjects. Once a high priesthood of the mathematically sophisticated is established, not only is there less incentive for the flock to learn the tools, there is actually a positive incentive for the clergy to keep such things as mysterious as possible. We end up believing that to analyze (or model) a system is to understand it. Not only is this untrue (you can model anything with enough variable parameters), it is stifling. We need biologists who can analyze data themselves, or at least critique the results of those who do.

Medical research creates an even greater demand for mathematical literacy, among both scientists and the scientific press. Not a week goes by without some study purporting to show that this food is bad for you or this activity protects you from that disease. And the following week, it is likely that some other study will purport to show exactly the opposite. No wonder the public is anxious, confused, and increasingly distrustful of science. Tragically, in many cases the fuss is over small differences in risk that are at the border of statistical significance. But when the researchers in question use p-values without really understanding what statistics should be applied to their data, when they bin things so as to produce an effect that they can publicize, and when most science reporters don't have the background to realize that the conclusions are questionable at best, the result is often much ado about nothing.

Yet statistics is the one branch of math that everybody should be able to grasp, because there is no need for a deep understanding of its foundations. Statistics can be taught - often is best taught, actually - as a simple set of tools that can be used to provide information about what sets of data mean, or don't mean. You can learn statistics without being able to derive a thing. It's eminently practical, not very sophisticated mathematically, and can be made fun. What a pity that, with the exception of some medical students, almost nobody is given any formal training in it apart from some half-hearted lectures as part of a lab course or two.

So here's a simple little proposal for reform in the educational system, starting at the elementary school level and leading right through graduate school. Students need to memorize basic math facts and learn simple algorithms that will allow them to do calculations - or at least estimate answers - without the aid of a calculator. I also think there should be an emphasis not only on the basics of math, but also on developing computational skills. There should be more numerical problems and fewer word problems, especially in high school. Every college science major should be required to pass a full semester course in statistics - no exceptions. And graduate students in biology need not only to have this background, but to show a familiarity with more sophisticated concepts such as hidden Markov models and network analysis. The best context in which to teach that material is a good elementary course in bioinformatics, which should be required of every life science doctoral candidate.

If we start to do this now, maybe we will produce a generation of young biologists who will actually be able to understand what genomic data mean. Maybe they will question the pronouncements of the modelers instead of accepting them blindly. Maybe they will challenge researchers who claim that behavior causing a 10% increase in risk of heart disease is something we should all worry about, when neither their sample size nor their margin of error justify paying any attention to it at all. And maybe they won't have to fight the math wars for the education of their children. Or if they do have to, maybe they will be equipped to win.

Published: 30 November 2006

A model worth considering?

Genome Biology 2006, 7:121

I'd like to introduce you to Scott Johnson, who thinks he has a better way of translating basic research discoveries into therapies for human diseases. Like many of the other people who have made a difference in the battle to cure diseases that pharmaceutical companies and governments have largely ignored - for example, the actor Michael J Fox in the case of Parkinson's disease and the financier Michael Milken in the case of prostate cancer - Mr Johnson has a very personal reason for wanting to see a particular disease cured. In 1976, when he was 20 years old, Scott Johnson was diagnosed with multiple sclerosis. He's 50 now, and he knows that, without a cure, his life expectancy is predicted to be about 7 years less than the average for a healthy adult. But that isn't the main reason that Scott Johnson is a man in a hurry. He's in a hurry because he thinks he's figured it out, and when you think you've figured it out, you're naturally anxious to see if you're right.

Based on his track record, it might be unwise to bet against him. Multiple sclerosis didn't prevent him from a successful business career with the Boston Consulting Group and several Silicon Valley startups. That wouldn't make him the first businessman who thought he could apply the principles of corporate management to a new area (government is a favorite one), not by any means. But Mr Johnson doesn't want to run a state, or even a city. He wants to change the way cures for diseases are found.

In 2003 he left business to start the Myelin Repair Foundation. The origins and progression of multiple sclerosis, which is thought to be an autoimmune disease, are mysterious and unpredictable, but the hallmark of the disease is the destruction of the myelin sheath that surrounds the axons of nerve fibers of the central nervous system. The resulting scar tissue (sclerosis) gives the disease its name. When Scott Johnson heard about myelin, he decided that the fastest route to a cure for multiple sclerosis was not to focus on the causes of the disease but rather to find a way to repair the damaged myelin. Hence the name of his foundation, and its goal.

Having decided that, the question then became how best to get there. Johnson looked at existing models for what is now often called translational research and decided that none of them was very efficient. "In traditional medical research, numerous individual scientists work in relative isolation, often in competition, focused on their specific field of expertise. With little or no collaboration, discoveries are transferred by publication, resulting in sequential investigations and greatly expanding the length of time necessary for validation and translation to further drug development and clinical trials," he says. He came up with a different model.

The Myelin Repair Foundation set about finding a way to accelerate the basic science necessary to achieve its goal of licensing at least one myelin repair drug target by 2009 that would lead to treatments for multiple sclerosis. To accomplish this, the Foundation developed what it calls the Accelerated Research Collaboration™ (ARC; the name is trademarked, actually) model, a business-science hybrid model for medical research that was designed to break down what Johnson saw as the barriers inherent in the traditional medical research model. He thought that, if he was right, this new model might be able to drive new discoveries toward clinical trials in record time.

Instead of the traditional single-investigator-driven model typical in virtually all academic research, the ARC model combines the efforts of multiple investigators into a collaborative, outcome-focused effort. Johnson tried to identify a set of top-flight basic research laboratories, some of which were not initially working directly on multiple sclerosis, and convinced them to get interested in both the disease and his approach to tackling it. Selection was based on their complementary knowledge and expertise, and their past contributions to understanding the key biological processes and interactions that control myelination. These were people who would quite likely have been competitors in the traditional research model. Five labs were chosen, scattered all over the US and Canada. To enable communication among them, the Foundation set up a web-enabled infrastructure designed to facilitate daily interaction and data exchanges; discoveries are therefore shared immediately, without the delays associated with the publication of scientific papers. A requirement of being part of the ARC scientific team is the commitment to design experiments that are part of a larger research plan focused on identifying therapeutic targets that will lead to patient treatments. The model provides a framework for establishing membership and technology transfer agreements with each participating university. Patents are filed on all discoveries that may contribute to potential treatments.

The Foundation believes the ARC model can be applied to any medical research problem once relevant basic scientific discoveries have been made. It states that more than 40 different disease research organizations have made contact with the Myelin Repair Foundation to learn about the ARC model and its potential application to each organization's research; these include the American Cancer Society, The Down Syndrome Research and Treatment Foundation, the Juvenile Diabetes Research Foundation and the Harvard Stem Cell Institute.

It's important to get past the marketing language and the PowerPoint slides showing in iconic form the revolutionary new approach to doing science. Versions of what the Myelin Repair Foundation is trying to do have existed for decades, differing in details but not in aims or overall philosophy. What is significant about the Foundation and its ARC model is that it has attracted so much attention. What does that tell us about the state of scientific research in the genomics era?

I think what it tells us is that the scientific community has sold the public on enormous increases in support for basic biomedical research by promising that such research would lead to cures for diseases, and that the public is growing impatient with the pace of that translation. Nowhere is this more evident than in the various genomics programs: the Human Genome Sequencing Project, the Structural Genomics Initiative, the Haplotype Mapping Initiative - all these and more have been funded because their proponents promised that the results generated by these massive, expensive programs would lead to a new era in medical treatments. As, of course, they will, but it's reasonable to ask whether the mechanisms for getting there are optimal. The excitement in some quarters over the Myelin Repair Foundation model suggests to me that government funding agencies have not managed to find, or at least to implement, mechanisms that encourage collaborations and that reward innovation and risk-taking. More than ten years after the human genome sequencing project began, it still takes, on average, more than 12 years and almost a billion dollars to make a drug. The Myelin Repair Foundation aims to license at least one myelin repair drug target to a major pharmaceutical company by 2009, five years after its inception. Given that much target validation is done outside of the pharmaceutical industry, it's hard to know how much of an acceleration that represents. The likelihood is that it will still take close to 12 more years before a drug reaches the market.

But consider the case of Gleevec, Novartis's Bcr-Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. The Philadelphia chromosomal rearrangement producing the activated kinase was observed in leukemia patients in 1960. The kinase itself was first identified as a possible cause of the disease in 1985. It was shown to be a cause of leukemia in mice in 1990. Gleevec was approved by the US Food and Drug Administration in 2001. Depending on whether you consider the story to have begun in 1960 or in 1985, it either took 17 years or 32 years to proceed from first glimpse of the target to the clinic. Seventeen years would be just about what the Myelin Repair Foundation can expect if its model works, maybe a bit faster if they're lucky. That wouldn't represent much of an acceleration at all. But going from 32 to 17 years would be a pretty big deal.

Genomics was supposed to produce a revolution in human health. It will, of course, but I think it's legitimate to question whether our mechanisms for translating the results of such research into real therapies aren't also ripe for a revolution. The RoadMap Program of the National Institutes of Health (NIH) has run into a lot of criticism; it is seen as an attempt by the NIH Director, Dr Elias Zerhouni, to drive biomedical research away from basic science towards translational research. As far as I can tell, that isn't what it's about at all. For one thing, it only consumes a very small portion of the total NIH budget. For another, it was conceived as a blueprint for how everything should be done; it was designed to be a laboratory in which different research models and different funding mechanisms could be tried out. I don't think that's a bad idea at all, and I think the criticism of it is based partly on its unfortunate name ('Laboratory' would be so much better than 'RoadMap') and partly on the fear that somehow it's taking money out of our own research pockets. Given the number of wasteful initiatives in other NIH Institutes and Centers, this is hardly a fair criticism. It's also totally inconsistent. I've heard many investigators claim, with much justification, that government scientific funding agencies are far too conservative. To go blithely from that charge to a charge that the RoadMap is too radical strikes me as bordering on silly.

Considering that our scientific enterprise is peopled largely by trained experimentalists, it's surprising that there is so much resistance to trying out new things. Fear that the experiment may fail would never be an acceptable reason for not doing it on the part of one's own graduate students or postdocs. The ARC model that Scott Johnson is so excited about may or may not represent a better way of doing certain things, but at least he's trying the experiment.

Published: 29 December 2006

Jumping the shark

Genome Biology 2007, 8:101

Popular culture, I've long believed, is the best way of finding out what most people care about at any point in time. That's the reason I have no patience with those who disdain watching television and refuse to even have one in their homes. By ignoring such a pervasive cultural reference point, they are distancing themselves from much of the rest of humanity. I'm not demanding that they watch television constantly, or even very often, but if they never look at it at all, they will never understand what most of those around them are seeing and talking about. I think most television programs are drivel, but I try to know at least a little bit about the most popular ones so that I feel somewhat connected to my culture. The same goes for mass-market movies and 'popular' literature such as detective fiction.

Besides, without popular culture, where would we get some of our most useful metaphors? Speaking metaphorically can itself be distancing, of course, if the listener doesn't understand the reference, but when the metaphors are drawn from popular culture that tends to be less likely. The problem with such metaphors is that they rapidly become stale and hackneyed, but even the more clichéd ones have the benefit of making conversation and writing more colorful than it otherwise would be in this age of technobabble and political correctness. Examples include 'drink the Koolaid', meaning to accept something blindly that an authority figure tells you - a reference to the 1978 mass murder/suicide by poisoned fruit drink in Jonestown, Guyana.

My personal favorite is 'jumping the shark'. It was first used to describe that time when a long-running television program begins to decline in both creative energy and ratings, and then tries all manner of gimmicks in an increasingly desperate attempt to hold on to its viewers. In so doing, it strays even further from the qualities that made it successful in the first place. The specific reference is to the low-brow situation comedy 'Happy Days', which concerned a group of teenagers in a typical 1950s suburban American community. In addition to the stereotypical popular kid, goofy kid and musically talented kid, the show featured one Arthur 'The Fonz' Fonzarelli, played by Henry Winkler: a leather-jacketed, tough-talking, basically kindhearted, motorcycle-riding dropout - sort of a toned-down version of the Marlon Brando character in the movie 'The Wild One'. For those of you not old enough to remember the thin, pre-Godfather Brando, virtually the same character type appears as the male lead in the musical 'Grease' (in the film of which, the part is played by John Travolta). 'Happy Days' ran for 11 years, far longer than its rather silly plots and thin characterizations could support, and as viewers dropped off the show turned to increasingly preposterous storylines, most of which featured The Fonz in bizarre, out-of-character situations. The apex - or perhaps nadir would be a better word - of this nonsense was the famous (infamous?) jumping the shark episode, in which The Fonz, still clad in his trademark leather jacket but wearing a swimsuit and lifebelt that even John Travolta would never be caught dead in, waterskied around a lagoon housing a man-eating shark, over which he jumped in the climax - if that word can be used to describe something like this - of the show. (If you don't believe me, and I don't blame you if you don't, you can watch the video clip online http://www.ifilm.com/ifilmdetail/2666632) The whole business was so monumentally stupid that it soon gave rise to the expression 'jumping the shark': that moment when a show, desperate for new ideas, tries ones that are so ridiculous that it fails to remain true to itself.

Over the years most long-running TV programs have jumped the shark in their quest to maintain their ratings. A precious few, in my opinion, never did, and so hold a special place in the annals of popular culture. (My list would include 'WKRP in Cincinnati', 'The Mary Tyler Moore Show', and 'The Phil Silvers Show'; there's a website http://www.jumptheshark.com/ in which fans of various programs debate - endlessly, it would seem - whether a particular program did or did not jump, and if so, exactly when and how it did.) Gradually, the phrase has crept - slithered? - into the lexicon as a general metaphor for losing one's core values in a quest for popularity or profits. The recent proposal by the Bush Administration to send more US troops into Iraq could be cited as evidence that they, too, have jumped the shark, if the only 'new' idea they could think of was to repeat the old one that didn't work. In this case, it's votes, not ratings, that they are angling for, but the principle is the same. Personally, I think they actually jumped several years ago, when they decided to invade Iraq in the first place. And that unforgettable image of the President on the aircraft carrier, in full flight regalia, with the 'Mission Accomplished' sign behind him, reminds me a lot of The Fonz in his leather jacket and swimsuit.

Such pandering - or is it prostituting? - isn't the exclusive province of television and political leaders, of course, although they may have perfected it. For an example more familiar to the readers of this column, consider the journals Nature and Cell. Both were wildly successful, general-content scientific journals whose very names became synonymous with high-quality, high-impact papers. Then came Nature Structural and Molecular Biology, Nature Medicine, Nature Immunology, Nature Genetics, Nature Chemical Biology, Mother Nature - OK, I made that last one up, but give the folks at MacMillan publishers time. Not to be outdone, Cell rapidly metastasized into Molecular Cell, Developmental Cell, Cancer Cell, Cell Metabolism, Cell Phone, and so on. To be sure, these are all high-profile journals that still publish good papers (I'd like to publish in them someday, so I have to say that) but can there be any doubt that the brand has been diluted at least somewhat by this proliferation? And since both families of journal are published as for-profit enterprises, it's hard to escape the conclusion that the primary motive behind the fission was the profit motive, and, therefore, that they've jumped the shark. (Their main rival for the title of Most Important Place to Publish, Science, is published by a non-profit scientific society, which may explain why it hasn't jumped. At least not yet.)

Which brings me to the point of this column (I bet you were starting to wonder if it had one, weren't you?): with the advent of genomics, has biology jumped the shark? You could make the case that genomics was born on waterskis with a Great White swimming below, because its values seem to be so at odds with what were once considered the core values of the life sciences. Instead of emphasizing hypothesis-driven, investigator-initiated inquiry, genomics focuses on large scale data gathering and analysis, usually done by big teams. Biology used to be thought of as low-tech; genomics is technology-oriented. So does the advent of genomics mean that biology has run out of good ideas, and is desperately hoping that data mining will produce some?

Ostensibly, the answer is no. Genomics was sold to the scientific community as big science in the service of small science. The argument was that systematic data gathering would provide the bases for countless new, hypothesis-driven experiments. To some extent, it has done just that, but there's a catch: the pool of available research dollars is relatively fixed, and money that funds genomics projects isn't available to fund those hypothesis-driven experiments, so their number is bound to go down. I think that tension between the two modes of biology research will work itself out, but until it does there will continue to be fears that genomics marks a transition away from the core values of the subject.

The real danger, it seems to me, is when some sub-discipline attempts to change its values to reflect those of genomics without considering the consequences to its intellectual health. That is exactly what has happened to structural biology. When a cadre of structural biologists sold the idea of structural genomics to the funding agencies, I think they jumped the shark. In the very early days of structural biology, when we had no idea what the universe of protein folds looked like, every new structure was interesting for its own sake, as a glimpse into a largely unknown world. It didn't matter what the protein did, if it was a 'new' structure it was important. But that excitement had largely faded at least 15 years ago, when it was pretty clear that we had seen most of the major fold classes and anyway they were all pretty much variations on similar themes. Then the function of the protein became the benchmark for the importance of its structure, and the best structural biology combined structure determination with functional insights and biological experiments. That was the core value of the discipline until, in an attempt to secure funding for routine structure determination, structural biologists tried to piggyback on the success of the Human Genome Project with a proposal to fund a set of consortia whose mission was to determine either the structures of a representative example of every protein fold, or the structures of all proteins in a particular genome. Such assembly-line crystallography (or nuclear magnetic resonance (NMR), in some cases) has started to produce a lot of structures, but I think almost no one cares. The goal of filling in the fold catalog was quickly abandoned, not only because it was too difficult but also because it was certainly true that no one except perhaps a few bioinformaticists cared. And the goal of determining all the structures in a genome also proved to be too difficult: the thing about high-throughput crank-turning is that it can't afford to stop to wrestle with difficult problems, and of course the most interesting proteins often seem to be the ones that are most difficult to express in a heterologous organism, then purify, and crystallize. Thus, the structural genomics initiative has, up to now, concentrated on the low-hanging fruit (one may say, in some cases, the fruit that has already fallen to the ground). And what do we have as a value system for the field now? Is it to churn out structures regardless of their importance? Is it to be a service for the drug companies and cell biologists, who will dictate what is important and reap the rewards from studying function and exploiting structure themselves? It certainly seems as though that's where things are heading, and if I'm right, I think future historians of science will point to the structural genomics initiative as the moment when structural biology put on its life belt and swimsuit and headed out over the shark pool.

It doesn't have to be that way. Fields should be able to make use of genomic information without attempting to absorb the ethos of big, data-gathering-science. If they can do that, then genomics will be an enabling technological revolution, which helps propel a lot of non-data gathering science forward. But if a field tries to become like genomics when it really is something very different, then it jumps the shark. Like a television program past its prime, if it thinks - or fears - that it has run out of good ideas, it will try bad ones. It will go backwards, not forwards. And when that happens, like the shark itself, which must constantly swim forwards to survive, it will begin to die.

Published: 31 January 2007

And the second shall be first

Genome Biology 2007, 8:103

It's one of the most famous photographs in history - almost iconic. It shows a jubilant US President Harry Truman, fresh from his unexpected victory in the Presidential election of 1948 over New York Governor Thomas Dewey, holding up that morning's edition of the Chicago Daily Tribune, whose headline boldly - and incorrectly - proclaims "Dewey defeats Truman" (Figure 1).

Figure 1

Harry Truman after his unexpected victory over Thomas Dewey in the Presidential election of 1948 with the Chicago Daily Tribune, whose early edition boldly and incorrectly proclaimed Dewey’s victory.

When Truman went to bed in the Elms Hotel in Excelsior Springs, Missouri, on the night of 2 November 1948, he was losing the election, as most of the polls predicted he would. In its haste to get the scoop on its rival papers, the Tribune printed an early edition with a headline giving the expected result based on the early returns. When Truman woke the next morning, he learned he had in fact won, so he took the train to Washington, DC that same day. On a short stop in St Louis, he was presented with one of the "Dewey defeats Truman" papers while on the back platform of the train. It was at this moment that the now famous photo of Truman holding up the paper was taken.

I first saw that picture in the 1960s, when I worked as a stringer for a big-city newspaper. My editor had it framed on the wall of his office. And underneath it, in his own hand, he had placed these words: "It's nice to be first, but it's better to be right."

I was reminded of this photo when I read about the recent retraction by a group from Scripps Research Institute in San Diego, California, of five papers describing protein crystal structures and their corresponding atomic coordinate sets that had been published in Science, Molecular Biology, and Proceedings of the National Academy of Sciences (see Miller: A scientist's nightmare: software problem leads to five retractions. Nature 2006, 314:1856-1857 and Chang et al.: Retraction. Science 2006, 314:1875). Apparently, a computer program used by the group had changed the sign of the anomalous differences, which are the differences between X-ray intensity data measured with the X-ray beam hitting the front and back of the crystal, in data sets collected for five different membrane protein crystal structures. Anomalous differences can be a powerful aid to solving the structure of a protein by X-ray crystallography. The head of the lab states that "...our MsbA structures were incorrect in both the hand of the structure and the topology. Thus, our biological interpretations based on these inverted models for MsbA are invalid. ...The error in the topology of the original MsbA structure (published in 2001) was a consequence of the low resolution of the data as well as breaks in the electron density for the connecting loop regions. Unfortunately, the use of the multicopy refinement procedure still allowed us to obtain reasonable refinement values for the wrong structures."

The problem might have gone unrecognized for some time longer had Kaspar Locher (Swiss Federal Institute of Technology, Zurich) not determined the correct structure of a related protein (Locher and Dawson: Nature 2006, 443: 180-185). Locher's structure was completely consistent with the body of biochemical and biophysical data on that class of protein (the so-called ABC transporter superfamily), in contrast to the structures generated at Scripps, which were notably inconsistent.

Their mistake has consequences beyond the damage to the unfortunate young investigator and his team. For five years, other labs have been interpreting their biophysical and biochemical data in terms of the wrong structures. A number of scientists have been unable to publish their results because they seemed to contradict the published X-ray structures. I personally know of at least one investigator whose grant application was turned down for funding because his biochemical data did not agree with the structures. One could argue that an entire sub-field has been held back for years due to the inordinately persuasive power of the pretty pictures that structural biology produces.

In retrospect, there were a number of serious red flags in the work (a major one being the low resolution of the first structure determination, 4.5 Å, a resolution at which it is all too easy to make major mistakes in interpretation). But why on earth Science, which published the original paper, and its referees didn't worry from the get-go about the failure of the structure to explain what was already known about this type of protein is beyond me. In an era when experimental details are relegated to 'Supplemental material', especially in the vanity journals, and when canned software makes it easy for people without a deep understanding of the method to determine structures and to referee the structure papers of others, it may be too much to expect that technical errors can be caught reliably, but that isn't the best criterion to use for the correctness of a protein structure anyway. As my Brandeis colleague Chris Miller notes, in a pithy letter on the retractions, "This case highlights the dangers of ignoring biochemical results, conventional but logically solid" (Miller: Science 2007, 315:459). I've said it before, but it bears repeating: the only reliable test for the correctness of a macromolecular structure is if it makes sense in terms of what is already known about the molecule. If it is consistent with the body of experimental data about the protein or its family, it is probably right. If it is not consistent, it is very likely wrong.

But it seems to me that in all the hoopla about this incident, another point that needs to be made has gotten lost. The hero of the story, of course, is Kaspar Locher, who was not deterred from completing and publishing his own structure even though he had apparently been scooped five years previously. That was easier for him in the field of membrane proteins, with rather few structures compared with their soluble brethren and where even structures of closely related ones are perceived as worthwhile. Imagine how much more difficult it would be for someone to decide to carry on in the case of an area that is not as hot? Yet if this story should convince us of anything, it is of the value of the second report, and the danger of overvaluing the first. Journals like Nature, Science and Cell place so much importance on being the first to publish something of general interest that they create enormous pressure on people to rush to print. No structural biologist would ordinarily settle for 4.5 Å resolution and expect to get things right unless they felt the need to beat their competitors and to have their work published in a journal with as high a profile as possible.

I think that feeling is often self-defeating, as it clearly was here. The high-profile journals don't ipso facto do the best job of reviewing manuscripts - in fact, in my experience, they are often a little worse than the so-called trade journals. And very often the first report of something is incomplete, hasty in its judgments, and not nearly as informative as the second paper, which has the advantage not only of calmer consideration, but also has the first paper to use for target practice. But try telling that to students and post-docs, who clamor to have their work sent to the vanity journals, even when it is patently too specialized. And try telling it to the editors of those journals, who, one worries, may have come to value priority over everything else.

How did we get to this state? It makes no sense to me, because in science what we are supposed to value above all else is reproducibility. The report that confirms a finding should, therefore, be considered of equal value to the one that first announces it, but somehow we have either forgotten that fact or succumbed to a collective frenzy for high-profile publications.

We're all guilty of feeding this beast. I have sat on postdoctoral fellowship panels and listened to people say of candidate X: "She has published five papers from her graduate work, two in Nature and one in Cell", as if that fact alone is all that needs to be said about the quality of the applicant. Frequently, stating where the papers were published is a surrogate for actually having read them. I'm ashamed to say I've done that myself. Does being the first into print mean more than publishing the best paper, the most thoughtful paper, or a more useful paper on a subject? Does content mean so little any more?

Right now the field of genomics is somewhat insulated from this problem. Nearly all the major genome sequences have been either collaborative or solo efforts. The one example of fierce competition, to be the first to sequence the human genome, resulted in an arranged dead heat, and as far as we know didn't affect the quality of the finished product. But as the $1,000 genome sequence edges closer to reality, and as the supply of really interesting organisms whose genomes have yet to be sequenced shrinks, you can bet there will be more races, more pressure to get there first, and more cutting of corners along the way. When that happens, will we remember that all too often the first report is sketchy, superficial in its analysis, and more prone to error? Will we value, as much as we should, the second report, which is often more thoughtful, more useful, and is essential to the scientific process of validation and self-correction?

I think that's the real lesson of the unfortunate events at Scripps. And it's a lesson that all of us - every student, every post-doc, every faculty member, every journal editor, every pharmaceutical executive and biotech science officer, every referee, every grants administrator, every scientist, everywhere - would do well to remember.

So I'm going to frame a copy of that Harry Truman photo, and put it on the wall in my office - or maybe in my lab. And underneath it, in my own hand, I'm going to write: "It's nice to be first, but it's better to be right."

Published: 26 February 2007

A day in the life of a genome biologist in the not-too-distant future

Genome Biology 2007, 8:104

Megalopolis, United States of Western Hemisphere, 18 June 2273. The following fragment was uncovered in an underwater archaeological dig, on the site now generally believed to be the location of the almost mythical engineering school, Screwloose La Tech. Ever since global warming led to the flooding of the entire Eastern Seaboard of North America in 2138, artifacts from the Cambrian Period, as the period of the great universities in Cambridge is called, have been very hard to come by. This document is therefore of great historical significance. Nothing is known about the writer, except that similarities of style suggest that he may actually have been the same as the master of the Genome Biology columns, whose work has recently been challenged as fraudulent.

Pursuant to Federal Paperwork Reduction Act 3,671 of 2016, herewith is submitted daily activities report for Saturday, 3 June 2030.

7:44 am to 8:02 am. Arrived shuttle parking lot number 4, located 11.25 miles from campus. Turned off motor on electric car and detached mandatory passive restraint devices (seat belt, shoulder harness, neck brace, ankle restraints and wrist locks) before exiting. Plugged battery cord into recharger built into parking meter. Inserted $255 in five dollar coins to cover daily parking and battery charging costs. [Personal note: must remember to get more five dollar coins from bank. Ever since university raised off-campus parking fees for faculty to $41,000 per year, have been lugging around more bags of coins than an armored car.] Waited 30 minutes for shuttle bus to campus.

8:46 am to 9:27 am. Arrived at office. Couldn't unlock door because minor head cold has altered appearance of eyes and eyeball-scanner security device couldn't recognize them. Waited 30 minutes for campus swat team to respond to security alarm and unlock door.

9:28 am to 11:11 am. Turned on computer and checked email. Only 1,459 new messages since last night. Ran new Microsoft anti-spam program, which automatically deleted 832 of them, including message from mother. Ran newer Microsoft anti-spam bug fixer, which restored message from mother and other 831 junk messages, plus 204 new junk messages it found from somewhere. Switched to personal examination of messages. Found that only two messages actually were important; all others were spam, including message from mother.

11:12 am to 11:54 am. Surprise inspection by agents from Government Office for Toxicity Checking and Hazard Assessment (GOTCHA). Examined all labs-on-chips at every student desk-bench. Found four minor violations (two chips were not dusted and the dust from two others was not properly collected and stored). Ever since scientific responsibility for wrongdoing (SCREW) mandate of 2020, signed into law by President George IJK Bush IV, scientist responsible for laboratory must pay fines for any GOTCHA violations immediately from personal funds. Presented debit card to agents for fines of $4,400 ($1,100 per violation). Oh well, still a lot better than last week.

11:55 am to 12:39 pm. Met with two students from advanced genomic, cell, molecular and psychological neurosociobiology course. Listened to complaints about their midterm grade. Students argued that grade of A+++, well below class average, severely hampered their ability to gain admission to medical school and therefore constituted grievous psychological harm. Threatened to inflict equivalent grievous bodily harm unless I changed grades. Ever since mandatory American national interpersonal armament concealment (MANIAC) statute law, signed by President George LMN Bush V, required that all citizens carry concealed weapons at all times, such student-faculty disputes have become easier to resolve. Started reaching for pocket grenade launcher but then considered that odds of 2-against-1 dictated non-violent response. Changed grades to class average of Super-A+++++++.

12:40 pm to 12:45 am. Ate lunch, which as always consisted of trans-fat sandwich on tobacco leaf bread. Paused to reflect how amazing that earlier generations of scientists actually considered this unhealthy - exactly the opposite of what careful research has now shown.

12:45 pm to 1:56 am. Reviewed results of latest genome sequencing project in the lab. Sequence of gerbil genome, begun at 12 noon, now complete. Immediately entered file of results into Microsoft Office 2025, which immediately crashed after erasing file. Restored file from backup microdot and relaunched program, which proceeded to write paper describing results, including changing spelling of my name to something it liked better. Attempted to change name back only to be told by the program that it was smarter than me, always would be smarter than me, and that I should go away and let my betters do their job. [Personal note: visit district court and change spelling of my name to that used by program].

1:56 am to 2:39 pm. Submitted finished manuscript, with Bill Gates III first author, as he is on all papers everywhere, to Nature Gerbil, Gerbil Cell, Gerbil Genome Biology, PloS Gerbil, and Current Gerbil Biology. (Ever since famous Supreme Court decision in case of J Craig Venter vs Nature, Science and Cell, scientists have had the right to submit their papers simultaneously to as many journals as they like, and to have the same paper published in up to five journals at once.) Since the Harold Varmus overthrow of capitolism (HAVOC) Act of 2011 made it illegal for journals to reject papers or to make a profit, all journals now accept all papers automatically so paper was immediately accepted by all five. Should appear on-line sometime in 2037 if the backlog doesn't get worse.

2:39 am to 3:55 pm. Attended mandatory daily sensitivity training workshop, required of all faculty by the Office of Self-Esteem, which has controlled all US universities since the Political Correctness Wars of 2014. Was reminded yet again that any idea, no matter how idiotic, must be respected since to do otherwise would stifle student creativity and self-expression.

3:55 pm to 4:00 pm. Thought about meaning of results of research.

4:00 pm to 6:15 pm. Realized I had forgotten to check e-mail for several hours. Found 2,651 new messages. Not bad. Deleted all except offer from ex-Nigerian government official who wants to give me $24 billion in return for promise to think happy thoughts about him. Must look into this tomorrow.

6:15 pm to 7 pm. Packed up to go home. Waited 45 minutes for shuttle bus to parking lot. While waiting, checked latest news on iPhone. Still no progress on ending war in Iraq.

Published: 29 March 2007

It can't happen here - can it?

Genome Biology 2007, 8:105

If scientific advice is to have any value, it must come from sources that are not under obligation to any organization, public or private. In the United Kingdom, that advice generally comes from the Royal Society of London. In the United States, it comes from the National Academy of Sciences. And in much of the former Soviet Union, it comes from the Russian Academy of Sciences. You wouldn't necessarily think they would have similar ideas about the importance of independence, but they do.

The oldest scientific society still in existence, the Royal Society of London, was founded in 1660. Its permanent Second Charter received the Royal Seal on the 23 April 1663. The motto of the Society, "Nullius in Verba" ("On the words of no one"), signifies the Society's commitment to establishing the truth of scientific matters through experiment rather than through the words of any authority. The Society is governed by its Council of Trustees, which is chaired by its President. The members of the Council and the President are elected from its Fellowship, new members of which are in turn elected by vote of the existing Fellows. The Royal Society has never depended on the Crown for either its finances or its governance.

The National Academy of Sciences of the United States was created in 1863 by a congressional charter approved by President Abraham Lincoln. The key part of the charter specifies the relationship between the Academy and the government. The Academy was created to be an adviser on scientific and technological matters, but the Academy and its associated organizations are private, nongovernmental organizations and do not receive direct federal appropriations for any of their work. (Studies undertaken for the government by the National Academies usually are funded out of appropriations made available to federal agencies.) The charter stipulates virtually complete autonomy for the Academy, including freedom to elect its members and officers and establish its own policies and procedures.

I could tell similar stories about the principal scientific organizations in most Western countries. Though the precise relationship between the state and scientific community varies in detail, for the most part there is at least a large measure of autonomy in scientific advice, and considerable nongovernmental scientific input into funding decisions and research directions. In short, the principle of independence from state control has guided the formation and governance of every scientific society in the world whose opinions have any credibility.

If Russian president Vladimir Putin has his way, that principle will no longer apply to the Russian Academy of Sciences. (During the period when Russia was part of the Soviet Union it was known as the Academy of Sciences of the USSR.) The Academy was founded in January 1724 in St. Petersberg by Peter the Great. For most of its existence it was effectively an arm of the government, and in 1917, Lenin decided that the Academy would address questions of state construction, in return for which the Soviet regime would give the Academy financial and political support. Partly to reflect this connectedness, its headquarters were moved to Moscow, the Soviet capital, in 1934.

But a curious thing happened during the post-Stalinist era: despite its close ties with the state, the Russian Academy began to assert its independence in many important matters. It frequently rejected for membership senior Communist Party officials whom it considered unqualified. In 1980, it refused to expel dissident nuclear physicist Andrei Sakharov, despite demands from Moscow that it do so. (Disclosure: much of my knowledge of the inner workings of the Russian Academy and scientific politics in Russia comes from conversations I had over the years with my good friend Vitalii Goldanski, who died in 2001. Vitalii, who was born in Belarus in 1923, was a great chemical and nuclear physicist. In addition to being a member of the Russian Academy, he was also a member of the Supreme Soviet and the Congress of People's Deputies. In 1991 he was honored by the New York Academy of Sciences for his work on behalf of nuclear disarmament.)

The Russian Academy has also tried to retain at least partial autonomy over what science was funded. Unlike the American and British scientific academies, whose primary functions are honorific and advisory, the Russian Academy effectively controls much of the scientific research in its country. The Academy's senior members oversee a $1.2 billion budget, 400 research institutes and 200,000 researchers and staff members across Russia. And just like most other Western academies, the institution is self-governing: research funding, as well as who becomes a researcher and who enjoys the prestigious title of full member - 'academician' - is determined by secret ballot among the members. Although over the years, the government has directed the Academy to support a number of specific areas of science, not all of these directives were accepted and the Academy was able to keep many areas of research alive against the wishes of the communist authorities. It is this tradition of political independence that Vladimir Putin is trying to eliminate.

Putin used to be a member of the KGB (Komitet Gosudarstvennoy Bezopasnosti, the Committee for State Security), the notorious combined intelligence and secret police organization that terrorized the Soviet Union for decades under communist rule. Lately he seems to be showing signs of wanting to take up his old hobbies. Last year, at Putin's urging, the Russian Parliament passed a law stipulating that the Academy's top executive must be approved by the president and that its charter must be approved by the government. Shortly thereafter, the Education Ministry, to which the Academy reports, proposed a new charter that would create an advisory council with nine members, only three of whom would be scientists; the other six would be a mixture of government officials, lawmakers, and ministers. This body would oversee all of the operations of the Academy, including the funding of research, and would make all decisions about what areas of science would be pursued. In other words, control of the operation of the Academy would be ceded to the state.

As might be expected, the Academy is fighting this proposal. A few weeks ago its senior members voted unanimously against the proposed charter. Given the tight control that Putin has established over virtually all aspects of Russian life, it remains to be seen if their courageous assertion of independence will prevail. (One thing is certain: they can use all the support they can get from their friends outside Russia.)

Before we in the West congratulate ourselves on being fortunate enough to live in countries where science is independent of state control, maybe we should take a close look at recent developments here. The Bush Administration hasn't tried to take over the scientific establishment, not because they don't want to (this is an administration that aspires to rule, not govern), but rather because they don't have to - they've simply ignored every objective scientific fact or report that didn't fit their ideologically driven policy goals. Why bother taking over what you can marginalize? True, they have tried staffing some federal scientific administrative posts with people who have minimal - in some cases, nonexistent - scientific credentials. Frequently these appointees appear to have been chosen for their fundamentalist religious, social conservative, or free-market beliefs. It's hard to assess the full measure of harm that has caused (environmental issues seem to have been most affected), but it hasn't had much of a direct impact on the scientific community as a whole, as far as I can tell.

But the independence of American science is being eroded nonetheless. And as is so often the case, this particular road to hell has been paved with the best of intentions, and the street plan was designed, not by our enemies, but by our friends.

It started, as so much has in the past decade, with the Human Genome Initiative. I have said before, and will say to the end of my days, that this project, wonderful and important as it has been, was oversold to the US Congress and the public. By promising that cures for diseases would emerge, as if by magic, from the oceans of data that were generated, the founders of that project and the funding-agency administrators who supported them raised expectations that simply couldn't be met in any reasonable period of time. Out of concern that lawmakers and their constituents would, quite reasonably, soon hold them to account, the administrators in the US National Institutes of Health (NIH) began a campaign to shift some of the science they supported away from basic investigations and towards translational research that was more directly focused on human diseases. That focus became the basis for selling Congress on another, even larger expenditure: a doubling of the NIH budget over about a seven-year period. Congress acquiesced to the doubling, which was completed a few years ago, in large part because it bought the argument that the investment in genomics would only pay off with a concomitant investment in its applications.

During the doubling I think there was a sense that there would be a surplus of money, which led many administrators to conceive of big projects that would give them, and their institutes, the same high-profile success as that enjoyed by the Human Genome Institute. In this, they were abetted by many from our own ranks of independent investigators, who wanted their share of the money and glory that had gone to the Craig Venters, Eric Landers, and Francis Collins' of the genomics projects. What followed was a subtle, but rapid shift in how scientific priorities are set. Instead of research directions arising largely from the open competition of individual research projects in peer-review, NIH began setting those directions itself through increased numbers of big new programs and specific allocation of large pots of money for certain types of projects - commonly, projects aimed at either exploiting the information from genomics studies or gathering more.

Such projects, consequently, have relatively stable funding, but individual investigator-initiated projects do not. As I've written before (The System is Broken, Genome Biol 2006, 7: 105 and Instructions for Repair, Genome Biol 2006, 7: 106), the result has been a disaster for American science. Funding of regular research grants is so tight that many mid-career investigators are being driven out of research; senior investigators, whose perspective is needed more than ever, are being driven into early retirement; and good young investigators are seeing their careers at the mercy of a process that, quite literally, is no better than a lottery. How have the funding agencies responded to this crisis? I know many administrators who are personally dismayed at the situation, but the culture seems to have developed some huge inertia: ironically, after the doubling of the NIH budget, when the crisis has been made worse by no budget increases for several years, the number of grants funded through government-initiated requests for applications and program announcements has increased even more than they did during the doubling. And the percentage of new awards that go to traditional basic science research projects has continued to fall.

We scientists in the trenches need to reclaim our rightful place as the setters of priorities and directions. One way to do this is to fix the peer-review system, so that once again the most creative and productive investigators are funded, and the importance of the question being addressed, not whether something fits into some preconceived program, largely governs what research gets supported. Another way is to demand - and play - a greater role in determining how big scientific funding decisions are made. To be fair, science administrators often hold workshops designed to give them advice about important areas to support, but many in the research community pay little attention to requests to attend. That needs to change. I also think it's time we started initiating that sort of process ourselves instead of waiting for the NIH to do so. The various scientific societies could take the lead in establishing such a program, with the help of the National Academy and, of course, the various NIH Institutes.

If we allow the top-down approach to determine what science gets done, the combined pressures of human ego and the need to make good on extravagant promises will continue to take science where it's already heading: towards big, flashy, but ultimately conservative, risk-averse, unexciting research. We'll produce a lot more data but fewer discoveries. We'll have predictability instead of surprises. Gone will be the marvelous principle that created perhaps the most successful scientific enterprise the world has ever seen: that the best path to innovation is that followed by hypothesis-driven, investigator-initiated inquiry. The Bush Administration won't have killed it, nor will any of our national competitors - we will have done it to ourselves. Vladimir Putin may well be jealous. We will have thrown away our own independence out of greed, apathy, timidity, and a failure of vision. And we may not even notice the irony that the Russian Academy of Sciences will have shown more of a commitment to freedom of inquiry than we have.

Published: 30 April 2007

Inconvenient truths

Genome Biology 2007, 8:106

"Persuade thyself that imperfection and inconvenience are the natural lot of mortals, and there will be no room for discontent, neither for despair."

Ieyasu Tokugawa, Shogun

The email seemed harmless enough. It didn't contain any hidden viruses or malware; it wasn’t phishing for personal or financial information so it could steal my identity; it didn’t even come from yet another student grubbing for yet another point or two on some quiz or exam. Yet, it was enough to send me into a paroxysm of rage.

The message was from a multi-user scientific facility I had last heard from 9 months ago, when I wrote a letter of recommendation for the promotion of one of their staff. It informed me that they had erred in their description of the job I had recommended him for, and asked me to please rewrite the letter with the correct job title and the current date.

Now, what made me furious was not the extra work - it was extra work, to be sure, but in these days of word processors and files of old letters, not that much. Nor was it their having, mysteriously, waited 9 months to do this, without explanation for the delay. Those things were annoying but not enough to light my admittedly short fuse. No, what set me off was the way their message ended: "We apologize for the inconvenience."

My response, I fear, was not the most courteous. I sent back the edited letter with a curt note saying that, if they were going to ask me for something like this after so long a silence, they owed me an explanation. And I ended by saying that they needed to get their facts straight: "This is not an inconvenience - it's an imposition."

I didn't feel much better afterwards. For one thing, I supposeI shouldn't have berated some poor administrative assistant who probably was embarrassed about having to send the message in the first place - although, to be fair to me, it didn't seem like they were embarrassed at all. But the real reason why I didn't cool down until much later (actually, since I'm using the incident as the basis for this column, I guess I still haven’t cooled down) was because I suddenly realized how much I hate that expression: "We apologize for the inconvenience."

Has there ever been a phrase in the English language more blatantly insincere? It goes way beyond 'clichéd', making it all the way to ‘hypocritical’. I have never yet seen it used as anything but an attempt to weasel out of the consequences of screwing up. Where it came from I don’t know, but wherever that was I wish it would go back. I think I first encountered it between ten and twenty years ago, when it started appearing on signs warning drivers approaching road construction projects. It had a sarcastic tone even then. "Bridge closed for repaving", it would say. "Twenty mile detour. We're doing this in the middle of rush hour just because we feel like it. We apologize for the inconvience".

Like a lot of meaningless expressions ("Have a nice day"; "Fine, thanks; how are you?"; or "That chartreuse outfit looks great with your purple hair."), this one probably arose out of a desperate need to find something to say. I mean, if you're trying to inform some hapless motorist that their day is about to become a living hell because of something you've done, and you don't want them to get out of their car and hurl their travel mugs at you, you can't say what you really feel, which is "We don't care what happens to you, so go rot." You need to find a way of seeming to be sorry without actually being sorry. "We apologize for the inconvenience" must have seemed to some public relations hack like a master stroke: it contains the magic word 'apologize' but at the same time trivializes the consequences of what was done by calling it an inconvenience. Who would sue anyone over that?

There are so many things wrong with this that I don't know where to begin, but I guess the biggest problem I have with it, besides its patent insincerity, is its presumption. Isn't it my place to decide what to call the effects of someone else's actions on me? If it's an inconvenience, I'm the one who should say so. And if it's actually a colossal pain in the rear end, justifying any sort of verbal - and perhaps non-verbal - assault as a response, well, I'm the one who should decide that, too. Having the person who has just imposed on you or wrecked your schedule or caused you to waste an hour of your life making up for their mistake calling it an inconvenience is like having the person who has just held you up at gunpoint apologize for making you hold your hands in the air.

The art - and it is an art, really - of apologizing seems to have gone the way of cars that look distinctive, or novels with plot, or songs with lyrics you can actually understand. I can't count the number of times that someone has said "I'm sorry, but…". Every time that happens, I can still hear my mother telling me "There is no 'but' in an apology. If you say, 'I'm sorry, but…', you're not really sorry." Just listen the next time a politician or a celebrity apologizes for some serious misdeed. I practically guarantee that there will be a 'but' in there somewhere, actual or implied.

Science is not immune to these meaningless locutions. Genomics is rapidly acquiring its own set as well. They aren't just used for convenience, or economy of words. They're used for the same reason as 'We apologize for the inconvenience' is used, as a way of camouflaging the truth. In the interest of public service, and in the hope of making all of you Sancho Panzas in my quixotic efforts to tilt at the windmill of scientific discourse, here are some of them, together with their translations (see Box 1).

Box 1

When a scientist says:

What he/she probably really means:

This is a well-written paper

The author should stick to literature

This proposal addresses an important topic

Too bad it doesn't address it well

I enjoyed your talk

The parts I was awake for sounded pretty good

Your conclusions are interesting

I don’t believe a word of it

The PI has been productive

If only he had produced anything worthwhile

Our project uses genome-enabled tools

Maybe this buzzword will get this piece of crud funded

Overly ambitious

If she does all this, it’ll make slobs like me look bad

Insufficient experimental details

I can nit-pick anything to death, no matter how good it is

Genomics

Who cares what any of these genes actually do?

Functional genomics

Misannotation on a genome-wide scale

Expression profiles

A very large number of very small changes

Protein profiles

Two-dimensional gels

Proteomics

Bigger two-dimensional gels

Advanced proteomics

Really big two-dimensional gels

Translational research

Maybe a new buzzword will get this piece of crud funded

Systems biology

Physiology, but if I called it that, no one would come

Genome-wide

I don’t know how to study anything in depth

Structural genomics

It sure beats thinking

Bioinformatics

Garbage in, garbage out

Rational drug design

Yeah, right

Oh, you write those Genome Biology columns

Don’t give up the day job

Published: 31 May 2007

An idea whose time has gone

Genome Biology 2007, 8:107

When I was in college, I had a roommate who was a little weird. OK - more than a little weird. One night, at about 2 am, the campus police woke me up to tell me that he was sitting in the middle of the main street of our college town, naked, with a blanket over his head. They wanted me to go and bring him home, so they didn't have to arrest him. I got dressed, walked into town, and sure enough, there he was, sitting naked in the middle of the street with a blanket over his head. I walked over to him, called his name, and said, "Warren, why are you sitting naked in the middle of Prospect Street with a blanket over your head at 2 o'clock in the morning?" He peered out from under the blanket, looked up at me, and said, "It seemed like a good idea at the time."

My guess is that whoever was responsible for the Protein Structure Initiative (PSI) must have felt the same way. The PSI is a fancy name for the US 'Structural Genomics' effort. The stated aim of Structural Genomics is determination of the three-dimensional structures of all proteins. Its members and proponents claim that this aim can be achieved in four steps: first, organizing known protein sequences into families; second, selecting family representatives as targets; third, solving the three-dimensional structures of targets by X-ray crystallography or NMR spectroscopy; and fourth, building models for other proteins by homology to solved three-dimensional structures.

The Initiative currently funds ten large centers scattered around the United States (similar efforts exist in Europe and Japan). They are supported for a five-year period to the tune of about $300 million total. The PSI website http://www.nigms.nih.gov/Initiatives/PSI/ states that "Expected benefits from the PSI include: structural descriptions to help researchers discover the functions of proteins, design experiments, and solve other key biomedical problems; faster identification of promising new structure-based medicines; better therapeutics for treating both genetic and infectious diseases; and development of technology and methodology for protein production and crystallography." The National Institute of General Medical Sciences (NIGMS), the main branch of the US National Institutes of Health (NIH) funding the PSI, is currently engaged in an assessment of the PSI. I know this because I was asked to provide my views on the initiative. I'm afraid they weren't very complimentary.

The PSI actually has had two incarnations. The specific goals of PSI-1 (which existed from 2000-2005) were to develop methodology and technology to increase success rates and lower costs of structural determination; to construct and automate the protein production and structural determination pipeline; and, finally, to determine unique protein structures. Lots of unique protein structures. By 2005, it became apparent that most of these goals weren't being met, nor were they likely to be met in the near future.

One of the many great scenes in the wonderful old Errol Flynn movie 'The Adventures of Robin Hood' is the archery contest. The finest archers from all over the kingdom are gathered in Nottingham to compete for a gold arrow. After many rounds, only two competitors are left: Robin Hood, disguised as a tinker, and one of Sir Guy of Gisborne's archers. After they both shoot and both hit the bulls-eye, Robin Hood asks that the target be moved back, "to a fit distance for men to shoot at." When it looked like the PSI wasn't going to be able to meet its goals, what did it do? It moved the target in. The specific goals of PSI-2 (funded from 2005-2010) are now to increase the number of sequence families with structural representatives, including families with high biological impact; to continue methodology and technology development, especially for challenging classes of proteins such as membrane proteins; and to facilitate the use of structures by the broad scientific community. These goals are so squishy, it would almost be impossible not to meet them. Or for it to matter much if they were.

But as I considered my assessment, it became clear to me that even if the goals of the original PSI-1 could be met, I wouldn't care. Nor, I think, should most anyone else.

Do we really need a catalog of structures? What will that teach us? We already know that proteins are composed of beta sheets and alpha helices, interspersed with loops. Filling the fold catalog might be of interest to bioinformaticists, but why should they drive the science that others do?

And I reject categorically the notion that enough structures will allow us to build homology models for every sequence. First of all, the methods for recognizing which fold a sequence belongs to aren't that robust. False positives seem to be fairly rare, but false negatives abound. Second, homology models aren't very accurate when the sequences are less than about 50% identical, which happens most of the time. For drug discovery and understanding biochemistry, accurate models are essential. Nor is it clear to me that when you have a structure, you necessarily have learned all that much about the function of the protein. The coupling between sequence, overall fold, and function is rather loose. Even when a fold has an accurately annotated function, which is not as often as it ought to be, there is a high probability that a homolog with less than about 50% sequence identity will have a different biochemical and cellular function. My guess is that a large catalog of structures will just lead to even more missannotation of function by homology - one of the greatest problems in genomics today.

It's also clear, I think, that it isn't enough to have the structure of a protein; you need to have the right structure. Small changes in sequence can lead to big changes in oligomerization state, which in turn can lead to changes in active site geometry and function (a good example can be found in a recent study by Wei et al.: Identification of functional subclasses in the DJ-1 superfamily proteins. PLoS Comput Biol 2007, 3:e10). We don't have any method for predicting the oligomerization state of a protein from its sequence or its homology to a protein of known structure when such changes occur. And what about changes in conformation? It did Novartis no good to have the structure of the Bcr-Abl tyrosine kinase for the design of the anti-leukemia drug Gleevec. The kinase exists in two structural forms, open and closed, and when Gleevec was being developed the only existing structure was of the open form. Gleevec binds to the closed state.

As for the stated goal of the PSI to develop technology to make protein crystal structure determinations easier, I'm afraid I have to say, so what? Solving structures isn't really the rate-determining step for most good structural biology projects - the bottlenecks are usually biochemical. The PSI's focus on high-throughput methods of expression, purification and crystallization means that it isn't really furnishing solutions for most of those problems. To be perfectly selfish, I have to say that it hasn't made any contribution to my own work, and I'd be willing to bet that it hasn't contributed much to yours either.

Another problem I have is with the entire mindset of such an initiative. It is focused on cranking stuff out as fast as possible, with little attention to whether the structures that it's determining are worth determining. I also reject categorically the notion that all protein structures are worth having. Structures have value when they are part of a larger effort to understand the biochemical and biological functions of the protein in question. Doing them in isolation has no more intellectual content than does assembling a car. As a structural biologist, I want to train people who use structure determination as part of what they do. It is not the end in itself, nor should it be, not any more. When we knew almost nothing about the universe of protein structures, every structure had value. But Adam Smith's law of supply and demand works in science just as it does in economics: with the supply of structures already in the tens of thousands, the value of any new structure in and of itself is likely to be rather small.

The argument can probably be made - almost certainly will be made - that it will be useful for pharmaceutical and biotechnology companies to have structures of all proteins from various pathogens and from certain human disease tissues. Maybe, though I doubt it - there's a big difference between a potential target and a validated one. And if such structural information is of value to the private sector, why shouldn't the private sector fund it? $300 million over five years is petty cash for a consortium of drug companies, but I don't see them lining up to pay even that pittance for this information.

But what's a drop in the bucket to drug companies is life and death to academic research. The $60 million a year in public money that is being spent - I would say, wasted - on the PSI is enough to fund approximately 100-200 individual investigator-initiated research grants. These hypothesis-driven proposals are the lifeblood of the scientific enterprise, and as I have discussed recently in other columns, they are being sucked dry by, among other things, an increasing trend to fund large initiatives at their expense. That $60 million a year would raise the payline at a typical NIH institute by about 6 percentile points, enough to make a huge difference to peer review and to the continuance of a lot of important science.

I simply can't see the justification, in a time when budgets are so tight, for continuing a program that has produced little useful information, has not furnished many widely disseminated technologies or methods, and has minimal intellectual content. Regular readers of this column (all five of you) will know that I am not a disparager of big science per se. Many such initiatives make a lot of sense, in large part because their information drives good small science. But I don't believe that the PSI has, or that it will.

So my overall assessment of the PSI is that it is an idea whose time has gone. Given its ability to change its shape (that is, reformulate its goals) so as to continue to suck blood - I mean funding - from the NIH, I think it isn't going to be enough to recommend that it be phased out. It should have a stake driven through its heart, and then it should be buried in a coffin filled with its native soil so that it can't rise again with the next full moon. If that seems harsh, then on its tombstone, if you like, we could engrave the words of my erstwhile roommate: "It seemed like a good idea at the time."

Published: 2 July 2007

A truly titanic figure in science

Genome Biology 2007, 8:108

I almost had this month's column finished when I got the news; then I knew I had to write a different one. The news was that Dan Koshland, one of the truly titanic figures in American science in the past fifty years, had died of a massive stroke at age 87 on Monday, 23 July.

Dan always said that his ambition was to die young as old as possible. He succeeded: very few people, of any age, have had a younger heart or a more open mind. He went the way we should all go: suddenly, while still sharp and having fun. In fact, he called his delightful autobiographical sketch "How to get paid for having fun" (Koshland DE: Annu Rev Biochem 1999, 65:1-13), and few scientists have enjoyed themselves more. His scientific accomplishments were vast, ranging from the development of fundamental concepts in enzymology to important advances in understanding sensory transduction through his work on bacterial chemotaxis. He managed to combine a gift for theorizing with a talent for clever but rigorous experiments - a feat that few have done so well. And throughout it all he gave the impression that he was just a kid playing with his favorite toy.

He was my friend for over thirty years. I first met him when I was a graduate student in England and he was on sabbatical there. I knew who he was, of course - he was already famous for his work on enzymes. In the late 1950s, he did a series of experiments on the enzyme hexokinase that were incompatible with the rigid 'lock-and-key' picture of how an enzyme works that had stood as dogma for half a century. To explain his results he formulated what he called the "induced fit" theory, invoking a moderately flexible enzyme fitting itself to a moderately flexible substrate. This revolutionary advance in our thinking about how enzymes work was greeted with resounding skepticism, which Dan recalled with the relish of the vindicated in his wonderful essay "Crazy, but correct" (Koshland DE: Nature 2004, 432:447). He also had demonstrated the phenomenon of absolutely negative cooperativity (where the binding of a ligand to one subunit of a multi-subunit enzyme completely blocks binding to another, identical subunit) and had proposed an alternative model for allostery to the 'all-or-nothing', symmetrical model of Monod, Wyman and Changeux. Dan's 'sequential' model, in which some subunits can be in the tense (or T) state while others are in the relaxed (R) state is now generally acknowledged to be correct, at least for some allosteric proteins. At the time we met he had just started to work on bacterial chemotaxis, a field that had been dominated for decades by beautiful genetics from the likes of Julius Adler but which was lacking in any molecular description of how a chemical signal generated a change in behavior. Over the succeeding twenty years, Dan and his students and postdocs, bringing not just the tools but also the quantitative rigor of the enzymologist to bear on the problem, delineated the structures and mechanisms of all of the major players in this pathway. Dan's enthusiasm for this new foray into cell biology - a field seemingly light years removed from his biochemical research - made a deep impression on me, and was largely responsible for my own effort to learn yeast genetics many years later so I could study the problem of cellular quiescence. ("Petsko," he said, when I told him of my plans, "I see you have learned a valuable lesson from me: if you have no conscience whatsoever, you can ruin more than one field in your lifetime.") At the time of his death he was excited about yet a new venture, an effort to use light energy to improve the efficiency of ethanol production from plant material. Biofuels has been something of a stodgy field in recent years; can there be any doubt that it would have become much livelier - and more scientifically interesting - with Dan Koshland in it?

Figure 1

Daniel Koshland, circa 1991. Image courtesy of Robert Holmgren (UC Berkeley News).

For some reason he took a liking to me, and to my ideas. I wasn't his student - there was nothing in it for him - but nevertheless he became one of my biggest supporters over the years (I suppose he has that to answer for, somewhere). Time and time again something good would happen to me and I would find out later that Dan was behind it. From the day we met in England until the day he died, I always felt like he was there for me, and I can't describe how important that was. We often don't realize the influence we have over others. We're supposed to be supportive of the people who work with us, but sometimes it's the support we give the stranger, the casual scientific acquaintance, that has the greatest influence. When a senior scientist, especially one of any eminence, takes an interest in a younger colleague, it can have a transforming effect on that person's life and career. I've been fortunate to have had several such supporters in my life, and they've made a huge difference. It doesn't take much, really: the right words at the right time, a phone call or e-mail, a remark dropped in the right ear, a willingness to write that letter or visit that poster or attend that talk. Who knows what, if anything, I meant to Dan Koshland? I sure know what he meant to me.

I didn't know for many years that Dan was fabulously wealthy - he was one of the heirs to the Levi-Strauss clothing fortune. Everybody was surprised when they learned that, because he was among the most down-to-earth people you would ever meet. He wore his wealth like he wore his scientific distinction: casually, unostentatiously. He used it well, too: he helped build several buildings - at Berkeley, where he taught since 1965, and in Washington, where he provided a major gift to endow the Marian Koshland Science Museum of the National Academy of Sciences, named after his wife Marian (Bunny), herself a distinguished scientist (in immunology). The couple were also the lead donors to the Marian E Koshland Integrated Science Center at Haverford College, which their two sons attended.

In 1985 he accepted the position of editor-in-chief of the journal Science. These days, when Science is considered one of the highest-profile places in which to publish biological research, it's hard to believe that it was once not even on the top twenties list, but that was indeed the situation when Dan took over. If you wanted to publish basic life sciences research in a high-impact journal, you published in Nature. Dan set out to change that, and did so, spectacularly. He created a board of reviewing editors with heavy emphasis on the biological sciences, brow-beat (charmingly, of course) his friends (including me) into publishing their hottest stuff there, and so changed the perception of the biological community that, by the time the first genome sequence of a free-living organism was completed, in 1995 by Claire Fraser, Craig Venter and their associates, Science was considered the most prestigious place for US life scientists to publish earth-shaking discoveries - as in fact, they did (Smith et al.: Science 1995, 269:495-511). Science continued to lead the way in publishing new genome sequences for some time, although Nature soon caught up. But Dan had changed the journal completely, and much for the better.

He told me that the only reason he took the job, which required him to fly to the East Coast almost every week for ten years, was so that he would have a place where they had to publish his little musings on any subject that took his fancy. Numerous times each year, he wrote editorials for the front of the journal - remarkable short essays on topics ranging from spousal abuse to the Clinton Administration's science appointments. They were always a delight to read - still are, after all these years. They're funny, insightful, irreverent, and candid. Dan never hesitated to speak his mind but managed to do it in an offhand, witty way that was both charming and effective. His style and fearlessness had a big influence on me when I decided to do this column (so I guess that's something else he has to answer for). Here's an excerpt from an editorial he wrote on the scientific funding crisis of 1990: "What is important is to think big about 'little science'. There will undoubtedly be some megaprojects, but what the nation and the world really need is a major expansion of investigator-initiated science, because that historically has been the source of great discoveries that have opened new frontiers." (Is anybody in Washington listening today?)

Dan was a big supporter of genomics, including the human genome project. In 1989, when support for this biological Manhattan Project was highly controversial, this is what he said in one of his Science editorials: "We must be vigilant about ethical concerns but not paralyzed by outlandish scenarios. The belief of biologists that studying simple organisms such as Escherichia coli, flies, and rats is relevant to human physiology and behavior has been brilliantly confirmed. But there are differences. One cannot extrapolate carcinogenic potency from the mouse to the rat with precision, and even less to the human. Some diseases involve speech and mental states unique to man. Sequencing the human genome puts us on the threshold of great new benefits and some real but avoidable risks. There are immoralities of commission that we must avoid. But there is also the immorality of omission - the failure to apply a great new technology to aid the poor, the infirm, and the underprivileged. We must step boldly and confidently across the threshold."

Dan was the doyen of biochemistry but nevertheless always behaved like, and loved, the maverick. "Later in life," he wrote a few years ago, "when I became editor-in-chief of the journal Science, my early experience allowed me to keep a friendly eye out for the non-conformist. But does science have any lessons for non-conformism in other spheres, such as politics and religion? Non-conformity is looked on with more hostility by religion, government and culture than by science - because each of them is more vulnerable to change than science is. The other segments of our society have yet to find a better mechanism for encouraging non-conformity to achieve progress, while still controlling non-conformity to prevent chaos. Science has achieved the best balance, but it must fight to preserve this and serve as a beacon to other sectors of our society." He was 85 when he wrote that.

I last saw him a month ago, at a dinner in New York. "Petsko," he said when he saw me (he never called me Greg, not once in 35 years), "what mischief are you up to now?" He actually looked disappointed when I told him I was being good.

I loved him greatly. I can't imagine what my life would have been like without his encouragement, enthusiasm, and interest. I know it would have been poorer. After he started to show his physical age a few years ago, I made it a point, every time I saw him, of telling him how much his friendship meant to me. Now I think I still didn't say it often enough.

Published: 31 July 2007

My worries are no longer behind me

Genome Biology 2007, 8:109

First they make you drink something that tastes like slime - or British beer. Then you spend the majority of your day in the smallest room in your house. Then they stick a tube into you in a place normally discussed only in scatological humor. And after it's over, you spend the rest of the day producing as much natural gas as Kazakhstan. I've had more fun at faculty meetings.

I had my first colonoscopy last month, at age 59. I should have had it nine years ago. In the US, as in Europe, about 4% of the population will eventually be diagnosed with colon cancer. In the United States alone, the disease accounts for 14% of all deaths from cancer, making it the second most common cause of cancer death. The average age of onset is 64. Like many other diseases, the majority of cases of colon cancer are sporadic, but a familial form, hereditary nonpolyposis colorectal cancer (HNPCC), is responsible for approximately 2-7% of the 160,000 cases of colorectal cancer that are diagnosed annually in the US.

Colon cancer is a solid cancerous growth that begins on the inner surface of the colon or rectum. Virtually all colon cancer develops from mushroom-like growths (called adenomatous polyps) that form on the inside wall of the colon. These polyps vary in size, but the larger a polyp is, the greater the likelihood that it will become cancerous. For the most part, it takes years for a polyp to become cancerous, and in fact most polyps never turn malignant. About one in four people develop adenomatous polyps by the age of 50, even though most of them will never develop colon cancer.

Individuals diagnosed with inflammatory bowel disease (not irritable bowel disease) are at increased risk for colon cancer. In addition, other nongenetic factors include age (isn't it always?), above-average consumption of red meat, a high-fat or low-fiber diet, obesity, a sedentary lifestyle, and cigarette smoking. The Japanese, whose diet is relatively high in fiber and low in fat, have significantly lower incidence of colorectal cancer than do Westerners (although their incidence of stomach cancer is higher), but when Japanese men and women live in the West for extended periods of time, their colon cancer rates rise, indicating that diet plays a significant role.

HPNCC (also called Warthin-Lynch syndrome) is inherited in an autosomal dominant fashion and people with this disorder also have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women with this disorder also have a greatly increased risk of endometrial and ovarian cancer. Despite the term nonpolyposis, people with HNPCC occasionally do have colon polyps, which occur at an earlier age than in the general population and are more prone to become cancerous.

Thanks to the tools of genomics, the molecular genetics of colorectal carcinoma are among the best understood of the common human cancers. Typically, inactivation of the APC (adenomatous polyposis coli) gene initiates colorectal neoplasia leading to polyp formation. In patients with familial adenomatous polyposis, germline inactivation of APC appears to be followed by its somatic inactivation in colorectal epithelium, typically leading to large numbers of polyps. As these progress to malignancy, additional alterations accumulate in proto-oncogenes, including ras, and in tumor suppressor genes on chromosome 18q (DCC, Smad2, or Smad4) and 17p (p53). The alterations, each of which appears to provide a selective growth advantage, are found in various combinations in colon cancers. About 15% of colorectal cancers are characterized by microsatellite instability (MSI), also termed DNA replication errors or ubiquitous somatic mutations. Inactivation of one of a group of genes whose products participate in postreplicative repair of nucleotide mismatches leads to insertions and deletions of nucleotides in intrinsically unstable repeated sequences (microsatellites) throughout the genome because of defective repair of the slippage mistakes made by DNA polymerases. MSI-positive tumors thus accumulate numerous frameshift mutations but also have a mutator phenotype that increases both base substitution mutations and frameshift mutations in expressed genes. In patients with HNPCC, germline mutation of hMSH2 (human MutS homolog 2), hMLH1 (human MutL homolog 1), hPMS1 or hPMS2 (human postmeiotic segregation 1 and 2), or the GTBP (guanine/thymidine mismatch-binding protein)/hMSH6 gene, all of which code for DNA repair proteins, predispose to tumorigenesis. In addition to germline and somatic alterations in these genes in HNPCC, somatic inactivation of mismatch repair genes has been identified as a cause of MSI in sporadic tumors.

The tragedy of colorectal cancer is that it is one of the most preventable of fatal diseases. Symptoms of colon cancer include rectal bleeding, unexplained weight loss, constipation or diarrhea, abdominal pain, and a marked decrease in the diameter of your stools. However, colon cancer often fails to produce any symptoms until the cancer has grown very large or metastasized, so the early identification and subsequent removal of polyps through regular screening is the best method of colon cancer prevention. Surgical removal of polyps before they progress to malignancy or metastasize leads to a very favorable outcome. All adults over 50 years of age should be screened for colon cancer since regular screening has been shown to reduce colon cancer deaths. People who are at increased risk of developing colon cancer (for example, those with a familial history of the disease) should begin screening at a younger age and be screened more frequently. The presence of polyps that are known to progress frequently to malignancy also means that the affected individual should be screened more often than someone with no such growths.

I indicated what the procedure is like at the start of this column. It involves first taking large amounts of laxative to clean out the colon the day before the examination. During the colonoscopy itself, the physician uses a colonoscope (a long, flexible instrument about half an inch in diameter) to view the lining of the colon. The colonoscope is inserted through the rectum and advanced to the large intestine. During the colonoscopy, polyps can be identified and removed for biopsy. In many cases, colonoscopy allows accurate diagnosis and treatment without the need for a major operation. Although the procedure sounds incredibly unpleasant, it's done under intravenous sedation (typically with midazolam and fentanyl or Demerol), and the patient usually has no memory of the procedure at all - I certainly didn't. So the worst part is actually taking the laxative, although periods of flatulence for a day or so are a common aftereffect because of the introduction of air into the colon during the examination (don't ask me how I know this). Colonoscopy has a low (0.2%) risk of serious complications; the most serious is a tear or hole in the lining of the colon called a gastrointestinal perforation, which is life-threatening and requires immediate major surgery for repair. However, the rate of perforation is less than 1 in 2,000 colonoscopies. Still, you want someone to do this procedure who does a lot of them.

The relative merits of colonoscopy versus sigmoidoscopy (which only examines the final two feet of the 4-5 foot long colon) in colon cancer screening has been a source of ongoing debate. Recent articles in The New England Journal of Medicine have suggested that colonoscopy is superior to flexible sigmoidoscopy as a colon cancer screening method, but to get regular screening of some sort is more important than what screening tests are used, according to experts.

As I said, I should have had my first screening nine years ago. I finally got one because I have a new primary care physician, who specializes in preventive medicine, and who makes my old army drill sergeant seem like a shrinking violet. Why did I wait so long? It wasn't because I was reluctant to undergo an unpleasant experience (OK, maybe it was a little), or because I was afraid of what might be found. Quite the contrary: with no history of colorectal cancer on either side of my family and an absence of most other risk factors (I've never smoked, I exercise regularly), I figured there was no rush. Now that I know more about the prevalence of this disease and the very high percentage of sporadic cases, I realize that I was stupid to delay being screened. My colonoscopy detected several small polyps, which were removed during the procedure and biopsied. I was relieved to learn that they were not malignant, nor were they the kind that turn malignant, which means that I don't have to undergo another colonoscopy for ten years. I guarantee you that I will have that one on schedule.

So if you're 50 or older, don't wait as long as I did to have your first colonoscopy. Do it now. I have to be honest with you: you won't enjoy the experience. As I said, I've had more fun. But it's a load off my mind. Or wherever.

Published: 3 September 2007

Strange days

Genome Biology 2007, 8:110

It's hard to do satire when reality is so bizarre as to be self-parodying. As I write this, the President of Iraq, Jalal Talabani, has left his war-torn country for three weeks to travel to the United States. To consult with President Bush, you ask? No. To beg Congress for more money or more American troops? Nope. To appeal to the American people to support the US presence in Iraq? Not at all. He came here to lose weight. He has checked himself into what is non-euphemistically called a fat farm - a place that combines the physical discipline of an army boot camp with the motivation of an evangelical tent meeting - all in the service of shedding unwanted pounds. It's the sort of place that's particularly popular with rich matrons.

Now, am I the only one who sees something mind-numbingly peculiar about the symbolic head of a country where a significant proportion of the population is malnourished, leaving that country in the middle of a civil war to go to the country with the most obese population on the face of the earth so he can slim down? I guess I shouldn't be. After all, nothing else has been logical about Iraq - why should this be any different? Yet, when it comes to strangeness, Iraq is just one example out of many. We seem to be living in a period characterized by events - and human behavior - that don't just defy reason. They laugh in its face.

For example, the most popular new tourist attraction in theUS is The Creation Museum in Petersburg, Kentucky. You have to see this place to believe it - and you can see some of it - without the bother of actually going there, because they have a website http://www.creationmuseum.org. The Creation Museum is sort of a theme park for the irrational (I call it Dizzy World), a place where four billion years of geologic and biologic history simply didn't happen, because, after all, the earth is only about 6,000 years old. This figure was arrived at in the 17th century by one Bishop James Ussher, based on the ages of the prophets in the Old Testament: he concluded that the first day of creation began at nightfall preceding Sunday, 23 October 4004 (BC); Dr. John Lightfoot, Vice-Chancellor of the University of Cambridge, UK, refined that calculation to 23 October 4004 (BC) at 9 am (it's not clear to me whether that was Greenwich Mean Time). In the Creation Museum, Adam and Eve live happily in the Garden of Eden alongside animatronic dinosaurs; computer animations show how plate tectonics could have produced tsunamis that covered the earth with water in about a month; the Tower of Babel explains the multitude of human languages, and so on.

Surprisingly, the museum does not spend much effort 'disproving' evolutionary ideas or 'proving' creation. It is assumed that anyone who visits needs no convincing of the literal truth of the Bible - that, as one supporter wrote, "God's Word is placed first and human reason is last". Despite that, there are a number of attempts to show that biblical explanations can fit 'scientific' facts: for example, that the diversity of life today can be understood in terms of what went into Noah's Ark. Some of the exhibits show modern times and imply that families and society are hurt by the acceptance of evolution. In one video, a male teenager is shown sitting at a computer looking at internet pornography and a female teenager speaks with Planned Parenthood about having an abortion; both acts are blamed on their belief that the earth is "millions of years" (sic) old. The Creation Museum cost about $27 million and is privately funded through donations. It opened on 28 May 2007. Based on projections, the museum is anticipating 250,000 paying visitors in its first year of operation and it's a good bet that it will exceed that: total attendance already surpassed 200,000 visitors on 20 September. (By comparison, the Smithsonian Institution Museum of Natural History typically draws around 5 million visitors a year, but it's in Washington, DC, not northern Kentucky).

Speaking of history, remember Al Gore, Vice President under Bill Clinton? He was elected President of the United States in 2000, until a Florida ballot count that many believe was rigged, and a Supreme Court decision that many believe was repayment for political favors, said that he wasn't, which made George W Bush president and relegated Al Gore to a footnote in the history books. (Can you remember who lost even half of the presidential elections in your lifetime? Try it - it's not easy.) Or maybe, he lost because he believes the earth is millions of years old, since that seems to be the root of all evil. Anyway, George W Bush became something of a hero after the tragic events of 11 September 2001. Al Gore disappeared off most people’s radar, and gained a lot of weight.

But then something happened: George W Bush and his cronies began making mistakes - not just little ones either, but colossal blunders. Al Gore became highly visible as a champion of the cause of global warming. (No, I don't mean he's in favor of global warming, I mean - oh, heck, you know what I mean.) He won an Academy Award for his excellent documentary film An Inconvenient Truth. He didn't lose the weight he'd gained, but he did begin showing a side of himself - relaxed, confident, in command of his material, self-deprecatingly funny and passionate about things other than the pursuit and exercise of power - that somehow never came through during his overly managed 2000 presidential campaign. Right now, a large percentage of the US population wouldn't vote for George Bush for garbage-collector, and Al Gore might just be the most popular politician in the country.

So he's going to run again in 2008, right? Of course not. That would make too much sense. If you believe what he says - and I do - he has no interest in running again. He's too busy, and having too much fun, doing other things. One of the other things he's done is write a book. And as befits a man who has always seemed to me to be more thoughtful and forthright than your typical US politician, it's quite a good book. It's called The Assault on Reason and no, it's not a discussion of the Creation Museum, though with that title it sure could be. It's a very well constructed argument that America is currently in the hands of an administration that is simply not interested in the truth. The book talks about the corrupting influence of the 300 second television 'sound bite'; the politics of fear; the cynical manipulation of people of faith; and the possible power of technology like the internet to reestablish a democracy based on facts, not driven by ideology. It's a powerful, disturbing, yet ultimately uplifting book. He doesn't have a lot to say about science explicitly, except in his chapter on the climate crisis, but he does point out that there are a number of scientific issues that have been treated by the Bush administration as religious issues, including several connected to genomics - research into human stem cells among them. And he cites a number of instances where scientific information has been distorted or suppressed because it did not fit the ideology of those in power. I suppose it shouldn't be surprising that an administration headed by a president who doesn't believe in evolution and is more likely to visit the Creation Museum than the Museum of Natural History would adopt illogical positions on a host of issues.

What else would constitute a completely illogical notion? Well, how about the idea that doubling funding for biomedical research would lead to a crisis in biomedical research funding? If you had proposed that idea prior to, say, 2004, you would probably have been laughed out of almost every scientific society in the US, but that's exactly what happened. Through the efforts of many prominentscientists, together with Congress, and, yes, the Bush administration, the budget of the National Institutes of Health doubled from $13.6 billion in 1998 to $27.3 billion in 2003 (interestingly enough, it already was doubling, on average, every 9 years since 1972). But then, starting in 2004, the budget essentially went flat, and it's stayed that way since. Now, given that by 2007 this would still make a9-year doubling period, same as usual, we ought to be OK, but that isn't the case. Human nature being what it is, everyone, from science administrators to scientists themselves, started spending money - and applying for more - during the doubling period as though the 15% annual increases in funding would continue forever. New programs were started, including a number of 'big science' projects aimed at exploiting, or imitating, the success of the Human Genome Project. New faculty were hired; new research buildings were built; existing research programs were greatly expanded - in short, growth in the biomedical sciences became, briefly, exponential. And in a period of flat funding, that spells disaster. It's now harder than ever to get a new research grant, conservatism permeates the grant-reviewing process, and young people are being discouraged from entering or staying in science. All because funding went up. And given that it's very hard to scale back or kill ongoing programs, especially big ones, itlooks like the only cure for what ails science at the moment would be another large increase in research funding, even though that’s sort of what caused the problem in the first place. The Bush administration, scrambling to find money to continue the quagmire in Iraq, is clearly not going to support that. Interestingly, most of the other presidential candidates, Democratic and Republican, don't seem to betoo interested either. They seem to be too busy shoring up their credentials as people of faith and attacking each other to spend any time, or political capital, planning to do anything about the crisis in biomedical science.

Well, we know someone who might: Al Gore. But remember, he's not running. I think it's too bad that someone who might be one of the few Democrats to be a good friend to science, whobelieves that reason, not faith or ideology, should decide issues, who is more likely to visit the Museum of Natural History than the Creation Museum, who has eight years of executive experience and actually knows something about the world outside his own country, isn't going to run for president. It's even harder to believe that a man who is so passionate about global warming isn't going to try for the one office where he could really do something about that problem, an office all the pundits say he has an excellent chance of winning. But he's not. Unless, of course, he changes his mind. Which he might, because in these profoundly weird times, when strange is normal, up is down, and irony has become superfluous, theonly thing we should expect is the unexpected. At least we'll have ample warning if Al Gore does change his mind: look for the telltale sign of him preparing himself to look good on television. By which I mean, of course, that he'll start to lose weight. Just like the President of Iraq.

Published: 1 October 2007

They fought the law and the law won

Genome Biology 2007, 8:111

Australia used to have a cane beetle problem. The cane beetle was slowly destroying the country's sugar cane crops, and there seemed to be no way to get rid of it. Then, in 1935, someone had the bright idea to import a box of cane toads from the Hawaiian Islands, where the large frogs (which were 25 cm long and up to 4 kg in weight) supposedly kept the pest in check. So, 102 cane toads were delivered to Gordonvale, just south of Cairns, where after a few rounds of captive breeding to increase their numbers, they were released into the sugar cane fields. Then the fun began. It turned out that cane toads can't jump very high so they did not eat the cane beetles, which tended to reside on the upper stalks of the cane plants. But they were able to eat just about anything else: dog food, mice, the insects that native Australian frogs eat, the native Australian frogs themselves, and so on. They bred like flies: a pair of cane toads can lay 33,000 eggs per spawning. They proved resistant to herbicides that would normally kill frogs and tadpoles. And they are deadly poisonous; so they had no natural predators. (Australian museums have exhibits of snakes that were killed by toad toxin so fast that the toads are still in their mouths.) The cane toad has turned out to be one of Australia's worst environmental disasters. Since 1935, it has spread across most of Queensland, the entire Northern Territory, and down the coast of New South Wales. So now Australia has a cane toad problem. Oh yes, and it still has a cane beetle problem.

The cane toad is one of the more spectacular examples of the only scientific law for which there is no exception: The Law of Unintended Consequences. Loosely stated, the Law says that all human actions can produce unforeseen effects, and these are often more momentous, and frequently damaging, than the original problem those actions were meant to solve. It has been expressed colloquially in many forms; my favorite is "when you are up to your ass in alligators, it is difficult to remember that your initial objective was to drain the swamp." The late, great sociologist Robert K Merton was fascinated by it; in his book On Social Structure and Science (The University of Chicago Press, 1996), he listed five causes of the law:

1. Ignorance (it is impossible to anticipate everything, thereby leading to incomplete analysis).

2. Error (incorrect analysis of the problem, or following habits that worked in the past but may not apply to the current situation).

3. Immediate interest, which may override long-term interests.

4. Basic values may require or prohibit certain actions, even if the long-term result might be unfavorable (these long-term consequences may eventually cause changes in basic values).

5. Self-defeating prophecy (fear of some consequence drives people to find solutions before the problem occurs; thus, the non-occurrence of the problem is unanticipated).

He left out the most significant one besides ignorance: arrogance, our persistent belief that we are smart enough to plan for all possible consequences.

The Law of Unintended Consequences shows up in all aspects of human endeavor. A familiar example would be the attempt by moral reformers in the 1920s to curb the evil of alcohol consumption by banning all such beverages in the United States ('prohibition'), which neither curbed excessive drinking nor increased public morality. What it did increase, of course, was crime: organized crime was born in the 1920s to cash in on the lucrative market for illegal drink. The law also abounds in time of war - look at how the disastrous invasion of Iraq, which was intended to improve the security of Western nations, has actually turned that land into a breeding ground for terrorists. But where it really seems to come into play is whenever mankind monkeys around with the environment or the ecosystem. Australia's cane toad story is by no means the only example. In the US, gypsy moth caterpillars were imported into New England by one Leopold Trouvelot in the hope of starting a new silk industry. That idea failed, but some of the moths escaped, and over the past 150 years their periodic outbreaks have led to the deforestation of millions of acres of trees and shrubs.

You'd think that after a couple of centuries of disasters like this, we would know enough not to tamper with the natural order. But hubris has no sense of history. The power of genomics has led to numerous bioengineering projects to improve food crop yields, increase disease and pest resistance in many plants, and express foreign proteins in farm animals and tobacco. The altered organisms have been carefully confined for the most part, but I'm sure that's what Trouvelot would have said about his gypsy moths. I'm not fond of quoting Stephen Spielberg - I think he's an antiscience opportunist philosophically - but he's right when he has the character Ian Malcolm state, in the movie Jurassic Park, that "if there is one thing the history of evolution has taught us, it's that life will not be contained. Life breaks free. It expands to new territories, it crashes through barriers, painfully, maybe even dangerously, but, uh, well, there it is!" (Now, don't get me wrong; I'm not opposed to genetic engineering of crops or to genetically modified foods. I think both can have important benefits, especially in countries where agriculture is difficult and famine is frequent. But given the difficulty of containment, I would argue that it behooves us to do everything possible to perform such activities with as much foresight as possible.)

So I hope you will understand why the new science of geo-engineering gives me the willies. Geo-engineering doesn't try to alter a few corn plants; it aims to tinker with the entire planet. It was born out of a desire to do something about global warming. You're going to be hearing a lot more about it, I'm afraid, because it could mean a lot of money for some companies and it is very appealing to conservatives, who have always had an exaggerated faith in our ability to manage the environment. Geo-engineering involves using deliberate human acts, based on novel technologies, to slow down or reverse the climate change being driven by technology-produced greenhouse gasses. Unlike conservation efforts, which are motivated by a desire to roll back the damaging effects of human activities, geo-engineering is based on the notion that ultimately we can actively manipulate the planet to have any climate pattern we want. Some of the more astounding ideas that geo-engineers have put forward lately include fertilizing the sea with iron particles to create explosions of plankton, which take CO2 out of the atmosphere; erecting giant mirrors above the earth to reflect the sun's energy; and dropping clouds of sulfur particles from high-altitude balloons to do the same. You may laugh, but this is no laughing matter - people are really serious about doing these things. A scientific meeting on iron fertilization was held at the end of September at the Woods Hole Oceanographic Institute, and while no one there could agree on the likely consequences of such intervention, no one was laughing about doing it, either. It isn't clear that a company or private organization that wanted to try this on a massive scale could even be prevented from doing so - the maritime laws don't really cover such things and there's an awful lot of water to patrol. It might well be profitable, too, since a company that seeded the production of lots of plankton could, in theory, sell carbon sequestration credits to other, polluting companies.

But the Law of Unintended Consequences makes any such efforts frightening, to say the least. Some of the long-term consequences of a massive, engineered plankton bloom might actually be an increase in global warming, since the dead plankton may give off nitrous oxide, which is an even worse greenhouse gas than CO2. Iron particles also will react with oxygen dissolved in the seawater; the resulting oxygen depletion may kill off countless fish, although no one knows for sure. The problem is that a number of people are getting very serious about trying this and other massive environmental engineering projects, and it's a sure bet that genome biologists are going to be asked to join such efforts (creating, for example, plankton that are more efficient in utilizing iron, or in absorbing carbon dioxide).

I think we should resist such siren calls, and indeed, campaign for a moratorium on all such geo-engineering projects. Some scientists are already calling for that, until an assessment of the likely consequences can be produced. But I would argue that there is no way we can ever assess all of the likely consequences; that the history of environmental tinkering should convince us that the probability of disaster is so high as to require that we prohibit this sort of nonsense forever. I would feel differently if there were no Law of Unintended Consequences. But Australia used to have a cane beetle problem, and now it has a cane toad problem and a cane beetle problem because there is such a law, and that law constantly winks at us, from those dark corners where our ignorance and our arrogance meet.

Published: 2 November 2007

What if Watson had said "Apes evolved from man"?

Genome Biology 2007, 8:113

I should have kept my big mouth open. I don't think it was largely cowardice that prevented me from speaking up; at least, I'd like to believe it wasn't. I think it was a combination of excessive politeness, shock-induced paralysis, misplaced reverence, and not knowing what to do. But if I'm honest with myself, I have to admit that there was an element of fear in there, somewhere.

By now, unless you read this column via satellite transmission to some distant galaxy, you probably know most of the facts about the forced resignation of James Watson, the legendary co-discoverer of the double helical structure of DNA, as Chairman of the Board of Cold Spring Harbor Laboratory. You know Watson was forced to resign because, during an interview with a journalist in Britain, he made some outrageous comments about the intellectual capacity of black people - and I don't have to say "allegedly" here because there is a tape record and besides, he never denied it. When confronted about it later, he simply said that he couldn't believe he had said it. He never said he didn't believe what he said. And in the flood of stories that broke about the incident, there were many comments to the effect that people weren't all that surprised - that he had a history of making disparaging public comments about women and ethnic minorities.

Now, the purpose of this column is not to pile further approbation on someone who's down. His legacy has been tarnished and he's had to step down in disgrace; anyone who wants more punishment is being vindictive. Nor is it to lament the ammunition that someone with the cachet of a Nobel Prize, the godfather of the Human Genome Project, has given the racists and bigots. In matters of racial prejudice no one is going to be swayed by some authoritarian figure (if you don't believe me, look up William Shockley the Nobel prize-winning physicist who is also remembered for his offensive racial views). Nor is it to discuss freedom of speech versus political correctness. I think most people agree that Watson has the right to say what he said, but that Cold Spring Harbor Laboratory also has the right to choose the public face of their institution. Nor is it to debate the nonsensical idea that there are racial differences in native intelligence: a friend of mine put it perfectly when she said that Watson's remarks were not only beneath contempt; they were also beneath comment.

No, I want to talk about something that nearly all the newspaper stories and outraged editorials passed over: why this incident has made me feel awful. You see, I can personally vouch for the truth of the statement that James Watson had a history of making disparaging remarks about women and minorities, because I was present on three occasions when he did. I was present, I heard him say those things, and I kept silent. As did everyone else.

How could someone of James Watson's stature have made so many hurtful remarks for so long and not been called to account sooner? Thinking back on the times I sat there and said nothing, I have to believe it's in large part because we enabled his behavior. Why? Certainly not because we agreed with it. A large part, I think, was not knowing exactly how to respond. I come from a generation raised to avoid public commotion, to be polite in the face of poor manners, and not to drag the discussion down to the lowest level. That can make for civilized discourse, but it also makes for paralysis in such situations. Having neither the training nor the experience in handling this kind of confrontation the right way, the default is silence. And, as any law student will tell you, qui tacit consentiere videtur (he who keeps silent is assumed to consent).

Part of it also was respect, misapplied. There have been few iconic figures in science and even fewer in biology, but Watson certainly is one. He's probably one of the greatest biologists of all time - he's told us so himself. Who am I to challenge him, berate him, make an enemy of him?

But I have to be honest, though I was afraid of saying anything, it wasn't Watson I was afraid of. It was everybody else. I have strong feelings about many things, and I know that expressing those feelings about issues of morality and ethics, right and wrong, lays me open to the charge of being self-righteous. If I didn't know that before, the nearly eight years I've been writing this column have taught me. It's the most common complaint I receive, and the most wounding. Because it wounds, it also can inhibit. The fear is not just that someone will say you're being preachy, acting like you think you're better than they are; the fear is that they may be right. It's an insidious charge, because it attacks the style without addressing the substance of what's been said. It redirects a critical discussion into an hominem attack on the critic.

Yet, I remain convinced that it's the life without principles, not the unexamined life, that is really not worth living. Put simply, I think you have to stand for something. The question is how to do it. Interestingly, we scientists don't have a problem when the issue is a scientific one.

What if, instead of making a remark that carried with it all the enormous baggage of race, class, prejudice and intolerance, Watson had said "apes evolved from man"? Is there a biologist worthy of the name who wouldn't have stood up and demanded, politely but firmly, to see the data on which such an outlandish statement was based? And wouldn't the absence of any such data, and the presentation of data that clearly indicated the opposite, expose the idea for the nonsense it was? Why couldn't I have done the same thing? The fact that the issue was morally charged might have been difficult - I am flawed and might feel that I have no moral platform from which to preach to others. But that should not have prevented me from acting as a scientist. Science is about evidence, and now, thanks in large part to the field of molecular biology and genomics, which James Watson, ironically, largely co-founded, we have the data to refute the claims that one race is superior and another inferior or that gender is linked to intellectual fitness. If someone says something different, we can challenge them to produce the evidence that supports their assertions, and we can cite the facts that prove them false. If we don't know those facts well, then I think we owe it both to ourselves and to our fellow humans to learn them.

Our status as genome biologists gives us both ammunition and a powerful line of attack when we are confronted with ignorance, prejudice, and bigotry. It gives us a way of calling such attitudes to account and exposing them for the fallacies they are without necessarily falling into the trap of self-righteousness, real or apparent. That's what I should have done the first time I heard James Watson make a remark of the kind that got him fired, and that's what I hope I will have the presence of mind to do the next time someone else says something similar.

Look, I am well aware that most of the trouble I've gotten into in my life - and believe me, I've gotten into my share - has either been caused or compounded by my inability to keep my big mouth shut. But the Watson case is humbling because it's reminded me of all the times that I should have kept it open.

I hope I'll find a way to do it without seeming to be holier-than-thou. I hope I won't come across like a pompous, moralistic ass. I hope somehow I can make it clear that I know full well that dark thoughts and wrong notions are no stranger to me, that my feeling that I should speak up stems not from the sense that I'm better than anyone else but from wanting not to be worse than I am. And that it's being a scientist, not a saint, that gives me the right to challenge an idea, because I am trained to do so on the basis of the facts behind it.

But most of all, I hope that I won't let the fear of being called self-righteous or taken for a pompous jerk cause me to be silent again. If I come across that way and make a fool of myself, it'll hurt. I don't like any part of the idea of embarrassing either myself, or those who might be with me. But if the outcome turns out to be that I feel embarrassed, I guess I can live with it. Because I think it would still be better than the way I feel right now, which is - ashamed.

Published: 30 November 2007

Medicine man

Genome Biology 2007, 8:114

"The surest road to health, say what they will,
Is never to suppose we shall be ill.
Most of those evils we poor mortals know
From doctors and imagination flow."

Charles Churchill

I live with a physician/scientist. Her father is a physician/scientist. Her ex-husband is a physician/scientist, and her oldest son is in medical school. I'm surrounded by doctors, so you might imagine that when I'm sick, I receive excellent medical attention. Nothing could be further from the truth.

Depending on my condition, the attention I get usually takes one of two forms. If there's something seriously wrong - say, my left arm is hanging by a tendon and the socket is gushing arterial blood - the typical response is: "Oh, that's nothing. Don't be a baby." Minor ailments, however, provoke a different reaction. Suppose, I cough. They say, "Is something the matter?" "No," I say, "just a cough." "Hmm," they say, "maybe. But, you know, it could be Hammacher-Schlemmer Syndrome, where your teeth turn green and then you die."

You may laugh (I hope), but these two reactions sum up rather nicely two of the fundamental facts that guide much of the practice of medicine today. The first is that most things get better by themselves. Treat the symptoms, keep the patient alive, and the extraordinary power of the human body to repair itself or fight off invading organisms can work seeming miracles. The second fact is that it is remarkable that we are ever well at all, because the number of things that can go wrong with the human body is almost infinite.

Living with physicians is one of the things that have made me conscious of what doctors know and what they need to know. My having taught freshman chemistry, largely to premedical students, for 25 years is another. It seems to me that there is a great disconnect between what medical schools say they want doctors to know and what we teach aspiring physicians before they get to medical school. Since the premedical curriculum is driven by the Medical College Admission Test (MCAT), a standardized test that nearly every medical school requires of its applicants, this disconnect is hard to understand. Yet, a glance at the subjects covered by the MCAT turns up topics like inclined plane problems (part of the physics requirement), the Grignard reaction (part of the chemistry requirement), various aspects of calculus and so on. It does not turn up the biochemical basis of prion disease, for example, or any of the basic facts about the human genome revealed by the human genome sequence. I don't know about you, but if I were lying in the hospital about to undergo open-heart surgery, I'm not sure the first thing I would want to know about my surgeon was whether he had mastered the Grignard reaction. Nor would I forego checking his or her medical credentials, saying instead, "Tell me, Doctor, if we have a 100 kg crate which is sliding down a plane inclined at an angle of 30 degrees, and the coefficient of friction between the crate and the incline is 0.3, what is the acceleration of the crate?" and recoiling in horror with a "get away from me, you quack!" when he doesn't know the answer (which, in case you care - and you shouldn't - is 2.35 m/s/s).

A number of medical schools are finally starting to examine not only their own curriculum, which in my view (and theirs) spends too much time teaching medical students the basic science they should have learned as undergraduates, but also the requirements for admission. The most enlightened ones have the sense that the issue should not be what courses the applicant has taken but whether or not they have learned a set of fundamental concepts and have developed certain essential competencies. It is becoming clear that the existing premedical curriculum does a very poor job of both, and wastes a lot time teaching things that are completely irrelevant to medicine.

In the US today, most premedical students are required to take two semesters of general chemistry, two semesters of calculus, two semesters of physics (at least one of which, as far as I can tell, is entirely devoted to inclined plane problems), two semesters of organic chemistry (the Grignard reaction!) and two semesters of biology. They are encouraged, but usually not required, to take a semester of biochemistry. What is not required? Genetics, cell biology, physiology, statistics, and microbiology, among other seemingly useless topics.

Here's a modest proposal to change the present curriculum, which at best is archaic and at worst is criminally stupid. Of course, the MCAT would have to change with it - in fact, it may be necessary to change the MCAT first, since that would force the universities to alter their premedical programs. Given the conservatism of, for example, the typical chemistry department, such forced reform may be the only practical approach.

I see no need for more than a semester of general chemistry. It should be followed immediately by a single semester of organic chemistry. Both of these should emphasize biochemical examples. (The Grignard reaction does not occur in biology.) In the second year, a two semester course in biochemistry and physiology would be required. The year of calculus would be replaced by, at most, one semester. In place of the second semester of calculus, statistics should be taught with a biomedical slant. The year of physics would be replaced by one semester, which emphasizes medically relevant physics such as fluid flow and mechanical stress. Anyone caught teaching inclined plane problems in this course would be pilloried. Instead of the second semester of physics, there should be a required course in genetics, one that emphasizes human genetics and genomics. The year of biology stays, but it should be taught with a cell biology slant. And here's the most interesting thing about this new curriculum: I think it would be absolutely suitable for students who intended to go on to graduate study in biomedical research as well as for medical students.

Like it or not, the emphasis in biological research is shifting towards one that favors human biology and human disease. To do such research properly, one doesn't just need a firm grounding in the basic principles of cell biology, biochemistry and biophysics. One needs perhaps a smattering of anatomy, at least a soupcon of organismal physiology, a pinch of pathology, and a heaping helping of statistics. The modern biologist needs to know how the work he or she is doing relates to disease, and they need to understand the disease as well. Not only does today's medical student require essentially the same basic science training as the modern biologist; I think that biologist would benefit from having some of the same training the medical student gets in his or her first two years of medical school.

I speak from experience here. My own research interests include the neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. There are fascinating basic science questions presented by these disorders, but the more I work on them, the more I find I need to know about neuroanatomy, pathology, neuropharmacology, and other clinical subjects. In other words, the more my basic research involves human physiology and human disease, the more I wish I knew what doctors know.

Charles Churchill, whose poem opens this column, had it wrong. Most of the evils that we poor mortals know come neither from doctors nor the imagination (admittedly, he may have been right in his century, the 18th). As genomics and other branches of modern biology deepen our understanding of the true origins of disease, it becomes imperative that our doctors bring to the practice of medicine a true scientific perspective, by which I mean the use of evidence to reach conclusions and an understanding of the basic biological and biochemical principles that govern all living organisms. But I also think in this era, when biology is trying to bridge the formidable gulf between molecules and cells, between pathways and organisms, it may be just as important that those of us doing biomedical research try to learn more of what doctors know.

I'd write more, but I had a slight cough this morning, and I've got to go check the color of my teeth.

Published: 28 December 2007

The story they missed

Genome Biology 2008, 9:101

The news made the front page of my home-town newspaper, The Boston Globe. Stories about Harvard or Massachusetts Institute of Technology (MIT) often do. Because such stories sometimes cast the institution in question in an unfavorable light, I'm often glad that my own little university, Brandeis, is so small that it tends to fly under many reporters' radar screens. The headline alone made it clear that this story would not be one that MIT would use in its recruiting literature: Tenure at MIT still largely a male domain [weblink].

I started reading it with the same Schadenfreude that Boston-area faculty who aren't employed at Harvard or MIT often experience when either of these two 500-pound educational gorillas slips up. But as I read it, that feeling went away, replaced by one I hadn't expected in this context: compassion. I felt sorry for MIT because I thought the story missed the point, missed it in such a way that the institute was unfairly blamed. And by the time I was finished reading it, I was also convinced that the real story was so much more interesting, and so important, that it was worth writing about.

The article starts with the statement that "just one out of 25 faculty members granted tenure this year at MIT is female" and continues, "a gender imbalance that appears to contrast with the university's decade-old effort to boost the status of women." There's much more, of course, including much gnashing of teeth on the part of the MIT administration and references to the history of gender inequality at MIT, where a famous effort, spearheaded by biology professor Nancy Hopkins, detailed systematic discrimination against women faculty through low pay, inadequate space, and a host of other inequalities. Since 2001, MIT has implemented policies designed to redress gender bias, and in fact, the institute is now headed by its first woman President, neurobiologist Susan Hockfield. So the Globe article caused consternation in its seeming demonstration that bias still existed in the matter of tenure.

But does it really? A close examination of the data suggests otherwise. True, only one woman was granted tenure at MIT last year out of 25 total promoted faculty, but the year before the figure was 5 out of 19, and the year before that, 6 out of 19. During the past ten years, the number of junior faculty women granted tenure at MIT has ranged from zero to eight a year, while the number of junior faculty men granted tenure has ranged from 10 to 24. These are very small numbers, and small numbers are prone to large statistical fluctuations. The average number of women tenured at MIT is about 5 per year in recent years, compared with about 16 per year for men, not unreasonable at an institution where only 20% of the faculty are women. I'm not arguing that MIT doesn't still discriminate against women - I have no special knowledge one way or the other. What I am saying is that the data don't prove that it does. In fact, the data are more consistent with the hypothesis that it doesn't: of junior faculty who could have vied for tenure during the last decade, 41% of 104 women were granted tenure, compared with 48% of the 372 men hired.

But could these same figures be used to show that MIT discriminates against women in hiring? After all, only 22% of new hires at MIT during the last decade were women. To answer that question, we need to look at the broad picture of women in the sciences in the US during the past quarter century or so.

Here are the facts, taken from Science and Engineering Indicators 2008, published by the National Science Board, part of the National Science Foundation (NSF; it's available as an online document that provides a broad base of quantitative information on the US and international science and engineering enterprise http://www.nsf.gov/statistics/indicators/). Among US citizens, the proportion of doctoral degrees earned by women in science and engineering has risen considerably in the past two or more decades, reaching a record high of 46% in 2005. During this period, women made gains in all major fields, although considerable differences by field still exist. Women earn half or more of doctorates in the social/behavioral sciences (which the report counts, along with math, physics and so on, as part of the sciences and engineering), and in the life sciences, but they earn considerably less than half of doctorates in physical sciences (29%), math/computer sciences (24%), and engineering (20%). Still, these figures are substantially higher than was the case in 1985 (16%, 17%, and 9%, respectively). MIT is largely a physical sciences and engineering institution, so a figure of 22% female for new hires doesn't look wildly out of line.

The increase in the number of science and engineering doctorates earned by women occurred in most major fields. For example, the number of engineering doctorates earned by US women increased from 119 in 1985 to 396 in 2005; biological sciences doctorates from 1,032 to 2,024; physical sciences doctorates from 323 to 516; and social/behavioral sciences doctorates from 2,224 to 3,117.

Things look similar when we consider post-education employment. For example, in 2003, women constituted 52% of social scientists, compared with 29% of physical scientists and 11% of engineers. Since 1993, the percentage of women in most science and engineering occupations in NSF's labor force surveys has gradually increased from 23% to 27% across all scientific occupations, but notably from about 35% to 45% in the life sciences, numbers that parallel the percentage of earned doctoral degrees (however, in mathematics and computer sciences, the percentage of women in the labor force actually declined about 2 percentage points between 1993 and 2003).

If we focus on the academic employment of women in science and engineering, we find that it too rose sharply. In 2006, women constituted 30% of full-time faculty, compared with 7% in 1973 - but this increase includes the social and behavioral sciences. Relative to male faculty, female faculty remain more heavily concentrated in the life sciences, social sciences, and psychology, with correspondingly lower shares in engineering, the physical sciences, mathematics, and computer sciences. As for the question of tenure, women hold a larger share of junior faculty positions than positions at either the associate or full professor rank. However, their share of all three positions rose substantially between 1973 and 2006. In 2006, women constituted 19% of full professors, 34% of associate professors, and 42% of junior faculty; the latter figure is comparable to their share of recently earned science and engineering doctorates.

These overall figures paint a fairly rosy picture, but the color changes when, once again, we examine the numbers in more detail. Let's focus on the life sciences, since that's the field that genomics is in, with the physical sciences as a counterpart. Right now, 63% of college students who study the life sciences are female, compared with 42% in the physical sciences. Women make up 58% of recipients of bachelor's degrees in the life sciences, and 40% in the physical sciences. Fifty-one percent of graduate students in the life sciences are female; the figure for the physical sciences is 32%. And when we get to the PhD degree, 44% of those awarded in the life sciences go to women, and 26% in the physical sciences. In other words, the closer we get to actual post-educational employment, the smaller the percentage of women at every stage, regardless of the field. The drop-off is remarkable, almost 50% in the physical sciences and a third in the life sciences. Women start out just about as interested in the sciences as men, but they drop out along the way at a much greater rate. The real problem, I think, is not that women aren't being hired in the sciences in academia, nor that they are not being tenured (of course, either or both of these may be a problem at some particular institutions, but the data suggest that it is not a systemic problem, at least not any more). The real problem is the pipeline.

Where do all these talented and accomplished women go? Many of them go into industry; the pharmaceutical and bio-technology companies hire significant numbers of women scientists every year. Others go into a variety of different professions, ranging from medicine to science journalism to patent law.

I don't know why the pipeline to academic jobs is so leaky for women - NSF hasn't done extensive surveys on that topic and the Globe hasn't covered the problem either. But I can offer some possibilities, based solely on anecdotal evidence, gathered from years of teaching and mentoring women scientists. I think the leak is caused by a number of factors. I don't know how important each one is, but taken together, I believe they constitute a serious problem with the culture of academic science.

A number of women have told me that they find our profession lacking in the opportunities it presents to help people directly. This is certainly one of the attractions of medicine, and part of the attraction of big pharma and biotech may also be the chance to work on treatments for human diseases. It's possible that our obsession with 'basic' research as the highest form of academic science, and the concomitant second-class citizenship that we often bestow on 'applied' research, may be driving away people who want to see the fruit of their work more immediately in terms of an improvement in the human condition.

Another problem is the increasing feeling that academic scientists must work long hours 7 days a week in order to be successful. Many women have told me that one attraction of industry is its relatively predictable work-day schedule, which is easier to integrate into a life involving children and their schedules. They have also indicated that they wanted the freedom to devote their weekends to their families and other pursuits without feeling guilty or inadequate.

Some fields have a macho culture of aggressive competition and self-promotion that is unappealing to women (and to many men, in fact). Synthetic organic chemistry, high-energy physics, most fields of engineering, and some branches of computer science are a few of many examples. Genomics is too new to have established a defined gestalt, but given its engineering connections it's worth keeping an eye on.

Finally, just look at the way academic life seemingly ignores the very existence of concerns that many women have. Research seminars are often scheduled for 4 or 5 pm - exactly the time when many women need to collect their children from day care or be home when they arrive from school. Visitors are taken out to dinner - a practice that often excludes women who need to prepare and serve dinner to their families. Men are increasingly helping out with these duties, but the majority of child-care and domestic concerns are still the province of women, whether by choice or necessity.

If I'm right about these things, then the problem isn't unique to MIT, and fixing it will require all of us to do our part. We have to work together to change the culture of academic science, to make it more friendly to women (and in the process, I bet it will become less stressful to men, too). I think even small changes would make a big difference. For example, why can't research seminars be held in the morning, or early afternoon? Why can't visitors be taken to lunch by the faculty, and to dinner with students, instead of the other way around? Why don't institutions see that providing day care is as important as offering health care? Why do we have to insist that work must consume 12-16 hours of every day? I've worked in Europe, and European scientists produce terrific science working chiefly 9 to 5 on weekdays only. (This is partly because when they are at work, they actually work - a lot of those 12-16 hours a day in the US are unproductive, in my experience.) And maybe we need to rethink our knee-jerk denigration of applied research.

That's the story I wish The Boston Globe had really reported on. There'd be no conclusions, of course, because the data don't exist. NSF hasn't studied this in depth and we male academic scientists haven't sat down with our female colleagues and asked them what we need to do to make our profession more welcoming to women. Maybe a newspaper story would provoke people to get those data and ask those questions. Of course, it wouldn't be as dramatic a story as a report based on the perception that gender bias was still prevalent at MIT.

Perception always has a hard time catching up to reality. And negative perceptions often make good stories. But in this case, reality is the better one.

Published: 31 January 2008

The right to be wrong

Genome Biology 2008, 9:102

The hardest promises to keep are the ones we make to ourselves. I promised myself that I wouldn't write about the presidential campaign this year, at least, not until the candidates from the two major parties were decided. I had no wish to add to the hot air generated by the bloviating political columnists and other self-appointed 'experts' whose constant presence is one of the biggest reasons I hate the protracted American primary process. I also didn't think anything I could say would have any connection to genomics. Yet, as I watched the campaigns for both parties unfold, a connection did occur to me - one that seemed not only to be ignored by most commentators but also to be surprisingly relevant. It has to do with the issue of 'flip-flopping' - of changing one's position on an issue.

In the 2004 presidential election Republican incumbent George W Bush got a lot of political mileage by painting his Democratic challenger, Massachusetts senator John Kerry, as a 'flip-flopper' on the issue of the Vietnam War. Kerry had fought, honorably, in that war - a war that George W Bush had managed to avoid participating in by virtue of family connections. But after returning to the US, Kerry decided that the conflict had been a tragic mistake and he spoke out against it at numerous rallies. So successful was Bush's campaign rhetoric in portraying Kerry as someone without principles, that a large segment of the voting public came to believe that the decorated war veteran was less patriotic than the man who had never fought at all, an example of 'doublethink' that George Orwell would have been proud of.

The primary campaign this year has seen the same tactics employed, this time by the Republicans against one of their own. Mitt Romney, the former governor of Massachusetts (what is it about candidates from my home state?), saw his candidacy go down in flames largely because he was shown, truthfully this time, to have changed his position 180 degrees on such insignificant matters as gun control and abortion rights. In contrast, his opponent, John McCain, successfully presented himself as a man of unwavering principle (even though he did a series of about-turns on the Bush tax cuts for the wealthy and several social programs).

The Democrats aren't immune from the problem either. New York senator (and former First Lady) Hillary Clinton, has shown impressive grasp of the issues and political savvy in debates against her chief rival for the presidential nomination, the eloquent senator from Illinois, Barack Obama. But she has spent much of her time trying not to apologize for her vote in the Senate in favor of the resolution that gave George W Bush the license to go to war in Iraq. She was lied to, of course, just like the United Nations and the American people were - there never were any weapons of mass destruction and Saddam Hussein had no connection with Al Qaeda or the terrorist attacks on 11 September 2001. So she certainly has every excuse, but she seems utterly unable to admit that the vote was a mistake. It's as though she were afraid to use the word.

When did admission of error become a mortal sin in politics? Many Americans believe that George W Bush is a great president because he has never admitted to making a mistake, has never changed his mind about any of the things he has professed, has never wavered in his convictions no matter what the evidence shows. (Of course, many Americans also believe that the Earth is 5,000 years old. Come to think of it, George W Bush is one of them.) To hold to your ideas when the facts show they are wrong isn't noble or steadfast, it's stupid. Yet, somehow we've come to equate closed-mindedness with toughness and integrity.

All of which would have nothing to do with science in general, or genomics in particular, except that I think it does. The worst thing that can happen to a scientist is to publish something that turns out to be wrong. It can wreck a person's career. All of us live in fear of it. And yet, should we?

So often we don't seem to make any distinction among types of error. I think there's a huge difference between sloppiness and honest mistakes, between bad experiments and naive interpretation, between a failure to do controls and promulgation of a theory that turns out to be wrong. In each case, the former is much worse than the latter, but we often make little distinction between them in terms of the consequences to the unfortunate individuals involved.

It's hard to do perfect experiments. Nature takes a perverse delight in finding ways to fool even the most diligent experimentalist. Only someone nervous to the point of paranoia is likely to go through their entire career without misinterpreting some result or overlooking a trivial explanation. When the refereeing process works as it should, such mistakes can be caught before publication, but many journals, particularly the vanity press, don't insist on enough experimental detail to make that process work as it should (and sometimes one wonders about their stable of reviewers, too).

It's also easy to fall in love with a hypothesis, and to hang onto it longer than the data say you should. These aren't good things for a scientist to do, but they shouldn't result in capital punishment. Yet, when funding is tight and competition for journal space and important discoveries is keener than ever, the temptation is to magnify the mistakes of our rivals, to exaggerate their 'wrong' conclusions and trumpet the deficiencies of their work. Which makes everybody even more afraid of making, or admitting to, a mistake.

The result of all this, of course, is a climate of fear, entrenched positions and conservative science. Funding agencies - and grant reviewers - don't want to be accused of supporting work that is incorrect, so they reward the incremental, safe projects at the expense of the bold and risky. Scientists don't want to be pilloried by their colleagues for having made a mistake, so they tend to do the incremental, safe projects and eschew the bold and risky. And those who do slip up are often punished far out of proportion to the real import of what they have done.

I worry that a significant component of the current enthusiasm for data-gathering, as opposed to hypothesis-driven, biology stems from this climate. 'Discovery-oriented' research seems much safer: so long as you get the sequence right, or the crystal structure right - so long as you deliver the mass of data that you promised - you can't make a mistake. With only obvious conclusions to draw from those data, errors of interpretation are practically impossible. And data gathering usually doesn't involve clever experimental design that requires numerous controls to avoid artifacts. Funding agencies love it because they can point to tangible results that are always 'correct'. If we're not careful, our rush to punish those of us who make mistakes may turn some of the best of a generation of scientists away from the difficult, but essential job of trying to figure out what all these data really means.

I think what is needed is a decriminalization of certain types of error. Of course it's right to condemn sloppy experiments, missing controls and unwarranted conclusions. But we should encourage the scientist who takes sensible chances, who is not afraid to do the unfamiliar, and whose theories challenge the accepted dogma when that dogma fails to explain all the facts. And we should not condemn him or her when, as will often be the case, those chances misfire and those explanations turn out not to be the answer. And we should not be afraid to abandon our chosen explanations and hypotheses when the preponderance of the evidence goes against them. Nothing holds science back longer than this clinging to what should not be clung to, and all too often it's fear - fear of the consequences of having made a mistake - that keeps ideas around long past their sell-by date.

Closed-mindedness is a very bad quality in a scientist. Intellectual courage is a very good one, and if we continue to deny ourselves the right to be wrong, we run the risk of seeing it go the way it apparently has in politics

What would you think about a biologist whose motto was: "I shall try to correct errors when shown to be errors; and I shall adopt new views so fast as they shall appear to be true views." My guess is that you would applaud such sentiments as the hallmark of an open mind, one that was not afraid to change an opinion when the data indicated that a previous position was no longer supported by the available facts. It might surprise you, in view of this column, to learn that those words were written by a politician. His name was Abraham Lincoln. He would have made a heck of a scientist.

Published: 29 February 2008

Going to the dogs

Genome Biology 2008, 9:103

Owing to an imminent grant deadline, Greg Petsko is unable to deliver his column this month. In the interest of interspecies cooperation, his two dogs, Mink and Clifford, have generously volunteered to take his place. For those of you not familiar with them (they have appeared on these pages twice before), Mink is a large chocolate labrador retriever; Clifford is a small spaniel/poodle mixed breed. In intelligence and character, Mink is basically a noble, albeit constantly hungry, human being in a canine body. Clifford is - well, a dog.

Mink: Clifford, did you see that a Hungarian scientist, one Csaba Molnar, has been developing a computer program to analyze dog's barks? There's even a paper about it (Molnar C, et al.: Classification of dog barks: a machine learning approach. Animal Cognition 2008, doi: 10.1007/s10071-007-0129-9).

Clifford: What does the paper say?

Mink: Here's the abstract: "In this study we analyzed the possible context-specific and individual-specific features of dog barks using a new machine-learning algorithm. A pool containing more than 6,000 barks, which were recorded in six different communicative situations, was used as the sound sample. The algorithm's task was to learn which acoustic features of the barks, which were recorded in different contexts and from different individuals, could be distinguished from another. The program conducted this task by analyzing barks emitted in previously identified contexts by identified dogs. After the best feature set had been obtained (with which the highest identification rate was achieved), the efficiency of the algorithm was tested in a classification task in which unknown barks were analyzed. The recognition rates we found were highly above chance level: the algorithm could categorize the barks according to their recorded situation with an efficiency of 43% and with an efficiency of 52% of the barking individuals. These findings suggest that dog barks have context-specific and individual-specific acoustic features. In our opinion, this machine learning method may provide an efficient tool for analyzing acoustic data in various behavioral studies."

Clifford: It says, "These findings suggest that dog barks have context-specific...acoustic features?" You mean this is news?? Well, I guess every person has his day.

Mink: Maybe the people who did this study had never been owned by a dog. I mean even Greg, who's basically clueless, can tell the difference between a bark to come inside, a bark when some stranger is at the door, a bark at another dog when we're out for a walk, or a bark with excitement when he throws us the ball.

Clifford: Throw the ball! Throw the ball!

Mink: Calm down. The New Scientist did a short piece on this back in January and they interviewed Dr Molnar. In the interview he said, "In the past, scientists thought that dog barks originated as a by-product of domestication and so have no communicative role. But we have shown there are contextual differences."

Clifford: No communicative role? I mean, did they ever listen to us? We have a very high-pitched bark when we're in distress; a deep, powerful almost continuous bark when we're warning off some intruder into our territory; well-spaced moderately pitched barks when we want to go inside or outside; and higher-pitched barks when we're playing with other dogs. The next thing you know, they'll be "discovering" that the different ways we wag our tails mean something. I'd like to meet that Dr Molnar. I have a bone to pick with him.

Mink: So to speak.

Clifford: Did you say the computer program was right 43% of the time? But I thought in similar studies humans were right about 40% of the time. Even Greg's right almost half the time.

Mink: Yes, I don't understand why they made a big deal about this. I mean, there's no significant difference between 43% and 40%.

Clifford: If they think this is a big improvement, they're barking up the wrong tree.

Mink: Uh, yes, as it were.

Clifford: But I don't understand what this has to do with this month's column.

Mink: By this point, neither do our readers, I suspect. But here's what I think we should tell them. I think we should tell them that what is really needed is a way to help scientists understand not dogs, but each other.

Clifford: Now I'm the one who's not understanding.

Mink: What I mean is that Greg is always complaining that chemists can't understand one another because the physical chemists speak a different jargon from synthetic organic chemists and so on. And he says that biologists are better off because most biologists can go to any talk by any other biologist, whether they are a structural biologist or a cell biologist or a geneticist or an immunologist or a genome scientist, and understand most of what's being said. They can go to any biology conference and have a ball.

Clifford: Ball?? Throw the ball! Throw the ball!!

Mink: For Pete's sake, get a grip. Anyway, I think that Greg's forgotten something very important. He's forgotten that in the age of genomics, when biology is becoming more quantitative and depending more and more on new techniques and tools that must come from the physical sciences, the real problem is that most biologists can't understand chemists and physicists and hardly any chemists and physicists know what to make of the typical biology seminar, with its lists of gene names and gel slides and acronyms that don't stand for anything sensible.

Clifford: Are you saying there should be a computer program that would translate jargon from one field of science into another?

Mink: Now that would be worth developing. If you couldn't use it at a research talk, at least it could be used to translate papers. Maybe Dr Molnar ought to work on that idea. But I doubt we'll see it any time soon. I'm not even sure it's what's most needed. Unless you're a chemist or physicist who wants to become a biologist, or vice versa, the real issue is not whether you can understand a seminar in some other field, it's knowing what applications of your field would make a big impact on that one.

Figure 1

Mink and Clifford are dog-tired, so they take a well-deserved rest after substituting for Greg Petsko in this month’s column.

Clifford: You mean knowing what the big important problems are?

Mink: Exactly. And what new tools or methods are needed to solve them. So here's a simple idea: At every big meeting of the American Chemical Society and the American Physical Society and so forth, there ought to be a special plenary lecture by a biologist, one who's really good at explaining things. The lecture ought to start with an introduction to some important area of biology and end with a list of some of the major outstanding problems in that area and what sort of things would help get them solved. That way, people from other disciplines who might have new ideas or who would be interested in developing new methods would know what was needed. I bet at least a few of them would get excited about it, too, every time.

Clifford: That's a very good idea. Greg ought to put it in one of his columns.

Mink: I think we just did that for him. To be honest, I don't think Greg has much chance of getting this to happen, but I hope I'm wrong. You know how I like to root for the under-man.

Clifford: Well, I'm just a puppy, but it seems to me that the Molnar business you started this column with is a classic case of the tail wagging the person. I mean, the solution to understanding us dogs isn't some computer program. All people need to do is just pay attention and listen more. But I suppose that's too much to expect.

Mink: Don't be too hard on them. After all, they're only human.

Published: 31 March 2008

Not debatable

Genome Biology 2008, 9:104

I just finished doing my income taxes. It only took me five hours, thanks to some good tax-preparation software that helped me navigate the paper maelstrom of forms and regulations. It's always surprising that it takes as long as it does, considering that the result in my case is usually the same as if I'd used a simple two-line form: line 1 - write down your income; line 2 - send the government the amount in line 1.

I had more time to do my taxes than I thought. I expected to take at least a day or two off this month to be involved in, and then watch, the first US presidential debate ever to concern itself entirely with science. But that debate never came off.

In the interest of full disclosure, I should point out that I am the president-elect of the American Society for Biochemistry and Molecular Biology (ASBMB), one of the scientific societies (along with, among others, the National Academy of Sciences, the Institute of Medicine, and the National Academy of Engineering) backing the call for such a debate. The organizers of Science Debate 2008, which began as a petition for a science debate that has so far been signed by almost 40,000 people, had invited the three remaining major presidential candidates, Democrats Barak Obama and Hillary Clinton, and Republican John McCain, to a debate on Friday, 18th April, in Philadelphia; but they were forced to cancel last week because of poor - almost nonexistent, really - response. Barack Obama declined to attend, while both Hillary Clinton and John McCain did not even bother to reply. The candidates have now been sent new invitations for a debate sometime in early May.

The idea of Science Debate 2008 arose in late 2007; it was the brainchild of a group of six people headed by Larry Krauss, a physicist from Case Western Reserve University in Cleveland, Ohio, US, and screenwriter Matthew Chapman. As reported in physicsworld.com http://physicsworld.com/cws/home, among those to have signed the petition are 80 university presidents, more than 100 representatives from various scientific associations, and over 20 Nobel laureates.

Backers of the debate proposal want the presidential candidates to discuss a number of key issues, including:

Inaccurate media coverage of science (which depends, of course, on which media you're referring to).

Poor science education (this is a problem that appears to have gotten worse lately, probably because of relative indifference on the part of many scientists combined with an aggressive, and effective, campaign by the religious right to insinuate itself into local school boards).

Public scientific illiteracy (obviously directly related to the two previous issues).

The current funding crisis (caused by either flat funding or outright funding cutbacks for research).

Insufficient public policy response to climate change and other environmental issues (note the distinction between 'public policy' and 'public' responses - the public has responded vigorously, both through lifestyle changes and local action; the policy makers in Washington have not).

Government suppression of scientific information and misuse of scientific data (a problem that has become particularly serious during the Bush administration).

Not to mention such minor matters as stem cell research, the impact of genomics, health insurance policy, biodiversity loss, the health of the oceans and the morality of balancing destruction of species against human needs and expenses, clean energy research, biofuels and their effect on the food supply, genetically modified organisms and crops, and educating children to compete in the new, technology-driven global economy and securing competitive jobs.

American science is probably in the worst shape it's been in since the 1970s, and yet the candidates can't be bothered to air their views on the situation. Of course, they're incredibly busy. But somehow they weren't too busy to discuss faith and morals. That's right, on 13th April, both Barak Obama and Hillary Clinton took time out from their overcrowded schedules to appear at the 'Compassion Forum', an event sponsored by Cable News Network (CNN), at Messiah College in Grantham, Pennsylvania, where they fielded questions about subjects such as whether life begins at conception and whether sexual abstinence should be taught to children in school. As an exercise in pandering to people of faith, a constituency that the Democrats have pretty much ignored in recent elections, it was a big success. Whether any of those in attendance or watching on television were made ill by the sight of the possible next President of the United States trying to seem holier-than-thou (where thou was the other candidate) was not reported.

Shawn Lawrence Otto, the CEO of Science Debate 2008, has stated: "For the last 60 years, science and engineering have been responsible for half the growth in the US economy. But if current trends continue, by 2010 90% of all scientists and engineers will live in Asia. Do the candidates have a plan to keep the American economy strong and to tackle America's major challenges like climate change, energy security, education and healthcare, all of which revolve around science?" If they do, they're not saying.

What are they afraid of? One possibility, of course, is that they are all ignorant about science, and they are afraid to have that ignorance exposed. Another possibility is that they are afraid attending such a 'secular' debate will cost them votes among people of faith, who make up a huge percentage of the US electorate. But a third possibility, and one that I favor, is that they aren't afraid; they simply don't care. They either believe there are more important problems (such as Iraq, the economy, and terrorism) that demand nearly all their attention, or they see scientific issues as the whining of a small, specialized group that usually votes Democratic anyway, no matter what any candidate says.

The argument that science and technology are of vital importance to the economic future of the country is one that has been made often, and is one that many Republicans, interestingly enough, have actually bought (the Republican former Speaker of the US House of Representatives, Newt Gingrich, was one of the best friends science has ever had in Washington). It's also one of the main rationales the Science Debate 2008 folks give for having a science debate. But I think there's another argument that has not been made much, if at all - one that might just get the attention of these oh-so-busy candidates. I think science is absolutely essential to national security.

Some of the biggest national security mistakes the US has made, mistakes that have weakened our ability to defend ourselves, have happened because of the ignorance or willful misuse of science. The Star Wars missile defense program, a multi-billion dollar white elephant of the Regan Administration that the Bush Adminstration has revived, was argued against by nearly every leading physicist. Both the Bush Administration in the US and the Blair Administration in the UK either misinterpreted or deliberately misrepresented the technological data on the likely existence of weapons of mass destruction in Iraq. The US is spending vastly more money on research against bioterrorism than it is on ways to prevent simple chemical and radioactive material attacks, despite reams of scientific data indicating that the former is much less likely than the latter. The plan to vaccinate the entire population of the US in the event of an outbreak of avian flu is not supported by any serious public health science; not to mention the fact that it completely ignores the high likelihood of severe, possibly fatal, neurological complications in a significant percentage of those vaccinated. The choice of weapons systems for the 'new, modern' military is often made for reasons that have nothing to do with weapons science. The Bush Administration's disregard for the climate crisis was bolstered by a handful of weak scientific studies, not by the overwhelming weight of the best scientific evidence. We simply cannot have a strong, protected democracy if our political leaders are scientifically ignorant, or if they only pay attention to pseudo-science that supports their ideologies.

So if you have a blog, please write about the refusal of the candidates to debate questions of science. Urge them to have the courage to confront one of the most serious crises of our time: the erosion of the US position as a world leader in science and technology and the increasing marginalization of science in matters of policy. If you know anyone on the staff of any of the candidates, call them and beg them to take this seriously. Write letters to the candidates. Write editorials in your local newspaper. Talk with your friends about it. Sign the petition that Science Debate 2008 has prepared; you'll find it, along with much useful information, on their web site http://www.sciencedebate2008.com/www/index.php. You'll also find suggestions for other ways you can help.

This is not some small special-interest group pleading for a government handout. Science is the engine that drives innovation, the light that shines in the moonless night of ignorance and superstition, and the best hope for solutions to most of the serious problems that plague all people, everywhere. If the presidential candidates don't understand that, then our future may be bleak. I suppose we could debate that point. But that the next US President needs to understand the importance of science, communicate that to the public, and use scientific information properly. That point is not debatable.

Published: 30 April 2008

The new Manichaeans

Genome Biology 2008, 9:105

I'm writing this on Memorial Day, a holiday in the US to commemorate those who gave their lives in defense of this country. Not far from where I'm sitting, in a town on the edge of Boston, there is a square named after a young man from that town who went to fight in the Vietnam War and never came home. The area around the square is mostly populated by immigrants now - from Vietnam. That simple fact says more than any churchyard sermon on the ultimate futility of war.

Of course, that war is stupid doesn't in any way diminish the courage and nobility of the young men and women who fight, and sometimes die, in it. But it does mean that those who use war as a metaphor should be aware of its inherent irony, and have a special obligation to get their facts straight.

George Bush did neither the other day when he made the following remark, which was calculated to be a criticism of Barack Obama, who has advocated opening a dialogue with nations like Iran and North Korea:

"Some seem to believe that we should negotiate with the terrorists and radicals... We have heard this foolish delusion before. As Nazi tanks crossed into Poland in 1939, an American senator declared: 'Lord, if I could only have talked to Hitler, all this might have been avoided'."

Now let's forget for a moment that this show of courageous defiance was uttered by a man who never fought in a war, but has shown no compunction about starting them, and sending other people to fight and die in them. Let's also forget that his administration is currently negotiating with North Korea, a country he himself has called part of the 'axis of evil'. Hypocrisy notwithstanding, the remark was factually incorrect: President Bush was equating negotiation with appeasement, but they are simply not the same. It may have been effective, however, because it invoked the specter of Naziism and Adolf Hitler, which are generally considered among the greatest evils mankind has ever known.

Comparing your opponent, or their position, to something connected with the embodiment of evil is a popular - and frequently successful - debating tactic. All you have to do to end the discussion in your favor is to accuse someone who criticizes Israel of being an anti-Semite, or to argue that those favoring socialism are no better than Stalin, or to say that someone who wants to talk to Iran would have favored appeasing Hitler. Or to say that someone who doesn't believe in God, or who advocates policies that go against what you think is God's word, is in league with the Devil.

The later is exactly the argument that some religious fundamentalists make about scientists, especially those who advocate embryonic stem cell research, or try to teach evolution in the public schools, or do any one of a number of things that seemingly contradict a literal interpretation of the Bible (or, for that matter, the Koran). Such tactics not only put science on the defensive, they are almost impossible to answer without changing the debate to a theological one. I wonder, though, if the God-fearing people who use these tactics realize that they are actually following in the footsteps of a famous group of heretics.

The idea that the world can be divided into two opposing, and opposite sides is called dualism. It has perhaps its ultimate expression in a religion that thrived between the third and seventh centuries, but was still practiced sporadically in the sixteenth century. It was called Manichaeism, after its founding prophet Mani, who was martyred in Persia around AD 277. Manichaeism had a complex theology but its fundamental principle was the existence of, and eternal conflict between, absolute good and absolute evil. Manichaeism was considered a heresy by all the major religions of the time, including Christianity, Buddhism, Zoroastrianism and Islam; despite this, at one point it was among the most popular religions in the world, spreading from the Middle East as far as China and Britain.

Augustine of Hippo, the famous Catholic philosopher, was actually a Manichaean for nine years before his conversion to Christianity in AD 387. A lot of what we know about Manichaean beliefs comes from his description of them in several of his most famous writings, including a number of treatises specifically directed against Manichaean teachings. The core of his philosophical argument was that absolute evil does not exist, because evil is not a thing in itself. Augustine argued that all things are inherently good in nature, and that what we call evil is merely the absence of goodness.

No doubt he would be appalled to learn that there is still a strong Manichaean streak in many modern religions today - especially in their fundamentalist forms. When the religious right calls scientists agents of evil or claims that those who believe in evolution are in league with the Devil, they are adopting an essentially Manichaean world view. To see things in black and white without realizing that there can be shades of gray, or that not everything is part of a moral dichotomy, is what philosophers call the Manichaean fallacy.

The danger of Manichaean thinking is that it can lead to terrible conclusions. If you believe that you are on the side of absolute good, and that your opponent is on the side of absolute evil, then it is a small step to conclude that any action you take against them is morally justifiable. Manichaeism is the philosophical underpinning behind the most reprehensible idea I know of: that the end justifies the means. That little notion has been responsible for more human misery than just about any other premise. Once you've demonized the opposition, you can take their land, their property, their freedom, even their lives and still believe you're a good person. How can you not be, when you're on the side of absolute good? This principle explains the detention, and torture, of suspected terrorists, because the term 'terrorist' has taken on a Manichaean connotation equal to that of 'Nazi' or 'devil-worshiper'. The President of the United States clearly has a Manichaean world view, and it is likely that Tony Blair did, too. That puts them in interesting company, as the Mullahs who run Iran certainly do, and Osama bin Laden obviously does.

Manichaean dualism also strikes me as intellectually lazy. If you make blanket condemnations, you don't have to do the hard work of trying to understand your opponent's arguments, or of making the difficult distinction between those who are truly malicious and others who are merely misguided. You also never question the actions, and intentions, of your own side.

If I were an evil person, this kind of laziness would offer me a great place to hide. When your enemies are quick to condemn your entire nation, or religion, it's not likely they will go after you or any other individual villain. Moreover, you can probably count on your own countrymen to shield you, no matter what you've done, since they are, after all, being lumped in with you. Collective guilt is a huge mistake; it makes it much less likely that the actual people responsible for atrocities will be called to account. Besides, collective guilt is just another manifestation of the Manichaean fallacy. Nations and religions and ethnic groups are not evil; only individuals are.

But the greatest danger of Manichaean thinking is that it begets more of the same. If your enemies appear to hate and vilify you, then you are more likely to feel the same way about them. And I am afraid this may be happening right now, to us.

I'm sure that great evolutionary biologists like Richard Dawkins have far more experience contending with creationists and fundamentalists than I do, so I suppose I ought to listen to them when they say that we shouldn't debate with those who oppose the teaching of evolution or who argue that a creationist view deserves equal place in science education, because doing so gives our enemies a platform and an air of credibility. But every time I hear such an argument, the ghost of the Manichaeans haunts me. Refusing to talk with your opponents sounds like George Bush refusing to talk to the Iranians; if it isn't Manichaeism, it's the first step on a very slippery slope that leads there. And it's also lazy: it makes no distinction between those who will never be convinced - either because they believe without thinking, or are using fundamentalism cynically for political purposes - and those who could be convinced that what they believe and what we as scientists know to be true can peacefully coexist. It also feeds the Manichaean fervor of the fundamentalists, who can then argue that, if we aren't agents of evil, why are we refusing to meet them on even terms?

If you think I'm reading too much into Dawkins' objection, his most recent book, The God Delusion, makes me pretty sure I am not. The book takes a very intolerant tone, scorning not just religion but its believers. Calling religion "nonsense" may be commendable candor, but I don't think it serves science well, especially today, to drift towards a Manichaean view of religion. I think many people who adhere to religious beliefs have done horrible things in the name of the God they profess to worship, but I also think many others have done much good for the same reasons. To lump both groups together is to forgo any possibility of a dialog, or maybe even an alliance. And it is just such an alliance that the great biologist Edward O. Wilson proposes in his latest book, The Creation: An Appeal to Save Life on Earth. In it, he suggests that people of faith may in fact be the natural allies of biologists when it comes to matters of ecosystem conservation, climate protection, and the preservation of endangered species. His arguments are well reasoned, impassioned, and wonderfully anti-Manichaean: he looks for connections between people the way he often has between fields of inquiry; he is inclusionary rather than divisive. Whether you agree with him or not, his approach is uplifiting.

Science is under siege today as it has never been before in my lifetime. Genomics is partly responsible, since the vast knowledge this branch of biology has provided forms the basis for many of the things that cause religious believers the most unease. As a consequence, we often appear to be surrounded by calls for the banning of this and the restriction of that. But if we let our defensiveness lead us to dualism, adopting an 'us-versus-them' viewpoint where 'they' are a nebulous group that is the object of our blanket condemnation, then we are doing exactly what we profess to disdain. If we demonize the opposition, substitute scorn for understanding, ridicule for dialog, and disregard individual differences in the name of some purity of approach, it doesn't matter how much we console ourselves with the thought that we are, after all, on the right side. There is one thing the failure of Manichaeism in all its guises should teach us: you are what you do.

Published: 29 May 2008

It is alive

Genome Biology 2008, 9:106

They're at it again. Armed with another new idea from the Discovery Institute, that bastion of ignorance, right-wing political ideology, and pseudo-scientific claptrap, the creationist movement has mounted yet another assault on science. This time it comes in two flavors: propaganda and legislative.

The propaganda is in the form of a poorly written, badly acted movie produced by Ben Stein, an attorney and entertainment figure who once served as a speechwriter for US Presidents Gerald Ford and Richard Nixon. As if working for Nixon didn't do enough to demonstrate his faulty judgment, he has become an ardent critic of evolution and an advocate for 'intelligent design', which is creationism poorly disguised as 'science'. He co-wrote and stars in the film Expelled: No Intelligence Allowed, which attempts to link evolution to the eugenics movement in Nazi Germany and to the Holocaust, and portrays advocates of intelligent design as champions of academic freedom and victims of discrimination by the scientific community. The famous evolutionary biologist and atheist Richard Dawkins has a spirited attack on the film on his website http://richarddawkins.net, and there's also a lively critique from the National Center for Science Education http://www.expelledexposed.com.

Fortunately, the film is sinking faster than the Lusitania. As far as I can discover, it has grossed less than US$8 million in ticket sales to date, far less than its cost, and is playing to virtually empty houses in the few theaters that are still showing it. Whether this is because people recognize its ideas as rubbish or because it is simply a bad movie, I don't know. So we can probably ignore it, as it so richly deserves. But the legislative attack is much more serious.

On 11 June 2008, the Louisiana House of Representatives voted 94:3 in favor of a bill that would promote 'critical thinking' by students on topics such as evolution, the origins of life, global warming, and human cloning. The Louisiana Senate already passed a similar bill, Senate Bill 733, by a vote of 35:0, but an amendment adopted by the House, which would allow the state Board of Elementary and Secondary Education to prohibit supplemental materials it deems inappropriate, means that the Senate must pass the bill again. If they do, and this seems a certainty, then the bill will be sent to Louisiana governor Bobby Jindal, at 36 the youngest governor in the United States and the first Indian-American to serve as the head of a state government. A former Hindu who converted to Catholicism in high school, Jindal attended Oxford University on a Rhodes Scholarship. Jindal was a biology major at Brown University, so he should understand the science at stake here, but he opposes stem-cell research and has publicly supported the teaching of 'intelligent design' in public schools. He has not stated whether or not he will sign Bill 733. A fascinating subtext to this story is that Jindal is reportedly under consideration by Republican presidential nominee John McCain as a possible vice-presidential nominee.

The bill is cleverly worded: it states in section 1C that it "shall not be construed to promote any religious doctrine, promote discrimination for or against a particular set of religious beliefs, or promote discrimination for or against religion or nonreligion." In an interview with the conservative newspaper The Washington Times (12 June 2008), Jason Stern, vice-president of the Louisiana Family Forum, a Christian right-wing lobby group, insisted "It's not about a certain viewpoint. It's allowing [teachers] to teach the controversy."

Let me say this as clearly as possible, so there can be no mistake about what I mean: there is no controversy. Just because a few misguided so-called scientists question the validity of the concept of evolution doesn't mean there is a controversy. There are still some people who believe the Earth is flat (there's even a 'Flat Earth Society'), but that doesn't mean that a grade-school science teacher should teach his or her students that the Earth might be flat. The fact that some people believe nonsense does not give that nonsense scientific validity. A challenge to existing scientific principles must be based on evidence, not on belief, and there isn't a shred of evidence to support either creationism or intelligent design. Those ideas belong in a religion or philosophy class, not in a science class.

By the way, speaking of religion class, if we accept the creationists' own rationale for this bill, then shouldn't right-wing fundamentalist Christian schools be forced to 'teach the controversy' about religion? It's a much more controversial subject than science. Shouldn't their students be forced to consider the possibility that there is no God, or that the Muslim faith, or the Hindu faith, or the Jewish faith might be the true one? Or that there are so many different translations and versions of the Bible that there is no way of knowing which one is the 'word of God'? You can see how quickly their argument breaks down.

What about the academic freedom argument? If someone wants to teach creationism in a science class, shouldn't they have the right to do so? Certainly - if they want to get fired. Because if they do that they deserve to get fired. It has nothing to do with academic freedom; it's about basic competence. Consider, for example, a science teacher who taught that the Sun revolves around the Earth. Even the intelligent-design advocates would probably have to admit that such a science teacher was incompetent and ought to be dismissed. That teacher might counter with a claim that his or her academic freedom was being infringed, but no court would uphold it, any more than a court would uphold a similar claim from a history teacher who taught that the Allies lost World War 2 or that Napoleon Bonaparte was emperor of Japan. Science, and history, may welcome speculation, but the speculation must be based on facts, and when it isn't, then it doesn't belong in that subject. Any 'science' teacher who teaches that the Earth might have been created about 6,000 years ago and that all the material evidence that it's billions of years old is controversial is simply incompetent. If the state of Louisiana wants its children taught by such people then they deserve the kind of workforce and citizenry they are going to get.

It's worth pointing out that in 1987, in the case of Edwards versus Aguillard, the US Supreme Court ruled as unconstitutional the idea of equal time for "creation science" and evolution in biology classes. That precedent will almost certainly be used as the basis for a constitutional challenge to the Louisiana law if it passes. Also, in the state of Pennsylvania, the 'Kitzmiller versus Dover' case in 2005 put to rest the idea of intelligent design as an alternative to evolution being taught in biology classes - the judge there, in a brilliantly reasoned opinion, demonstrated that intelligent design was just creationism by another name. Although not a Supreme Court case, this decision was strong enough to cause creation science advocates to switch tactics to arguments about academic freedom, the focus of the current legislation at issue in Louisiana.

Lest you think this is merely some Bible Belt aberration, let me assure you that the creationists are marshalling this argument in other states as well. In Michigan, Senate Bill 1361, introduced in the Michigan Senate on 3 June 2008, and referred to the Senate Committee on Education, is yet another 'academic freedom' bill aimed squarely at the teaching of evolution. Identical to Michigan House Bill 6027, which is still in the House Committee on Education, Senate Bill 1361 would, if enacted, require state and local administrators "to create an environment within public elementary and secondary schools that encourages pupils to explore scientific questions, learn about scientific evidence, develop critical thinking skills, and respond appropriately and respectfully to differences of opinion about controversial issues" and "to assist teachers to find more effective ways to present the science curriculum in instances where that curriculum addresses scientific controversies" by allowing them "to help pupils understand, analyze, critique, and review in an objective manner the scientific strengths and scientific weaknesses of existing scientific theories pertinent to the course being taught." And in Texas (why is it not a shock that the state that gave us George W Bush would show up here), the Texas State Board of Education is again considering mandating a science curriculum that teaches the "strengths and weaknesses" of evolution. On 7 June 2008, the Houston Chronicle wrote that "strengths and weaknesses" language is "a 'teach the controversy' approach, whereby religion is propounded under the guise of scientific inquiry". The editorial went on to say: "What students really need is to be able to study science from materials that have not been hijacked by creationists whose personal agenda includes muddying the science curriculum. Creationism is not a 'system of science'."

As scientists, we need to protest with our feet and our wallets. I am about to become the president of the American Society for Biochemistry and Molecular Biology, a scientific society with about 12,000 members. Our 2009 annual meeting is scheduled to take place in New Orleans. If Bill 733 becomes law in Louisiana, it will be too late to move the meeting to another state. But we need to see to it that no future meeting of our society will take place in Louisiana as long as that law stands, nor should we hold it in any other state (are you listening, Michigan and Texas?) that passes a similar law. I call upon the presidents of the American Chemical Society, the American Association of Immunologists, the Society for Neuroscience, and all the other scientific societies in the US and around the world to join me in this action and make clear to the state legislators in Louisiana, the governor of the state, and the mayor and business bureau of New Orleans that this will be the consequence. You can do the same. Governor Jindal can be reached through his website http://www.bobbyjindal.com and Ray Nagin, mayor of New Orleans, can be reached through the Mayor's office http://www.cityofno.com/Portals/Portal35/portal.aspx.

In its ability to rise again just when we think we've got it licked, creationism is like Frankenstein's monster. "Come see, villagers! It is alive!" We'll never be rid of it by being silent and doing nothing, so one important thing is to force governments that ally themselves with this monster to pay for their folly by denying them our business. In addition, we must all arm ourselves with the one weapon we have that, in the end, the monster cannot overcome: the truth. All of us need to familiarize ourselves with the facts of evolution so that we can mount a spirited defense against the forces of ignorance and the charlatans who would exploit human insecurity and need for certainty.

Carl Sagan memorably called science "a candle in the dark". Well, the darkness is always around us, closer than you think sometimes. Yes, it is alive. Creationism's alive because some of our fellow men and women keep it alive. In the dark.

Published: 23 June 2008

Having an impact (factor)

Genome Biology 2008, 9:107

The time: Some time in the not-too-distant future.

The place: The entrance to The Pearly Gates. There are fluffy clouds everywhere. In the center is a podium with an enormous open book. A tall figure in white robes with white hair and beard stands at the podium. Approaching is a thin, middle-aged man with glasses and a bewildered expression. He is the soul of a recently deceased genome biologist.

GB: My gosh is this...? Are you...? Am I really...?

St Peter: Yes, I'm St Peter. And yes, this is where souls such as yours enter heaven.

GB: Wow. I mean, I didn't expect to live forever, but still, this is something of a shock. (Pauses.) OK, I guess I can live with it. Uh, I mean ...

St Peter: I know.

GB: Well, at least I'm here. I'm not thrilled to be dead, but it's a relief to know I'm going to heaven.

St Peter: I'm afraid it's not that simple. We have to check.

GB: Check what?

St Peter: Your life history. (He leafs through the enormous book.) It's all here, you know.

GB: I'm sure it is. I can imagine you guys keep records that make PubMed seem like a stack of index cards. I'm a little surprised you don't use something more up-to-date, though.

St Peter: If you mean a personal computer, no - we don't. After all, they were invented elsewhere.

GB: You mean on earth?

St Peter: No, somewhere a lot warmer. (He stops at a page.) Here you are.

GB: Hey, I'm not worried. I was a good scientist, a good citizen, a good family man, I think, too. I never...

St Peter: Yes, yes, I'm sure, but you see, none of that matters. The only thing that matters is your IF.

GB: IF?

St Peter: Your impact factor. That's all we use now. If your IF is above 10, then you enter here. If it's lower, well...

GB: My impact factor? What the hell - oops, sorry - is that?

St Peter: It's something we borrowed from you science chaps on earth. Oh, we used to do it the hard way: send a fledgling angel down to check on your deeds; look at how your life affected your friends and family, consider your intentions versus your actions. All that sort of thing. It was tedious and required huge numbers of new angels, who have become somewhat scarce since free-market capitalism became all the rage down there. Then we noticed that you scientists never bothered to do anything like that. If you had to evaluate someone, all you did was look at this number called the impact factor. So we did the same thing. Now when anyone comes here, all we do is look up their number.

GB: A single number? Are you nuts? You can't sum up someone's whole life in a single number!

St Peter:You do. At least, you sum up their career that way, when you decide if they've published in the best journals or done the best work. It's how you work out who gets promoted and who's a star and who gets funded and...

GB: Yes, but it's a terrible idea! We should never have done it. It ruined European science in a matter of a few years, and then it spread to Australia, China and Japan, and finally to Canada and the US; and before too long, science was totally controlled by unimaginative bureaucrats who just used that number for everything. It was a disaster!

St Peter: That's not what St Garfield thinks.

GB: St who?

St Peter: St Eugene Garfield, PhD. He invented citation analysis, remember? He thought using the IF was a great idea - really, a logical extension of his own work creating the Citation Index. So we set it up: for example, I see here that you contributed regularly to several local charities.

GB: Of course. They do good work. I never did it because I thought it would get me into heaven, but...

St Peter: Just as well, because it won't. Local charities, you know. Small impact factor. Doesn't really add much to your total. Besides, how bad could the idea be? Why, the journal Genome Biology advertises its impact factor right at the top of their website. Didn't you use to write a column for them? (He looks at the ledger again.) Oh my, I see that won't add much to your total either.

GB: But that's all ridiculous! It's the whole problem I was trying to explain to you. That's like saying that a paper only has significant impact if it's published in Nature, Science, or Cell. Once you do that, then the impact factor of where you publish becomes a surrogate for the use of your own judgment. No one bothers to read anyone's papers when they're up for a fellowship or being considered for a job or for a promotion or having their grant proposal evaluated; all you do is look to see how many papers they've published in high-impact journals. No one considers whether the work was better suited to a more specialized journal or a journal where other work that puts it in context was published previously; no one considers whether those handful of high impact-factor journals have the best referees or whether they in fact may have a disproportionate number of incorrect papers because of the pressure to publish there. And look, over reliance on one stupid number gave a small bunch of editors enormous power over the careers of people who, for the most part, they never met or heard speak, and whose body of work they never read. It was probably the worst idea since General Custer thought he could surround the whole Sioux Nation with a couple of hundred troops.

St Peter: Ah, yes. St Sitting Bull still talks about that.

GB: Huh? (Shakes himself.) Look, once the impact factor dominated scientific judgments, creative people were doomed. Bureaucrats didn't need to know anything or have any wisdom; all they had to do was rely on arbitrary numbers. And now you're telling me you're doing that to determine who gets into heaven?

St Peter: Yes; it's a lot simpler. It doesn't matter if you were kind or tried hard or did good work or were pious or modest or generous. The only thing that matters is how big an impact we calculate you had.

GB: But that's just wrong! Look, maybe I could talk to the people who thought up that idea and pushed for its use. If I can just get in for a minute...

St Peter: Oh, they're not here. (He waves his hand and an image appears on a cloud. It shows a huge pit of boiling sulfur and brimstone. In it, up almost to their necks, are a bunch of men in business suits.) As you can see, they're in a warmer climate.

GB: Well, at least, that seems fair somehow. Wait a minute - is that George W Bush?

St Peter: Yes.

GB: But his impact factor should have been huge.

St Peter: Oh, the absolute value was off the charts. But we do take the sign into consideration...

GB: Then why is he only in brimstone up to his knees?

St Peter: Oh. He's standing on Dick Cheney's shoulders. (The image vanishes.) Now let's get back to you...

GB: But don't you see, the idea that you can determine someone's impact in the future from where they publish today is totally absurd. On that basis, God would have an impact factor of zero. I mean, He did his best work a long time ago; it has never been repeated by anyone; and all His ideas were published in a book, not in a peer-reviewed journal!

St Peter: Very funny. Go to hell.

Published: 29 July 2008

Biodefense versus bioterrorism

Genome Biology 2008, 9:108

We always knew, didn't we, that he was probably one of our kind. When the deadly envelopes laced with anthrax spores claimed their first of five eventual victims - Robert Stevens, a 63-year-old photo editor for the Florida-based tabloid 'newspaper' The Sun - just a few weeks after the 11 September 2001 terrorist attacks on New York and Washington, most scientists figured that the killer was connected with the US biowarfare program, and was almost certainly a scientist. Using anthrax as a weapon required just too much specialized knowledge for the low-tech terror groups we were used to dealing with; it was simpler to imagine that the powder came from someone with access to a bioweapons stock and knowledge of how to handle it. Now, with the recent suicide of a microbiologist who worked at the US Army Medical Research Institute of Infectious Diseases at Fort Detrick, Maryland, and the partial release of evidence from the Federal Bureau of Investigation (FBI) that indicates he was probably the person responsible, our worst fears have been realized. Pogo, Walt Kelly's philosophical cartoon possum, was right: "We have met the enemy, and he is us."

In the past few days, new details of how this case was finally solved after almost seven years have come to light, and what they reveal is the critical role of genomics in identifying the source of the anthrax. In fact, many of the techniques did not even exist at the time the anthrax letters were mailed. As he prepared his poisonous envelopes, the murderer could not have imagined that their origin would eventually be revealed by technology beyond his/her ken. As Hamlet put it: "For murder, though it hath no tongue, will speak with most miraculous organ." In this case, the miraculous organ of genomics.

The best account I've read of this fascinating piece of microbial forensics is the front-page story by Nicholas Wade in the 21 August edition of the New York Times [weblink]. I'm drawing heavily on this superb article as I try to summarize what happened.

Paul Keim, a biologist at Northern Arizona University in Flagstaff, was able to determine from an anthrax sample taken from Robert Stevens' corpse that the strain used was the virulent Ames strain. To identify its source, the FBI hired a team at The Institute for Genome Research (TIGR), where the first microbial genomes had been sequenced in the dawn of the genomics era, to determine the complete DNA sequence of the lethal strain. This they did, in about four months (it could be done in days today). When the sequence was compared with that from a culture of Ames anthrax maintained at Porton Down in Britain, the UK government's research establishment for defense against biological weapons, several differences were found between the anthrax genome taken from Stevens and the genome of the Porton Down strain. The Ames strain originated from a cow that died of anthrax in Texas in 1981, so the next step was for TIGR to sequence that ancestral strain, so that a phylogenetic tree of anthrax substrains could be constructed. Unfortunately, the bioterror strain turned out to be virtually identical to the original Ames strain, so it looked as if its source could not be identified by sequencing.

What finally cracked the case was an inspired bit of old-fashioned microbiology. An army scientist at Fort Detrick noticed that cultures of the bioterror strain were not uniform: one of the colonies had an altered morphology, suggesting that a small percentage of the cells in the sample harbored mutations. The odd colony was grown up and TIGR sequenced its genome; sure enough, there was a small but significant change. Eventually, a total of eight morphological variants were identified in the bioterror strain, and all were sequenced. The lethal strain now had a genetic fingerprint, the first ever obtained for a microbe: the pattern of genetic changes in the 1% of spores in the sample that were different from the other 99%. It turned out much later that the reason there were so many variations was that the flask that contained the anthrax strain used in the attacks held the results of 35 separate preparations of anthrax, giving the strain ample opportunity to develop mutations. It was soon determined that all of the anthrax letters contained bacteria from the same source.

The FBI was now able to compare this signature pattern of variations, the bacterial version of the single nucleotide polymorphisms (SNPs) that are used in DNA fingerprinting of people, to those of anthrax samples obtained from laboratories around the world. By 2006 it was clear that the source of the bioterror strain was a flask in the laboratory of Bruce Ivins, a microbiologist at Fort Detrick with a history of mental instability. But it took two more years before the investigators succeeded in eliminating other scientists who might have had access to the flask as possible suspects. As the FBI began to focus its inquiry on Ivins, he took his own life.

Genomics cannot prove that this man sent the anthrax letters in 2001, but its success in identifying the source of the strain marks a landmark in scientific detective work. As whole organism sequencing becomes even cheaper and faster, we may see the day when the genetic signature of microbes found at the scene of the crime, or on the clothing of a suspect, become as damning evidence as the suspect's own DNA. And the new heroes of Crime Scene Investigation (CSI) could be microbial genome biologists.

Ivins was not a bioweapons scientist. His job at Fort Detrick was to find an effective vaccine against anthrax strains that had been turned into a bioweapon. It has been speculated that his motive in sending the anthrax letters - if he was the person who did so - may have been to increase demand for the vaccine he developed. Another possibility is that, as he is known to have believed that the United States was taking the possibility of bioterrorism too lightly, he may have carried out the attacks to raise awareness of the danger and generate political support for increased focus on biodefense. That would explain why Senate offices were among the targets.

If that was the tactic, it had unintended consequences: immediately after the anthrax attacks, White House officials repeatedly pressured FBI director Robert Mueller to prove that they were by Al-Qaeda, but the FBI knew very early in the case that the anthrax used was a version requiring sophisticated equipment and was unlikely to have been produced by a low-tech terrorist organization. Nevertheless, President Bush and Vice President Cheney both speculated publicly about the possibility of a link between the anthrax attacks and Al-Qaeda. The Wall Street Journal published an editorial stating that Al-Qaeda perpetrated the mailings and that Iraq was the source of the anthrax, thereby displaying their remarkable ignorance of Middle Eastern affairs: a secular state like Iraq, ruled by a secular dictator, would be the last place Al-Qaeda would go for help. A few days later, Senator John McCain, who will soon be the Republican contender for the presidency of the United States, displayed equal ignorance of foreign affairs by suggesting on the David Letterman Show that the anthrax may have come from Iraq.

Of course, this possibility was one of the many falsehoods that the Bush administration used as the rationale for their later invasion of that country.

In another sense, however, the attacks may have had the intended consequences, because shortly after they occurred, Congress voted massive increases in spending for biodefense research, to the tune of more than a billion dollars earmarked for the National Institute of Allergy and Infectious Diseases (NIAID). Since the recent revelation that the source of the anthrax was our own army research program and that one possible motive for the killings was to provoke just such an increase in support, there has been criticism that the government overreacted and is investing far too much money in research aimed at counteracting bioterrorism and far too little to deal with less sophisticated forms of terror attacks.

I think this criticism is half right: we are paying too little attention to the possibility of simple methods of achieving widespread destruction. In our focus on foreign terror groups and high-tech weaponry, we seem to have forgotten that, until the events of 11 September the deadliest terror attack on American soil was perpetrated by a clean-cut former US soldier, who used a truck full of diesel fuel and fertilizer to blow up the Oklahoma City Federal Building. Chemical weapons are cheap and easy to manufacture and simple to deliver. The same is true of spreading radioactive material. Low-tech terror offers far more choices of means and plenty of technical and operational options.

But I don't think we are spending too much money on biodefense, even though I believe the possibility of more attacks like the anthrax letters is remote. I think we need every dollar we're spending, but not to protect us from bio-terrorism. It's to protect us from infectious diseases.

More than 25% of the world's deaths are due to infectious disease, and there is no effective means of prevention or treatment for many of the most deadly agents, such as Ebola, Marburg and the other hemorrhagic fever viruses. HIV/AIDS is controllable with expensive drug cocktails in the developed world but has so far resisted all attempts at effective vaccine development. Multidrug-resistant tuberculosis is becoming endemic in some parts of the world and is a potential public-health catastrophe should it spread widely. The devastating economic consequences of the SARS virus outbreak point up how vulnerable the world's economies are to heath-related disruption. Avian flu seems to have quietened down but is still out there somewhere, waiting to learn how to jump the species barrier. Methicillin-resistant Staphylococcus aureus and other so-called 'superbugs' are threatening to turn every hospitalization into a game of Russian roulette. There have been hardly any new classes of antibiotics developed in the last quarter century, and resistance to the ones we have is on the rise. Vaccine development is technically difficult and economically risky; antibiotic development has largely been ignored by the major pharmaceutical companies in recent years and is now in the hands of a few underfunded, and undermanned, biotechnology companies. We are dangerously close to returning to the situation of my mother's childhood, 90 years ago, when virtually every cut or scrape was potentially life-threatening, and more people perished from infectious disease during wars than died on the battlefields.

But exactly the same research that is needed to combat low-probability bioterror attacks is needed to combat high-probability natural infectious agents. Every project that NIAID funds to protect soldiers and civilians from manmade bioweapons could provide a breakthrough in the fight against AIDS, or tuberculosis, or the flu, or any of the thousand other natural shocks that flesh is heir to. And as such research is not going on to the necessary degree in the private sector, it must be publicly funded if we are to have a hope of success.

In a world where irony is commonplace, this may be one of the great ironies of all: that the anthrax attacks of 2001 may have prodded us into much-needed research on biodefense, even though bioterrorism is a remote possibility. But that's the great thing about effective agents of defense: they don't care where the attack is coming from - whether it's from nature or, God forbid, from one of us.

Published: 1 September 2008

When bubbles burst

Genome Biology 2008, 9:110

Chutzpah used to be defined as audacity so shameless that the usual example was someone who murdered his parents and then asked for mercy because he was an orphan. These days, an even better example would be that of the chief executives of financial firms, a group of - typically, but not always - conservative Republicans who, having spent much of the past decade railing about the evils of big government and trumpeting the virtues of the free market, are now traipsing in droves to Washington, whining to that same big government to save them from - you guessed it - the free market. If you or I were to do the same when we lost money at the racetrack, Washington would have a good laugh at our expense. So these captains of industry got the same response to their naked hypocrisy, right?

Yeah, right. At the time of writing, the US government has spent, by some accounts, approximately $900 billion over the last year or so to prop up the failing financial services and mortgage industries. Now the Bush Administration is asking Congress for authority to borrow another $700 billion to buy up mortgage-backed securities, to prevent the financial sector from collapsing altogether. Congress is still wrangling over the details, but it seems almost certain that some sort of bailout will have been passed by the time you read this. Let's forget about the money they've already spent and consider just that $700 billion sum. That would fund the National Institutes of Health for the next 25 years, and is more than twice as much as the government has spent on all biomedical research in the past 100 years. No wonder nobody can get a grant.

(Come to think of it, maybe we've been going about this the wrong way. Instead of applying for more grants, maybe each of us should just overspend our existing grants by, say, several million dollars, and then the scientific community could demand that Congress bail out the NIH rather than let the biomedical establishment go bust. Just a thought.)

What's caused all this, of course, is the bursting of an asset price bubble. One of the meanings of the word 'bubble' is a state of expansion that is unstable and so is unlikely to last. Remember the 'dotcom' bubble of the 1990s, so named because employees of companies doing business on the internet were making huge paper profits from options to buy stock in their overvalued companies, and millions of investors were driving the prices of those stocks ever higher in a frenzied attempt to get rich too. When people realized that almost none of these companies could ever make a profit, the bubble burst and internet company stock fell faster than a 3-tonne safe dropped off the Eiffel Tower. Companies with no products and no income, yet whose paper value had once exceeded that of the Ford Motor Company, became worthless - which was, of course, their true worth - overnight. It took the spectacular successes of Amazon, eBay and Google to restore some investor confidence in internet businesses.

The real-estate bubble that occurred in Japan in the 1980s is even more instructive because of its disturbing parallels with the present situation. Then, prices of commercial properties in Tokyo and other Japanese cities skyrocketed to the point where some offices - not office buildings, just offices - were among the priciest real estate on Earth. The fact that their intrinsic value was obviously much less didn't stop companies from buying them as investments and - here's the real parallel - didn't stop banks from both lending huge sums of money to buy them (after all, their value would go up forever, right?) and, worse still, using them as collateral to cover their own borrowing. When the value of that property began to fall, the entire financial sector was so entangled that the bursting bubble triggered an economic depression in Japan from which that country has still not completely recovered.

In much the same way, the current worldwide financial crisis, considered by some commentators as the most serious since 1929, was triggered by overvalued real estate - in this case, homes. Without going into a lecture on finance - which I'm not remotely qualified to give - let's just say that the United States is now paying the price for living beyond its means for the past ten years. Foreign investors, eager for the high returns and stability that Wall Street represented, poured money into the financial markets here. But for the most part, the investment banks and brokerage firms that took in that money didn't invest their profits in infrastructure improvements or job-creating new industries. Instead, they put the money into risky home mortgages and then went after even bigger profits by creating a dizzying array of complex financial instruments (such as derivatives and hedge funds), most of which were based on borrowed money secured by those same mortgages. Housing prices were going to go up for ever, weren't they? People were always going to need a place to live, right? And individuals also borrowed vast sums of money to fund a spending spree, secure in the knowledge that they had the wealth to cover their debt in the form of their suddenly valuable homes.

Inevitably, the overvaluation of houses created one of the great bubbles of our time, and when it burst, it did so spectacularly. As house prices fell and people defaulted on their mortgage payments in the shrinking economy, the assets that secured the vast, borrowing-driven boom in the financial sector became insufficient to cover all that debt. The past few months have seen one financial giant after another go bankrupt, or be taken over by the government, or be bought for pennies on the dollar.

But what, you are certainly asking by now, has all this got to do with genome biology? If a bubble occurs when things assume a value way out of proportion to their true worth, then big science, which in biology is epitomized by genomics, may be on its way to becoming one. As I've pointed out before, the success of the Human Genome Project, not only from a scientific perspective but also in terms of commanding both resources and attention, spawned a host of imitators. Some of the resulting large-scale, technology-driven, data-gathering projects have real value. Others, like the Structural Genomics Initiative and the Cancer Genome Project, have, in my opinion, much less. Yet the failure to terminate the former or to realize that the data gathered by the latter may not be very useful (owing to, among other things, the heterogeneity within any one tumor), argue that these 'assets' have a perceived value way above what they should have.

Value to whom? Well, certainly to the people being funded by them, but also, I think, to the scientific administrators in Washington who can use them to point to the productivity of the institutes and programs they manage. We might be able to live with that if it weren't for one thing: the pie is finite. Two plus two makes four, not five or six, and when someone takes two out of four there is only two left. A lot of these projects have earmarked funding; they do not compete in open peer review against your grants and mine. They are evaluated on their own by ad hoc reviewing panels, and even when those evaluations are scathing, as was the recent evaluation of the Structural Genomics Initiative, they rarely lead to the program's termination. A severely negative review of an individual's research proposal typically results in that grant never being funded or not being renewed. Big-science projects typically just have their objectives repackaged.

The enormous paper wealth created by the financial bubble didn't enrich anyone but the financial industry itself. While brokers, traders and chief executives raked in bloated salaries and obscene bonuses, the infrastructure of the United States crumbled, job creation almost stopped, the social fabric rotted, and the federal budget surplus bequeathed to the Bush Administration by the Clinton Administration shrank into a deficit that is now the biggest in the country's history. Similarly, I worry that many of these newer big-science projects, unlike the Human Genome Project, will not produce many results that are helpful to individual investigator-initiated research. And as long as they are sucking up pieces of that finite pie of research dollars, there will be insufficient government funds to support the backbone of science - the individual research grant, which is driven by the curiosity and vision of the individual scientist, not dictated by the top-down fiat of an administrator or the self-interest of some powerful cabal of senior investigators.

What's to be done? We as a community of individual investigators have to take back control of the scientific enterprise. Not administratively - believe me, you don't want that - but in terms of input into the setting of priorities. We need to demand that big science receives scrutiny as critical -and suffers consequences as severe - as our own grants do. We need to lobby our scientific societies to take firmer stands about these issues, and we need to help science administrators and policy-makers in Washington find the right way to phase out programs that should die, and explain to Congress and the people why this is the smart thing to do.

There is an alternative, of course: we could all jump on the big-science bandwagon. We could form teams to do even more huge data-gathering projects and encourage the government to put even more of its research dollars into such programs; after all, they would then be benefiting us. There's only one problem with that. If I'm right that this is a bubble, then some day that bubble is going to burst. There never has been a bubble that didn't.

Published: 29 September 2008

Meta-morphosis

Genome Biology 2008, 9:111

There's an old chemistry joke, based on the ortho, meta and para nomenclature for substituents attached to a benzene ring, that goes like this:

Answer: metaphysician.

OK, I know it's not very funny, but how many funny chemistry jokes are there? Anyway, someone reminded me of this joke the other day and while I was busy not laughing I was also thinking about something else. Because these days, for most people in the life sciences, and I bet nearly everybody in genome biology, the prefix meta doesn't conjure up images of di-substituted benzene. It calls to mind the meta-analysis of data.

Meta-analysis - sometimes contracted to metanalysis - is one of those Sudoku-like fads that seem to pop up overnight and sweep the entire country in about as little time. 'Metanalysis' doesn't mean the same thing to scientists as it does to other academics. In linguistics, metanalysis is the act of breaking down a word or phrase into segments or meanings not original to it. The term was coined by the linguist Otto Jespersen, and comes from the Greek for 'a change of breakdown'. Here's an example, courtesy of Wikipedia: in the phrase "God rest ye merry gentlemen", originally merry was a complement with rest (as in "God rest ye merry, gentlemen" - note the position of the comma - that is, "[may God] give you gentlemen a pleasant repose"). But now, by a process of metanalysis, merry is frequently construed as an ordinary adjective modifying gentlemen ("God rest ye, merry gentlemen") - and in all probability it can be relexicalized with the current sense of merry, that is, cheerful, jolly, though that is harder to be certain of. (The expression "to rest merry" and the like was once generally current, by the way.) Incidentally, I love this sort of thing, but it isn't what 'meta-analysis' means in biomedical research.

Meta-analysis for us is a technique whereby all data from all available studies of something are combined, often regardless of the relative quality of the data. The method is used by researchers to get a maximum amount of statistical information from a set of studies that might not have large enough individual sample sizes, or whose results may be of marginal statistical significance.

In a typical meta-analysis, the results of, say, four different clinical trials of a drug, or the data from five independent studies of the association of a genetic variation with a particular disease, are merged into a single statistical sample. The sample is then analyzed for the same correlation, or lack thereof.

I don't know where it the practice came from but it's of relatively recent origin - the late 1970s or so. Certainly when I was a student there wasn't an entire subfield devoted to pooling studies and reinterpreting the results. But the medical literature, and the literature of human genetics, is awash with it now.

Imagine the excitement of the person who thought this up. "Omigod! I can take other people's results, throw them together, and come up with a conclusion that in some cases will horrify them, and I can get it published in good journals -sometimes with quite high visibility if the data concern an important human disease or a dietary substance that's popular - and I don't have to do any of the really hard work! I don't have to actually do the studies. I don't have to find the patients, or collect the questionnaires, or analyze the genomes, or any of that difficult, real science. They'll do it for me, and then I can use their data for my own benefit. This is like making money with other people's money! This is how the first banker must have felt!!"

I am not a professional statistician, but I have taught statistics, and as a protein crystallographer I have to be familiar with most of the rudimentary forms of statistical analysis of data. And everything I know about the subject suggests to me that meta-analysis could lead to all kinds of trouble. One of the things I've learned is that you don't improve bad data by combining it with good data. In fact, exactly the opposite occurs: the bad data degrade the better. "When in doubt, leave it out" is what I usually tell my students - occasionally modified to "when in doubt, weight it down". But most meta-analyses don't apply relative weights to the studies they combine (it's pretty hard to see where they would get the weights anyway), so studies of all sorts of varying quality are sometimes pooled as though they were equally reliable.

And even if we allow that the people who do this may get better statistical precision this way, owing to an enlargement of the sample size, I don't think statistical precision is the issue here. Adding more data may reduce the random errors, but I believe that in most biomedical and genomics studies - especially the latter - the real importance may lie in the systematic errors, or, more precisely (pun intended), the systematic differences.

Meta-analysts justify combining data from different studies in part because doing the same experiment in different ways has long been a way to avoid problems caused by non-random or systematic errors. And it is true that using multiple studies that involve different questions or different experimental techniques, with different patient populations and other variations, may allow global trends to emerge from underneath spikes of systematic differences. But there is a danger there. The first meta-analysis I ever encountered, some years ago, concerned a gene I was interested in. It had been reported that a particular polymorphism in this gene was associated with a reduction in risk for certain diseases in the Han Chinese population. Several other studies, including some with much smaller sample sizes, had looked for a disease association in other ethnic groups but had failed to find any. The meta-analysis pooled all of these studies and concluded, rather definitively, that the particular variant did not confer a change in risk for any of the diseases in question. And their overall statistics certainly bore that out.

There was just one problem: I had read the original Han Chinese study rather carefully, and the work was well done, and the statistical correlation with disease risk was absolutely significant. But if you only read the meta-analysis -and I've seen that referred to repeatedly since and even quoted from at meetings - you wouldn't know that.

Because in the age of genomics, it's not about the general population anymore. Personalized medicine is coming, and our studies of haplotypes and other natural variations make it clear that, even if we can't quite get down to the level of the individual yet in all studies, the genetic (and environmental) background of the population being evaluated can make a huge difference. Ethnic and geographical differences aren't not systematic errors to be averaged out; they're essential components of the ways genes (or drugs, or nutrients) interact with the human body. The right question to be asking in the case of the study I referred to is not whether the polymorphism alters disease risk in the general population, but rather why it does so in the Han Chinese population. What are the particular combinations of other genetic and environmental factors that cause this variant to become associated with a set of diseases? That's where the really interesting science, and medicine, lies. Average different studies together willy-nilly and you run the risk that sometimes you may average out precisely the those variations that provide the clues we are looking for as to how human health really works.

Now you may think that this column is all about trashing meta-analysis, and, to be honest, it started out that way. But then I had a discussion with David Altshuler, a human geneticist at Harvard Medical School and the Broad Institute at MIT, that made me rethink what was about to become a blanket condemnation. He pointed out to me another goal of meta-analysis in current human genetic studies. The key issues, as he put it, are first, the different statistical thresholds needed in discovery science with a low prior (as compared with hypothesis testing in a well-established field), and second, in human genetics the ability to use the rest of the genome as independent tests to assess the matching of cases and controls in human genetics.

Here's how he explained the first issue: in genetic mapping with the goal of initially determining which genes might actually play a role in human disease, there is a very low a priori probability of any variant being associated with any risk (on the order of one in a million), and - that is, with an initial goal of determining which genes might actually play a role in human disease risk - one can't say that a p value of 0.01 or even 0.0001 is 'absolutely significant'. He's right: most findings of that magnitude turn out to be entirely irreproducible, and are likely to be false positives. But finding consistent results by meta-analysis increases evidence that the null hypothesis is wrong - and confidence that there is a relationship between the variant and risk. Without that confidence, he asserts, the field was awash with wishful thinking about lots of candidate genes that reductionist biologists had found in cells and in animal models, and wanted to believe were 'genetically validated in people' - but that turned out to be noise.

If you look into it, you will find that there is a long history in genetic mapping of setting the right threshold based on the number of tests. In linkage mapping, the LOD score that indicated linkage between a gene variant and a trait was 3.0 -not p < 0.05 (LOD stands for logarithm to the base 10 of odds; a LOD score of 3.0 means the likelihood of observing the given pedigree if two loci are not linked is less than 1 in 1000). By contrast, in genome-wide human genetic studies, a p of less than or equal to 0.0000001 is typically required for proof of association of a gene with a trait. And while biologists often like to say that for 'candidate genes' like the one I mentioned above it is more like p < 0.05, that threshold has a history of not always supporting reproducible discoveries. It is in gathering enough data to really get the confidence level to where it needs to be that meta-analysis has proven proved valuable in many cases.

The second issue is the quality of the data that goes into meta-analysis, and the ability to compare and align it. In most studies, Altshuler agrees with me that you can't know if you are washing out good data with bad. But he makes a strong case, with which I am forced to agree, that in the current wave of genome-wide association studies, the studies often use the same phenotype definition, or the same microarray protocols, and so the data may well be comparable (clearly, it is important to see whether that is the case, if you want to evaluate the meta-analysis critically). When done properly, information from the rest of the genome can be used to assess the properties of the data, matching of cases and controls, and so on, which, as he puts it, "can result in valid combination of lots of good data, rather than sloppy mashing up of lots of bad data". Finally, sometimes you actually may want to test the hypothesis across ethnicity or age or other variables. In those instances, meta-analysis allows you to put the data together in a valid way - a way that is probably better than just reading the papers and trying to compare them.

Dr Altshuler went on to make a very valuable point, which I think belongs in this column: he feels there that is currently a big and unfortunate divide between cell and molecular biologists and people using human genetics to find disease genes. The tone of the first part of my column just reinforced his concern, I'm sorry to say. For disease research, it's certainly true that knowing up front that a gene influences the disease in humans is invaluable, and I think he's right that meta-analysis can be a powerful tool for getting that correct. (As he asked me: "Would you want to do functional work on a gene that turns out to be a false positive?")

A final point: meta-analysis is currently being used in two ways in human genetics, and I may have given a false impression that there is only one. One method is when there is a pre-existing hypothesis that needs to be tested. A good example comes from Altshuler's own work (Altshuler D, et al.: Nat Genet 2000, 26:76-80). The data the authors had collected gave a positive result, but others had claimed the opposite. The studies were comparable enough that meta-analysis was able to show that the data were actually consistent and reinforced one another. In such cases meta-analysis serves as a reality check, and helps avoid possible bias in the selection of data that might support one hypothesis or another.

But careful meta-analysis can also in some cases be hypothesis generating, because enough studies might, as I mentioned above, allow previously undetected signals to rise above the noise. These can then be tested experimentally, and of course, need to be.

Dr Altshuler closed our discussion with a nice comment: "Meta-analysis," he pointed out, "is just a method. Garbage in, garbage out. But in genetic mapping of common complex diseases, where it is clear there are many different variants contributing, and where studies are expensive, combining data to learn the most is well justified and valid."

It is true that it's often the original studies that matter, that data need to be examined carefully, and that a study ideally must be accepted or rejected on its own merits. People are fond of saying that the devil is in the details. But God is in the details too. In the age of genomics, the details are ultimately what matter: the complex interplay of individual gene and genetic background, diet, environment, perhaps even state of mind, is what determines whether we are prone to this disease or that, react poorly or well to this drug or that, age well or badly. Meta-analysis can hide those details, but used properly, it can also be revealing. I guess you could say that writing this column has led to a meta-morphosis in the way I think about this subject, and that I have to back away from my meta-phor about making money with other people's money. In the right hands, meta-analysis can be a valuable tool, which is a pity, because it's so much more fun to write a column that completely trashes something. Meta-physically speaking, of course.

Published: 03 November 2008

The wisdom, and madness, of crowds

Genome Biology 2008, 9:112

In reading the history of nations, we find that, like individuals, they have their whims and their peculiarities; their seasons of excitement and recklessness, when they care not what they do. We find that whole communities suddenly fix their minds upon one object, and go mad in its pursuit; that millions of people become simultaneously impressed with one delusion, and run after it, till their attention is caught by some new folly more captivating than the first...Money, again, has often been a cause of the delusion of multitudes. Sober nations have all at once become desperate gamblers, and risked almost their existence upon the turn of a piece of paper... Men, it has been well said, think in herds; it will be seen that they go mad in herds, while they only recover their senses slowly, and one by one. Charles Mackay, L.L.D.

This quotation comes from a book first published in 1841. In the 167 years since, it has never been out of print. Its author was a Scottish poet, journalist and songwriter, yet many have called it, after The Wealth of Nations by Adam Smith (a fellow Scot - there really was something to the Enlightenment, you know), the second greatest economics treatise ever written.

The book is Extraordinary Popular Delusions and the Madness of Crowds, by Charles Mackay. The quotation is taken from its preface. If it sounds amazingly relevant to our current economic crisis, it's because it is. It may be the most relevant book you will ever read.

Though published over time in two volumes, it is the first volume, and in particular, the first three chapters, on what Mackay called money mania and what we call economic bubbles, that have given the book, which I shall refer to as EPD&MOC for convenience, its well-deserved reputation. The economist, and popular writer about personal finance, Andrew Tobias, who contributed the Forward to the edition I own, had this to say about it: "Once upon a time, there was an emperor with no clothes. For the longest time no one noticed. As you will read in this marvelous book, there have been many naked emperors since. There will doubtless be many more... As with any true classic, once it is read it is hard to imagine not having known of it - and there is the compulsion to recommend it to others."

My favorite chapter is the third, on tulipomania. For those unfamiliar with this psychological illness, which once affected the entire country of Holland in the mid-seventeenth century, and spread to some people in other nations of Europe as well, the term refers to a maniacal desire to possess rare tulip bulbs. Fervor for collecting, and trading, these essentially worthless botanical objects reached such a peak, that at around 1635, the average price of a tulip bulb exceeded its weight in gold, and a single rare bulb might easily trade for more than $50,000 in today's money. "A trader at Harlaem," writes Mackay, "was known to pay one-half of his fortune for a single root - not with the design of selling it again at a profit, but to keep in his own conservatory for the admiration of his acquaintance... In 1634, the rage among the Dutch to possess them was so great that the ordinary industry of the country was neglected, and the population, even to its lowest dregs, embarked in the tulip trade. As the mania increased, prices augmented, until, in the year 1635, many persons were known to invest a fortune of 100,000 florins in the purchase of forty roots."

My favorite story from this bubble is so well-told by Mackay that I will quote it rather than summarizing it:

"People who had been absent from Holland, and whose chance it was to return when this folly was at its maximum, were sometimes led into awkward dilemmas by their ignorance... A wealthy merchant, who prided himself not a little on his rare tulips, received upon one occasion a very valuable consignment of merchandise from the Levant.

Intelligence of its arrival was brought him by a sailor, who presented himself for that purpose at the counting-house, among bales of goods of every description. The merchant, to reward him for his news, munificently made him a present of a fine red herring for his breakfast. The sailor had, it appears, a great partiality for onions, and seeing a bulb very like an onion lying upon the counter of this liberal trader, and thinking it, no doubt, very much out of its place among silks and velvets, he slyly seized an opportunity and slipped it into his pocket, as a relish for his herring. He got clear off with his prize, and proceeded to the quay to eat his breakfast. Hardly was his back turned when the merchant missed his valuable Semper Augustus, worth three thousand florins, or about 280 pounds sterling. The whole establishment was instantly in an uproar; search was everywhere made for the precious root, but it was not to be found. Great was the merchant's distress of mind. The search was renewed, but again without success. At last some one thought of the sailor. The unhappy merchant sprang into the street at the bare suggestion. His alarmed household followed him. The sailor (a simple soul!) had not thought of concealment. He was found quietly sitting on a coil of ropes, masticating the last morsel of his "onion". Little did he dream that he had been eating a breakfast whose cost might have regaled a whole ship's crew for a twelve months; or, as the plundered merchant himself expressed it, 'might have sumptuously feasted the Prince of Orange and the whole court of the Stadtholder.'

By 1636, special markets for trading in tulip bulbs were established on the floor of the Stock Exchanges in Amsterdam and other towns. Many people grew suddenly rich, and others, not wishing to be left out, began speculating madly themselves. If this all sounds like the 'dotcom' bubble in the stock market at the end of the 1990s, or the subprime mortgage credit bubble of the past few years, it's because the same psychological factors that Mackay first dissected so brilliantly in 1841, and that were at work in Holland in the 1630s, were behind those follies as well: greed, stupidity, the herd instinct, and a reckless belief that the old rules of economics were somehow repealed in this instance.

Of course tulipomania couldn't last, and it didn't. Mackay again: "At last, however, the more prudent began to see that this folly could not last for ever... It was seen that somebody must lose fearfully in the end. As this conviction spread, prices fell, and never rose again. Confidence was destroyed, and a universal panic seized upon the dealers. A had agreed to purchase ten Sempers Augustines from B, at four thousand florins each, at six weeks after the signing of the contract. B was ready with the flowers at the appointed time; but the price had fallen to three or four hundred florins, and A refused either to pay the difference or receive the tulips. Defaulters were announced day after day in all the towns of Holland. Hundreds who, a few months previously, had begun to doubt that there was such a thing as poverty in the land, suddenly found themselves the possessors of a few bulbs, which nobody would buy, even though they offered them at one quarter of the sums they had paid for them. Many who, for a brief season, had emerged from the humbler walks of life, were cast back into their original obscurity. Substantial merchants were reduced almost to beggary, and many a representative of a noble line saw the fortunes of his house ruined beyond redemption." Substitute 'mortgage contracts' or 'derivatives' for 'bulbs' in this description, and you have a perfect accounting of the events of the past few months of 2008. No wonder the book has never been out of print.

Mackay wrote to warn people of the foolishness of the collective mind. His warning seems to me to be particularly relevant now, and not solely for economic reasons. The central thesis of EPD&MOC is one we should at least consider as we examine a new movement that has swept the online publishing world and is beginning to creep into genomics: the collective encyclopedia.

Everybody is probably familiar with the first, and best-known, manifestation of this phenomenon: Wikipedia. The name is a portmanteau of the words wiki (a technology for creating collaborative websites) and encyclopedia. Wikipedia is a multilingual encyclopedia project supported by the nonprofit Wikimedia Foundation. Wikipedia's 10 million articles have been written collaboratively by volunteers around the world, and almost all of its articles can be edited by anyone who can access the Wikipedia website. Launched in January 2001 by Jimmy Wales and Larry Sanger, it is currently the largest and most popular general reference work on the Internet.

The idea of a free encyclopedia encompassing all subjects, written not by a panel of chosen experts but by teams of people interested in the subjects and subsequently updated and amended by anybody has been wildly popular but has also attracted much criticism. Obviously, articles can, at least initially, have severe biases and inconsistencies. The question is whether in the end they get to the truth: does consensus produce something that is not just readable - most of the articles are pretty good in that regard - but reliable?

It turns out I have an entry in Wikipedia (don't ask me who contributed it; I certainly didn't, and I haven't edited it either). If you do a Google search for my name, the Wikipedia article will be the second entry in the resulting list. Here's an excerpt: "Gregory A Petsko is an American biochemist and member of the National Academy of Sciences. He is currently the Gyula and Katica Tauber Professor of Biochemistry & Chemistry at Brandeis University... Petsko is co-author with Dagmar Ringe of Protein Structure and Function. He is also the author of a monthly column in Genome Biology modeled after an amusing column in Current Biology penned by Sydney Brenner. Petsko is best known for using X-ray crystallography to solve important problems in protein function, including protein dynamics as a function of temperature and problems in mechanistic enzymology." All perfectly accurate, though Sydney may blanch at the thought that he's responsible for this.

In my experience, Wikipedia is often inaccurate when it comes to scientific facts, variable but occasionally quite good when it comes to topics in history or politics, and absolutely first-rate on any matter of popular culture. I suspect this reflects the interest of the Internet-savvy population as a whole, though I haven't done any surveys to find out. I do know that every teacher warns his or her students not to trust it as an unconfirmed source of facts for term papers or theses; it would appear that the wisdom of crowds is not trustworthy without independent checking.

What does this have to do with genomics? Well, one of the most highly accessed articles in recent issues of Genome Biology was a piece by Barend Mons et al. entitled 'Calling on a million minds for community annotation in WikiProteins' (Mons et al. Genome Biol 2008, :R89; http://genomebiology.com/2008/9/5/R89. WikiProteins, which is most conveniently accessed by entering keywords at the WikiProfessional portal http://www.wikiprofessional.org/portal/, has pages for more than a million biomedical concepts, derived from authorities such as the Unified Medical Language System (UMLS), UniProtKB/Swiss-Prot, IntAct and the Gene Ontology (GO). By adding information to concepts in WikiProteins, scientists are invited to "expand an evolving knowledge base with facts, connections to other concepts, and reference information." In other words, the collective mind, scientifically speaking, is being called upon to annotate gene functions, connections to diseases, and other information relevant to functional and biomedical genomics. Ideally, WikiProteins, which is still in the beta-testing stage, should contain both reliable information from experts and potential connections among data that haven't previously been noticed, or explored.

Here's an example, called up by me by searching for 'triose-phosphate isomerase', the name of an enzyme. I got a list of triosephosphate isomerases from many different organisms. Clicking on the one from Escherichia coli gave me the following functional information: "isomerase activity Definition: Catalysis of the geometric or structural changes within one molecule. Isomerase is the systematic name for any enzyme of EC class 5. [ISBN:0198506732 "Oxford Dictionary of Biochemistry and Molecular Biology"]." Perfectly accurate, though perhaps not ideally helpful. Doing a similar search for 'DJ-1', a gene involved in Parkinson's disease, produced (after leaving out the hyphen): "Acts as a positive regulator of androgen receptor-dependent transcription. May function as a redox-sensitive chaperone and as a sensor for oxidative stress. Prevents aggregation of SNCA. Protects neurons against oxidative stress and cell death.

Plays a role in fertilization. Has no proteolytic activity. Has cell-growth promoting activity and transforming activity. Interacts with: with DAXX (accepted by Swiss-Prot); with AR (accepted by Swiss-Prot)." Again, as far as I can tell, accurate, and probably more helpful. There are a bunch of links as well, only some of which I've explored, and the site provides the opportunity not only to edit any entry but to establish other links.

It is fairly well accepted that the functional and other annotations in the commonly used genome and protein sequence databases are at best accurate only about half the time (my guess would be closer to 25%), so there's real hope that this community-based project might improve that appalling figure. (It certainly would seem to have nowhere to go but up.) It's worth watching to see how WikiProteins does, and I hope genome biologists will try it out, and contribute to it. As an experiment in the wisdom of crowds, it's fascinating. But if you read Mackay (and I hope you all will; it just may save you a lot of money some day), you will know to take what's in WikiProteins, or WikiAnything, with a good dose of caution. Remember, 'the community' once thought tulip bulbs were worth a fortune.

Published: 01 December 2008

A seat at the table

Genome Biology 2008, 9:113

I should start with a disclaimer: I was a strong supporter of Barack Obama during the recent US presidential campaign, and I remain a strong supporter of the President-elect today. That may open me to changes of bias as far as this particular column is concerned, because I'm going to be lauding one of his recent decisions. But another disclaimer I probably should include is that I am a life scientist, and that admission may reveal additional prejudice, because what I am going to say will be self-serving in that it is meant to promote the life sciences. However, I think my argument will stand up to objective scrutiny. See if you agree.

I learned in mid-December that President-elect Obama would choose, for the dual position of presidential science advisor and head of the Office of Science and Technology Policy (OSTP), John Holdren, a Harvard physicist and outspoken critic of the Bush Administration's science policies. Holdren's primary appointment is not in the physics department - he is the Teresa and John Heinz Professor of Environmental Policy at the Kennedy School of Government at Harvard University, and also Professor of Environmental Science and Public Policy in the Department of Earth and Planetary Sciences. He earned a bachelor's degree in physics from MIT in 1965, and worked as a consultant on re-entry vehicles in the 1960s at Lockheed Martin before receiving a PhD in plasma physics at Stanford University in 1970. Since then, his work has focused largely on science policy rather than on fundamental physics, with emphasis on global environmental change, energy technologies and policies, nuclear proliferation, and science and technology policy in general. He is a prominent and vigorous advocate for strong response to the global climate crisis. Holdren is also director of the Woods Hole Research Center in Woods Hole, Massachusetts.

In many respects, this looked like a fine choice. Holdren has a very distinguished record. Before moving to Harvard in 1996, he was Professor of Energy and Resources at Berkeley for over 20 years. He was President of the American Association for the Advancement of Science in 2006. He is the author of over 300 articles and papers, mostly on policy issues, and has co-authored or co-edited 20 books and book-length reports. He is a member of the National Academy of Sciences, the National Academy of Engineering, and was a member of President Bill Clinton's science advisory team from 1994 to 2001. When the Pugwash Conferences on Science and World Affairs won the Nobel Peace Prize in 1995, he delivered the acceptance speech in Stockholm. He's spent much of his career trying to save the planet. Sort of a scientist's Al Gore, if you will. It's likely that he has more combined expertise on climate science and clean energy technology than anyone, with the possible exception of Obama's nominee for Secretary of Energy, Nobel Laureate Steve Chu. But when I heard of his likely appointment, I was disappointed.

I wasn't disappointed because I have anything against Holdren - he's certainly highly qualified and I love his positions on issues like climate change. He'll probably do a terrific job. I was disappointed because he's a physicist. No disrespect to Holdren, but I am wary of physicists as presidential science advisors. Nearly all have been so. It's partly a legacy from the days when they knew how to make nuclear weapons, and partly, I think, because when most non-scientists think about scientists, they tend to think of physicists (call it the Einstein Effect). Most of the physicists I know, and certainly all recent presidential science advisors, have little knowledge of or feel for the life sciences, believe physics to be superior to all other sciences (with the possible exception of higher mathematics), and tend to think in terms of big science programs as opposed to individual investigator-initiated research. Certainly physics is important in issues such as energy policy and response to climate change, and I suspected that the Holdren appointment was meant to emphasize the significance the Obama Administration attaches to those issues, but we already have someone, of cabinet rank with direct access to the President, with exactly the same qualifications and mission as Holdren: a strong physics background and a track record of vigorous advocacy for alternative energy. I refer to the aforementioned Steve Chu, the nominee for Energy Secretary. I didn't understand why we needed to duplicate that expertise and focus, when the Presidential Science Advisor seemed to me the best opportunity to bring someone knowledgeable about the life sciences into the President's inner circle. And if we ever needed people in government to listen to the voices of the life scientists, we need them now.

Figure 1

The rapidly aging world. (a) The world today, showing in blue areas where greater than 20% of the population is over the age of 65. (b) The world in 2050, showing the huge increase in areas where the population will be over 65 years old.

I believe it's essential that there be people in Washington who can explain to President Obama, for example, the science that must be done to combat a coming global crisis that is comparable in its effects to the climate crisis: the rapidly aging population. Figure 1 shows what I mean. On these maps I have colored in blue every country in which more than 20% of the population is over 65 years of age. The map on the left is the world we live in. The map on the right, where virtually every country is blue, is the world our children will live in. In most of the developed world, by 2050 at least a quarter of the people will be older than 65, and in some countries that figure will exceed 40%. In the US alone, there are more than 10 million people over the age of 80 today; by 2050 there will be more than 30 million, and half of them will have some degree of dementia. Another 3 million, at least, will have Parkinson's disease. Millions more will suffer from stroke. The incidence of all three of these disorders rises exponentially after age 65. The total cost of age-related neurological diseases in the US is currently more than $300 billion a year. In 40 years the annual cost will exceed a trillion dollars. Yet the federal expenditure on AIDS research in 2008 is more than four times the federal expenditure on Alzheimer's disease research, despite the fact that there are ten times more new Alzheimer's cases per year than there are AIDS cases. (This is not meant to imply that we're spending too much on AIDS research; my point is that we're not spending nearly enough on research into age-related neurological diseases.) Heart disease and cancer rates, too, are likely to increase in coming years, because the vast majority of new cases of both occur in people over age 65.

Aging of the population is a time-bomb that is ticking in most of the world - an impending medical crisis of magnitude similar to global warming. Health care reform, as important as it is, will not solve this problem. Alternative energy, as important as it is, will not solve it. The only thing that will is biomedical research, both basic and applied.

I'm emphasizing the coming biomedical crisis because it is the nature of people, and politicians, to focus on crises, but there are many other reasons why the life sciences deserve a seat at the table of power. The post-genomic revolution in our understanding of biology has the power to transform all of our lives. One of the answers to the climate crisis, and to the problem of energy independence, is biofuels. Another answer, which could wean us away from petroleum-based plastics, is biomaterials. Basic biomedical research is essential to arm our pharmaceutical and biotechnology companies for the fight against weapons of biological warfare, as well as the increasing threat from emerging infectious diseases. The life sciences have central roles to play in addressing the collapse of the environment, the disappearance of species, and our efforts to combat developmental disorders, to name but a few areas of importance. But when I started to write this column, I was afraid that there would be no advocate for biomedical research at that table where policy makers sit down to decide the nation's priorities.

Then something (well, actually, someone) told me to wait until after the President-elect's next radio address. I just finished listening to it, and I urge you to read the transcript (you can find it, and a video, at http://change.gov/newsroom/entry/the_search_for_knowledge_truth_and_a_ greater_understanding_of_the_world_aro/); it's so unlike anything we've heard from recent US Presidents as to be almost revolutionary. Here are just two excerpts:

"Whether it's the science to slow global warming; the technology to protect our troops and confront bioterror and weapons of mass destruction; the research to find life-saving cures; or the innovations to remake our industries and create twenty-first century jobs - today, more than ever before, science holds the key to our survival as a planet and our security and prosperity as a nation. It is time we once again put science at the top of our agenda and worked to restore America's place as the world leader in science and technology."

"...promoting science isn't just about providing resources - it's about protecting free and open inquiry. It's about ensuring that facts and evidence are never twisted or obscured by politics or ideology. It's about listening to what our scientists have to say, even when it's inconvenient - especially when it's inconvenient. Because the highest purpose of science is the search for knowledge, truth and a greater understanding of the world around us. That will be my goal as President of the United States..."

President-elect Obama then went on to name the key members of his science and technology team. One, as I already expected, was John Holdren as Assistant to the President for Science and Technology and Director of the White House Office of Science and Technology Policy. He would also, as is customary, chair the President's Council of Advisors on Science and Technology - or PCAST, a board that advises the President on all matters pertaining to science and technology. (Under George Bush, PCAST had consisted almost entirely of CEOs of big corporations. It had almost no scientific expertise at all.) But then came the surprise: PCAST would have two additional co-chairs, and both of them would be distinguished life scientists.

One is Harold Varmus, 1989 Nobel Laureate in Medicine or Physiology for his work on cancer genes and former Director of the National Institutes of Health during the Clinton Administration - and during the completion of the Human Genome Project. Arguably the most effective NIH Director in decades, Varmus is currently President of the Memorial Sloan-Kettering Cancer Center in New York City. The other is Eric Lander, Professor of Biology at MIT, member of the Whitehead Institute, the Founding Director of the Broad Institute at MIT and Harvard, and one of the driving forces behind the mapping and sequencing of the human genome.

Varmus probably needs no introduction from me, but some of my readers may be a little less familiar with Lander. He is one of those rare individuals who might just be as smart as he's supposed to be. A mathematical prodigy, he did his doctoral work at Oxford University as a Rhodes Scholar. He then taught economics at Harvard Business School before, looking for new worlds to conquer, he did a postdoc in genetics with David Botstein at MIT, joining the Biology faculty there afterwards. He is - get ready for it - a genome biologist, the first to have the ear of a President. Now you might think, or even fear, that a genome biologist, especially one who has built a mighty institute for large-scale genomics, would not be an ideal friend for individual investigator-initiated research, but let me set your mind at ease. The 'big' science that Eric Lander has pioneered has always been in the service of hypothesis-driven 'small' science, and his track record as Director of the Broad Institute has been one of encouraging young investigators, providing tools and information to the broader biological community, and promoting basic as well as applied research.

Two better appointments could scarcely be imagined. Both men are vigorous advocates for basic biomedical science, both men know how the industry-academic partnership is supposed to work, both men understand the way the age of genomics is transforming the life sciences, and both men are not so far removed form running research laboratories of their own that they will not appreciate the problems of the average scientist.

So for the next few years, at least, when policy makers in the Obama Administration sit around that table to plan the future of the country, the life sciences will have a seat alongside the physical sciences. And a President who promises to listen to the voice of science will be hearing the full scope of that voice at last.

Published: 31 December 2008

Life is a Ponzi scheme

Genome Biology 2009, 10:101

Unless you've spent the last month on a spacecraft returning from Mars, you've probably heard of Bernard Madoff, the American financier who stands accused of perpetrating what may be the greatest investment fraud in history. Estimates of the amount of money lost by investors in the investment fund managed by Madoff, a former chairman of the NASDAQ Stock Market, range up to US$50 billion. One of Madoff's biggest investors, René-Thierry Magon de la Villehuchet, committed suicide on 23 December 2008 following the disclosure of the scheme. Villehuchet is thought to have lost as much as $1.4 billion in Madoff's fund. A number of charitable foundations, several of which provide funding for disease-related biomedical research, lost huge percentages of their endowments. Several universities have been significantly harmed as well, since either some of their own money or the savings of some of their biggest regular donors turned out to have been invested with Madoff.

The particular type of con game that Bernard Madoff practiced is surprisingly simple for someone whose web of deceit appears to have been so tangled. It's called a Ponzi scheme. The fraud takes its name from Charles Ponzi, who was one of the greatest swindlers in history. Born Carlo Ponzi in 1882 in Parma, Italy, he emigrated to the United States in 1903. After working at a series of low-paying jobs for several years, he moved to Montreal in 1907 and became an assistant in a bank that had been set up to serve the needs of Italian immigrants to Canada. The bank eventually failed because of bad real-estate loans - sounds familiar? - but Ponzi stayed on in Canada where eventually he was jailed for three years for check forgery. On his release in 1911 he joined a scheme to smuggle illegal aliens across the border to the United States, was caught, and served a further two years in prison, this time in Atlanta, Georgia. There he met Charles W Morse, a financier who had been convicted of violating federal banking laws. Morse became a sort of guru to Ponzi, who began to see the possibilities in white-collar crime. After his release, Ponzi made his way to Boston, Massachusetts, where he set up the investment scheme that was to make him famous - and notorious.

To call his pitch to prospective pigeons attractive would be to understate the case. He promised clients a 50% profit within 45 days, or 100% profit within 90 days, by buying discounted postal reply coupons in other countries and redeeming them at face value in the United States, a form of what we currently call 'arbitrage' (the practice of taking advantage of a difference in price between two or more markets). A simple, and classic, example of arbitrage would be to collect discarded soda cans in Massachusetts, where they are sold with a deposit of $0.05 each, and truck them to Michigan, where the returned deposit is $0.10 per can. (For those of you thinking of funding your research this way, forget it: the cost of collecting and transporting the cans eliminates the profit. However, about $10 million worth of empty bottles and cans do get smuggled into Michigan from neighboring Ohio and Indiana, which do not require a deposit on beverage containers. Returning those out-of-state bottles and cans in Michigan does make a small profit. Michigan lawmakers have proposed requiring that beverage manufacturers put a code on all bottles and cans that are sold in Michigan, and that automated bottle return machines be programmed to read the code so they accept only containers originally sold in Michigan.)

Ponzi wasn't arbitraging soda cans, though. The commodity he claimed to be buying and selling was international postal reply coupons. A postal reply coupon is a piece of paper included in a message sent by someone in one country to a correspondent in another country, so the recipient can use the coupon to pay the postage for a reply - the modern equivalent, within one country, is the stamped, self-addressed envelope. What made them attractive for arbitrage is that the coupons were priced at the cost of postage in the country of purchase, but were exchanged for stamps to cover the cost of postage in the country where redeemed; if these values were different, there was a potential profit. Inflation after the First World War had reduced the cost of postage in Italy as expressed in US dollars, so an international postal reply coupon bought in Rome could, in theory, be exchanged in Boston for stamps with a much higher dollar value. As explained by Ponzi, investors would give him money; he would send that money abroad, where his agents would purchase reply coupons; the agents would send the coupons to the US, where Ponzi would redeem them for stamps of a higher value; and he would then sell the stamps. Ponzi claimed that the net profit on these perfectly legal transactions, after expenses and exchange rates, was in excess of 400%.

In the first two months of 1920, some people invested and were paid large returns (100% profit in a few weeks). Word spread, and investment came in at an ever-increasing rate. Ponzi hired agents to drum up new business and paid them generous commissions for every dollar they brought in. At that time all investors were being paid impressive rates, which encouraged others to invest. By May 1920, Ponzi had made $420,000 (over $4.5 million in 2008 dollars). By July 1920, he had made millions. People were mortgaging their homes and investing their life savings in his company. Most did not take their profits out, but reinvested them, believing that the enormous returns would continue forever.

What none of them knew was that Charles Ponzi wasn't buying and selling postal reply coupons. In fact, he wasn't arbitraging anything. What he was actually doing was running what is called a pyramid scheme: as long as money kept flowing in at a greater rate than people were withdrawing it, existing investors (the top of the pyramid) could be paid with a portion of the money brought in from the larger horde of new investors (the pyramid bottom). By 24 July 1920, the pyramid scheme was returning for Ponzi's firm, The Securities Exchange Company, the astounding sum of $250,000 a day.

Well, my father, who was trained as an economist, always said that if something seems too good to be true, it probably isn't either good or true. Clarence Barron, the financial analyst who founded the financial magazine Barron's, started to examine Ponzi's outrageous returns. Barron first noted that Ponzi hadn't invested his own money with his own company - always a red flag. Then he calculated that, to cover the investments made with the Securities Exchange Company, about 160,000,000 postal reply coupons would have to be in circulation. However, only about 27,000 coupons were actually circulating worldwide. He checked with the US Post Office, who confirmed that postal reply coupons were not being bought or redeemed in large quantities, either at home or abroad. Finally, Barron crunched the numbers, and found the same thing for arbitraging postal reply coupons that you would find if you tried to redeem Massachusetts soda cans in Michigan: the gross profit margin in percent on each item was huge, but the actual return per item was very small, and the overhead required to handle the purchase and redemption of the necessarily huge number of items, which were sold individually, would have far exceeded the gross profit.

The Boston Post published the results of Barron's investigation, and ran a headline on 2 August 1920, declaring Ponzi hopelessly insolvent. On 10 August federal agents raided the Securities Exchange Company and shut it down. Of course, they found no large stock of postal reply coupons. On 12 August 1920, Ponzi was arrested. Seventeen thousand people had invested millions, maybe tens of millions, with him over a period of less than nine months. Most lost everything.

After serving years in prison on both federal and state charges, Charles Ponzi was deported to Italy in 1934. He died a pauper in a charity hospital in Rio de Janeiro on 18 January 1949.

It now appears that Bernard Madoff was running a similar pyramid scheme, on a colossal scale. He was cleverer about it, of course, since he had Ponzi's mistakes to learn from. Rather than offer suspiciously high returns to all comers, Madoff instead offered modest, but steady returns (about 10-15% per year). Furthermore, Madoff didn't solicit business; instead, he deliberately made it difficult to invest. By catering to an exclusive clientele, one that had to be both super-rich and selected by him, he drove up the demand for his services through their scarcity. The scheme also differed from Ponzi's in that a number of other investment funds invested much or all of their holdings in Madoff's fund, which meant that many individual investors, who believed they were diversified, unknowingly had all their eggs in the Madoff basket.

There were a number of red flags that should have alerted both financial analysts and government regulators to the probably fraudulent nature of Madoff's business (to be fair, a small number, such as Boston financial specialist Harry Markopolos, did sound warnings about Madoff for years, but were ignored). For one, almost identical returns were produced in both up and down markets - an impossibility with honest trading. Another red flag is that the investment method was stated to be a proprietary secret.

The slow pace and 'insider' marketing enabled the scheme to survive for an unusually long time and also to grow far larger than would be expected of a common Ponzi scheme. What caused it to collapse? The general market downturn of 2008 caused new investments to decrease and forced a larger than usual number of existing investors to cash out their positions. That's what usually brings down a pyramid scheme: when the top of the pyramid demands more money back than the bottom is putting in ('illiquidity' in finance-speak).

Now, the reason you're reading about this here, is that I just realized that life itself is basically a gigantic Ponzi scheme, and the pyramid is dangerously close to collapsing. In the developed world, we have evolved a society in which a relatively small number of old people have many of their needs cared for through the financial contributions of a larger number of much younger people. And that made sense, because for over 12,000 years the age distribution of the human population was, in fact, in the shape of a pyramid, with a huge base of young children rising to a smaller number of teenagers and a still smaller number of young adults, and so on up to a tiny tip of the elderly. But sometime in the 1950s, as the birthrate declined and life expectancy continued to increase, the pyramid started to be shaped more like a column. Within the next 40 years it will become one, and then it will slowly invert.

Worldwide, the average life expectancy at birth in 1955 was just 48 years; in 1995 it was 65 years; in 2025 it will reach 73 years. By the year 2025, it is expected that no country on Earth will have a life expectancy of less than 50 years. That has never happened before in human history. Globally, the population of children under 5 will grow by just 0.25% annually between 1995-2025, while the population over 65 years will grow by 2.6%. The average number of babies per woman of child-bearing age was 5.0 in 1955, falling to 2.9 in 1995; it will reach 2.3 in 2025. While only 3 countries were below the population replacement level of 2.1 babies in 1955, there will be 102 such countries by 2025. The World Health Organization has estimated that the proportion of older people requiring support from adults of working age will increase globally from 10.5% in 1955 and 12.3% in 1995 to 17.2% in 2025. In 1955, there were 12 people aged over 65 for every 100 aged under 20. By 1995, the old/young ratio was 16/100; by 2025 it will be 31/100. By the end of the century it will approach unity. Eventually - and eventually isn't that far off - we will live in world where a smaller number of young people will be asked to support a larger number of the very old. No Ponzi scheme can survive that.

Consider healthcare. Total healthcare costs in the United States now exceed $1 trillion, 14% of the gross domestic product. Of this total, a disproportionate share is spent on the care of elderly patients shortly before their deaths. Most elderly people have the bulk of their medical care paid for by Medicare, a state-supported program. Workers pay into it during their years of peak employment, and as retirees they then draw down from it as they age. However, the 5% of Medicare recipients 65 years of age and older who die in any one year account for around 30% of all costs of the Medicare program. Seventy-seven percent of the Medicare decedents' total healthcare expenditures occur in their last year of life, a staggering 52% in the last 2 months, and 40% in the last month. We are basically spending a fortune as a society for healthcare for very old, very sick people that does not increase the lifespan of the individual by more than 30 days, if at all.

We could, of course, handle this cost imbalance by draconian decisions about life and death, but that is probably a political (and maybe ethical) non-starter (although don't be surprised if it doesn't become part of the conversation if we don't find other ways to control costs). And the population pyramid would change dramatically if we had a global thermonuclear war or a planet-wide plague, but we probably won't be so lucky. And science may actually be on its way to making the problem worse.

There are a number of genomics-driven research programs, some based on model organisms but others involving mammals right up to people, that aim to increase the human lifespan. If successful, they would spell the rapid and certain ruin of the Ponzi-like social contract between old and young, by guaranteeing a completely inverted population pyramid. I believe that it is pointless to increase the human lifespan unless the quality of life for the elderly is also increased. Specifically, this means that we must greatly improve the health of our oldest citizens unless we wish to see our economy collapse, soon, from the burden of caring for them.

That's going to be a tall order, because age is a major risk factor for just about everything bad that can happen to a human being. Incidence of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases rises exponentially with age after 65, until people over 80 have almost one chance in two of suffering from one of them. Half of all cancer deaths occur in people over 75 years of age. The greatest risk factor for prostate cancer is age: more than 75% of all prostate cancers are diagnosed in men over 65. Over 80% of deaths from circulatory disease occur in people over 65. Stroke, the third leading cause of death in the United States (after heart disease and all forms of cancer), is 30 times more likely in men over 90 than it is in those aged 55-59. When you add in bone density loss, arthritis, and other age-related disorders, it's hard not to agree with the Rolling Stones' lyric from the song Mother's Little Helper: "What a drag it is, getting old."

Controlling healthcare costs and making sure that everyone can afford basic care, though essential, is not going to be enough in the long run - not with that demographic time-bomb ticking away in the background. Our only hope as a species lies with biomedical research. And that research needs to be aimed at prevention, not just treatment, because it's always more expensive to treat an illness than it is to prevent it. Oddly, we tend to be more easily alarmed by the relatively improbable prospect of epidemics such as avian flu than we are by a certain likelihood that most of us will, if we live long enough, fall prey to devastating chronic ailments. As a result, we invest much more money in planning for and warding off the former than we do in dealing with the latter. This mindset has to change.

The line of succession from Charles Ponzi to Bernard Madoff is more than a chronicle of cupidity. It's a microcosm of the way we've organized our society. For thousands of years it made sense to assume that there would always be more young people to pay for the care of older ones. But Ponzi and Madoff failed because they forgot that no pyramid lasts forever. We had better remember that.

Published: 27 January 2009

Many happy returns

Genome Biology 2009, 10:102

No one knew it at the time, of course, but 12 February 1809 was a red-letter day for the human race. On that day, thousands of miles apart, were born two of the greatest men in history.

Their lives were, in most respects, quite different. The American was born poor and endured many failures; the Englishman was the son of a wealthy doctor and never had to work for a living. The Englishman lived out his biblical threescore years and ten; the American was murdered before he reached 60. The American was a man of faith and remained so in spite of a family tragedy; the Englishman lost his faith because of a similar family tragedy. The Englishman hated politics; the American reveled in it.

But they had more in common than is sometimes recognized. Both men valued reason over ideology. Both men were not afraid to take unpopular stands when they thought they were right. Both men were widely reviled, and still are by some people. Both men were gentle of manner but courageous and tough. Both men changed the world. And both men are famous as much for what they wrote as for what they did: their words had the power to transform the way people thought. The American was Abraham Lincoln, 16th president of the United States. The Englishman was Charles Darwin, co-discoverer, along with Alfred Russel Wallace, of the principle of evolution by means of natural selection.

This being a scientific journal, my subject is Darwin (although it is worth noting that Lincoln was the founder of the US National Academy of Sciences). Most scientists probably know something of his story: destined for the ministry, he abandoned his studies to serve as companion to Captain Robert FitzRoy of the ship Beagle on its voyage around the world from December 1831 to October 1836.

On 24 November 1859, Darwin at last published his great book on evolution. The entire press run of 1,250 copies sold out on the first day at a price of 15 shillings each; if you can find one on the rare book market today, it will cost you about US$100,000. It has what may be the longest, dullest title in the history of great books: On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. For the rest of his life, through five more editions (some of which were considerable revisions), Darwin clung like a barnacle to this title, although he did drop the word 'On' for the sixth edition.

Here are some little-known facts about what Darwin said, and what he didn't say, and when:

The one thing about which On the Origin of Species has almost nothing to say is the origin of species. The term 'species' is never really defined, and the idea of a species barrier based on reproductive isolation is never developed. Darwin cannot really be blamed for this, as he knew nothing about the concepts of genes, the genome and the laws of genetic inheritance. At exactly the time he was laboring over the manuscript, his contemporary, the Moravian monk Gregor Mendel, was busily breeding peas and discovering the transmission of characteristics in a predictable way by factors (genes) that generally remain intact (though they may mutate) and do not blend (though they may mask one another's effects). But Mendel published his findings in an obscure journal, Proceedings of the Natural History Society of Brünn, in 1866, and Darwin never incorporated them. (Pretty much nobody read about them then either; Mendel's work had to be rediscovered, 34 years later, by Hugo de Vries and Carl Correns.) Darwin died in 1882 without knowing the mechanism underlying his theory.

The word 'evolution' appears, I believe, fewer than ten times in even the sixth, and final, edition of On the Origin of Species, but the last word in even the first edition is 'evolved'.

In the entirety of On The Origin of Species there is only a single sentence on the subject of human evolution ("Light will be thrown on the origin of man and his history"). Darwin didn't explicitly address that topic, the one that causes apoplexy in so many religious fundamentalists, until 12 years later, in The Descent of Man, and Selection in Relation to Sex. But he didn't have to. The implication of his theory was immediately apparent to every educated person, because several previous, quite popular books by other authors had already advocated applying the idea of evolution to human beings. Given the anatomical similarity of apes, they were the obvious ancestor of choice. But all those authors proposed a direct line of descent from apes to man; none of them realized that the two are separate offshoots, derived from a common primate ancestor. Darwin didn't realize that, either.

The phrase 'survival of the fittest' doesn't occur in the first four editions of On the Origin of Species. In the fifth edition, published on 10 February 1869, Darwin used it for the first time, as a more graphic way of describing the concept of natural selection. The phrase wasn't original to him; he borrowed it from the philosopher Herbert Spencer.

Although Darwin was a good draftsman, like most Victorian naturalists, On the Origin of Species could have benefited from a judicious use of Photoshop™. There is only a single figure: an amateurish hand-drawn evolutionary tree (reproduced for this column, see Figure 1) that conveys almost no detailed information.

Figure 1

Darwin’s graphical representation of the principle of descent with modification and how new varieties would be formed over long periods of time by natural selection. The intervals indicated by Roman numerals “may represent each a thousand or more generations” (Origin of Species, 6th edition, p85). The capital letters along the bottom indicate original species. “The little fan of diverging dotted lines of unequal lengths proceeding from (A), may represent its varying offspring. The variations are supposed to be extremely slight, but of the most diversified nature; they are not supposed all to appear simultaneously, but often after long intervals of time; nor are they all supposed to endure for equal periods. Only those variations which are in some way profitable will be preserved or naturally selected.” So, after a thousand generations, “species (A) is supposed to have produced two fairly well-marked varieties, namely a1 and m1”, and so on. Darwin explains that he has chosen the “extreme species (A) and the nearly extreme species (I) as those which have largely varied, and have given rise to new varieties and species”.

You can probably win some money around the bar at many scientific meetings by betting on how many scientific voyages Darwin undertook in his life. The answer is one. After the Beagle voyage he never left England again; indeed, after he moved out of London in 1842, he seldom left his country town. Poor health is one reason (he suffered from a debilitating chronic illness that may have been Chagas disease, contracted in South America), but basically, after his marriage and the birth of the first of what would eventually be ten children, Darwin became a homebody - not particularly adventurous, except intellectually. The man whose travels produced the foundation of our understanding of the development of living things rarely traveled.

Though polite and soft-spoken, Darwin was not modest about his theory. On more than one occasion, he said that he expected all future biological observations would be consistent with natural selection, and would serve to confirm it. As scientific hubris, this remark ranks close behind that of Einstein, who, when asked how he would have felt had the famous experiment to measure the effect of gravity on light waves not produced the result predicted by his Theory of Relativity, replied, "In that case, I would have been sorry for God. The theory is correct."

One of the biggest misconceptions about Darwin is that On the Origin of Species had a hostile reception when it was published. It did attract some severe criticism from a few conservative clergy, but in general the book was well received. Most British clergymen of that era were quite progressive, and were prepared to accept the ideas in Darwin's book as a description of how the Creator worked. It was in America that the pot really began boiling. America was always more conservative in religious terms than Europe, so fundamentalist objections to evolutionary theory were much more widespread there. But what really stirred things up was the popularity among American intellectuals of Social Darwinism, Herbert Spencer's attempt to show that societies are organisms and, like living creatures, evolve. Social Darwinism was eventually used to justify notions of racial superiority and forced sterilization of the retarded - things Darwin would have abhorred. (For a detailed account of all this, I heartily recommend Barry Werth's wonderful new book Banquet at Delmonicos: Great Minds, the Gilded Age, and the Triumph of Evolution in America, Random House, 2009.)

So if On the Origin of Species isn't about the origin of species, what is it about? It's not about the idea of evolution (which the Victorians usually called 'transmutation'); Darwin took that as a given. It's about the mechanism of evolution. The problem with all the previous books and articles and philosophical discourses on evolution - and in a preface to a later edition of his book Darwin traces the concept all the way back to Aristotle - is that no one could explain how it happened (which led many naturalists to reject the idea and claim that species were immutable). Why were some traits, but not others, retained in a species over time? Why did different traits become fixed in certain populations and not others? What drove this relentless differentiation, which evolutionary theory said must have started with a small number of ancestral species, perhaps as few as one? Thanks to his observations on the voyage of the Beagle, years of thinking about how animal husbandry led to the diversity of livestock and domestic animal breeds, and an inspired insight concerning the implications of Malthus's ideas on overpopulation leading to competition for resources, Darwin was able to provide the answer to what was called by some the philosophical question of the day.

His answer, of course, was the concept of natural selection. For reasons he couldn't explain (not knowing about genes and how they mutate), populations contained a distribution of traits that appeared to arise by chance (although Lamarckian ideas were not ruled out). If a particular trait - say, longer length of the beak on a finch - conferred a particular survival advantage - say, increased ability to acquire food - over members of the population that did not have it, that individual would be more likely to produce offspring and they, too, would have that trait, which would make them more likely to produce offspring, and so on until the trait became characteristic of the species. Darwin did not actually devote much space in his book to his famous finches, but they have been much studied since as examples of how morphological changes can aid survival.

Ironically, Darwin's finches have been employed by creationists as examples of the supposed failure of evolutionary theory: they claim that beak changes in Galapagos finches during a severe drought cannot explain the origin of species by natural selection because the changes were reversed after the drought ended, and no net evolution occurred. Of course, this is one of those misnamed 'exceptions' that really do prove the rule: the finch data perfectly illustrate that populations change their average physical features in response to changes in the environment, and document how the physical features of an organism can affect its success in reproduction and survival. Moreover, they show that such changes can take place more quickly than was previously thought - an important point in the timeline of evolution. That complete new species did not arise within the duration of the study is a feature of the short time-scale of the climate changes involved.

The theory of evolution by natural selection is the cornerstone of biology, and one of the towering achievements of the human intellect. Yet there isn't a statue of Darwin (or of Wallace, who ought to get at least some of the adulation as well) in any public space in the United States, as far as I know. Religious fundamentalists still fight to keep his ideas out of public school science classes, and when they can't do that, they attempt to teach a trumped-up 'scientific controversy' about alleged 'weaknesses' in the theory of evolution, though the theory is practically as solid as atomic theory. Even the National Academy of Sciences failed to honor him until this year: a statue of Einstein graces the arbor outside its headquarters on Constitution Avenue in Washington, DC, in full view of passers-by, but you have to go inside to find a life-size bust of the greatest biologist of all time.

Darwin is probably the most controversial scientific giant since Galileo - and we all remember what the forces of ignorance did to Galileo. More so than anyone else, Darwin's findings demand that we give up the idea of the literal truth of the Book of Genesis, and see it as metaphor - soaring, beautiful, lyrical metaphor, but metaphor nonetheless. Yet, despite the widespread use of metaphor elsewhere in the Bible ("Behold the lamb of God", "I will make thine enemies thy footstool", and so on), many people who would never take those other passages literally still insist that we do just that with the story of creation. Surely it is not too much to ask that, on this 200th anniversary of Darwin's birth, his fellow biologists stand up and proclaim, with the same courage he showed in the face of opposition, "Happy birthday, Charles. You were right."

Fifty years ago, on the sesquicentennial of 12 February 1809, the poet Carl Sandburg gave this eulogy in the United States Congress: "Not often in the story of mankind does a man arrive on Earth who is both steel and velvet, who is hard as rock and soft as drifting fog, who holds in his heart and mind the paradox of terrible storm and peace unspeakable and perfect." He was referring, of course, to Abraham Lincoln. But the words could equally well apply to Charles Darwin.

For more on Darwin, why he didn't discover Mendelian inheritance, and his influence on modern biological research, see the February issue of Journal of Biology:

Q&A: What did Charles Darwin prove: Paul Harvey

Why didn't Darwin discover Mendel's laws?: Jonathan Howard

Evolutionary genomics and the reach of selection: Laurence Hurst

Mayr, mathematics and the study of evolution: James Crow

Darwin and Huxley revisited: the origin of allometry: Charles Stevens

Apes, lice and prehistory: Robin Weiss

Published: 27 February 2009

Too big to succeed?

Genome Biology 2009, 10:103

We hear the phrase 'too big to fail' a lot these days. It means a company that is so vital to the national economy that its demise would be catastrophic, so the government will go to extraordinary lengths to keep it afloat. General Motors Corporation, the sinking US car maker, is said to be too big to fail. Lehman Brothers, the investment bank whose collapse precipitated financial crises around the world, was too big to fail - although George W Bush's Secretary of the Treasury, Henry Paulson, didn't realize that in time. And, as the world credit market tries to become unstuck before a global depression sets in, we hear the same thing about two US bank holding companies, Bank of America and Citibank.

But what exactly does it take to make a company too big to fail? In the case of General Motors, it is the huge number of jobs that would be lost if it went under, but that consideration doesn't apply to a financial services firm - at least not directly. In the case of banks, it's the magnitude of the monetary loss that matters. Bank of America has assets of approximately $2.7 trillion and Citibank has assets of around $2.3 trillion. The GDP of the United States is $14 trillion, so each of these banks has assets in excess of 14% of the yearly output of the largest economy on Earth. That's too big to fail.

But I would argue that, if you can be too big to fail, you also can be too big to succeed. Your very size can be your undoing, as it may have been for the huge, lumbering dinosaurs, who weren't flexible enough to survive the global catastrophe that our small, furry, mammalian ancestors were able to weather.

Consider the two giant banks. Over $2 trillion in assets sounds great, right? Well, maybe, but there's also the small matter of their liabilities. Both banking companies hold enormous quantities of so-called 'toxic securities', which is a polite way of saying mortgage-backed debts. As many of the mortgages are effectively worthless, these companies may have huge liabilities. It's estimated that there might be as much as $11 trillion of such debt in the US economy, because many large banks essentially bet the farm on the incredibly naive idea that house prices would rise forever. The fact that they had always gone through cycles of rising and falling for, oh the previous 5,000 years or so, seems to have been lost on the self-styled geniuses who created the mess we're in.

The real problem, though, is that nobody knows if that $11 trillion figure is right, because nobody knows what the toxic securities are really worth. They may be worth anything from close to their nominal value to zero, and that's a heck of an error bar. So let's look at Citibank. Yes, it has $2.3 trillion in assets, but it also has big liabilities. How big? It's unknown. There might be, say, $1 trillion in liabilities, in which case Citibank is in great shape. But there could well be $3 trillion in liabilities, in which case this enormous bank is actually broke. And no one, not the chief executive of Citibank nor the head of the US Treasury nor a gypsy reading tea leaves, can say which is the case. The banks had grown so large, and had created such an elaborate web of interdependent, chopped-up, over-leveraged securities that their own financial people had no real idea of how much debt they were taking on.

In other words, I think Bank of America and Citibank (and Lehman Brothers and most of the other companies at the heart of the global financial crisis) have become too big to succeed because they are too big to be managed. No one individual - or group of individuals - can assimilate the amount of information needed to keep tabs on what goes on at a company that size, so even if they themselves are not crooked or incompetent, they are fated to be hostages to crooked or incompetent people who work, undetected, at some lower level of the Byzantine corporate structure. Yet until recently, these companies were touted as the epitome of excellence, precisely because, through mergers and acquisitions, they had grown so enormous.

Why do we mistake growth for success? When did sheer size become equivalent to excellence? Because a monomaniacal insistence on being the biggest so often derives entirely from the person at the top, it seems fair to ask if there isn't some psychological explanation. Washington Post columnist Sally Jenkins has a marvelous article in the 19 February 2009 issue, 'Armchair Field Generals, Getting Sacked on Wall Street', in which she notes that the hypercompetitive CEOs of large corporations were usually good sportsmen, but never quite good enough to become great. "Maybe the real lesson," she writes, "is to beware of the wannabe. Some of these people seem to fall into the dangerous category of 'pretty good' athletes ... Experience plus some armchair Freudian analysis tells us there are a fair number of overcompensated jerks out there who almost made it in sports ... There's the sneaking suspicion that more than one shareholder is suffering from these guys' sublimated failures to reach the top in the more primal competitions of their youth ... The most important quality of leadership," she goes on to state, "is not competitiveness, but judgment".

And as corporate boards, which appoint CEOs, are usually stocked with present or past CEOs of other corporations, it shouldn't surprise us when these win-at-all-cost shortsighters pick people like themselves to head the companies they oversee. And so the culture of 'whoever has the most when he dies, wins' goes merrily on.

But where did that culture come from, and why did it get so out of control? I think the answer might be pretty simple, and if I'm right, it explains why I also think the current debate about excessive CEO compensation misses the point. You will recall that, as part of the financial bailout, the government proposed to limit the bonuses and other payouts to the CEOs of the corporations receiving federal funds, which provoked an immediate outcry on the part of their boards, the claim being that, without enormous compensation, companies would not be able to hire or retain the best people. Don't worry about this side issue, they said, fix the real problems.

Well, never mind that 'the best people' have just lost hundreds of billions of dollars and nearly wrecked the economy of the world. (I could do that, and would happily accept a lot less in pay and bonuses than they keep demanding.) And never mind that I am unaware of a single study that shows a correlation between the salary and bonuses paid to executives and their talent (in fact, in many professions, like ours, money usually isn't the motivating factor in a career at all). The uproar in the United States over bonuses just paid to some of the very employees of the insurance giant AIG who caused the mess that company is now in suggests that the public has realized something that the Bush Administration never did and that the Obama Administration may not have figured out yet: CEO compensation is not a side issue; CEO compensation is the problem. If you offer outrageous salaries to people who run your companies, and give them even more outrageous bonuses if they increase share prices and revenues - not profit, revenues - then it stands to reason that you will probably attract greedy, aggressive people who are only interested in short-term results. That's what created the Wall Street culture that's got us into this fix.

And the reason you're reading this in Genome Biology, instead of in The Economist, is that I fear this culture may now be spreading, like some virulent flu strain, to the pharmaceutical industry. Look at what has happened in the past 15 years. A wave of mergers is threatening to reduce the number of so-called 'big pharma' companies to a handful, and the results haven't always been pretty. Pfizer almost choked to death from swallowing Pharmacia/Upjohn a few years ago, and now is planning to acquire Wyeth. Merck has announced plans to merge with Schering-Plough. And analysts (more about them later) are busily proposing other fusions.

I'm not sure this trend makes much sense from the point of view of the primary purpose of these companies, which is to discover new drugs (although in the short term it may help fill one of the companies' empty pipeline). There are no data indicating that increasing the size of a pharmaceutical company leads to increased ability to make pharmaceuticals. In fact, there are worrying suggestions that it may often do the opposite. Innovation usually scales inversely with bureaucratic complexity. If a merger or acquisition is proposed solely for the purpose of acquiring a drug that one company makes, longer-term issues of research complementarity or synergy of talent might get secondary consideration, leading to internal culture wars and strategic paralysis.

Recent history may bear this out. Despite more than a decade of mergers and acquisitions, big pharma actually makes no more drugs per company today than it did in 1995 (although one has to be careful to take into account drug approval rates by regulatory agencies, which also change with time). Larger companies also have a tendency to be more conservative, so the worry is that innovation could suffer as firms merge. Biopharmaceuticals, the newest trend in the industry and the source of about 50% of its profits last year, originated in biotechnology companies, not pharmaceutical houses. The notion that proteins such as antibodies could be profitable drugs was resisted for years by big pharma, which is now scrambling furiously to catch up.

Of course, giant pharmaceutical companies can buy innovation, new targets, and even lead compounds from small biotech companies - and frequently do. That may well be the future: big pharma 'outsourcing' target discovery and some other aspects of innovation to smaller, independently-operating biotech arms, with the parent company focusing on chemistry, testing, and marketing. It might not be a terrible model, but I still think we'd end up with fewer drugs, since the large pharmaceutical companies actually used to discover the bulk of them, and there are a lot of weak biotechnology companies out there.

Industry analysts love to tout mergers and acquisitions as tools to raise share prices, and if stockholders clamor for their advice to be followed it can seriously affect those share prices. I've never understood why analysts seem to exert such influence on the market. I've known a few, and I have to say I was not that impressed. It seems crazy that part of the financial health of companies whose output is so important to human health should rest with people who are not scientists or business executives, who don't have the public welfare in mind, and whose track record is spotty, to say the least.

Look, I'm not trying to bash the pharmaceutical industry here. I have enormous respect for it, and for the people who work in it: most of them are motivated by a sincere desire to improve the health of mankind. It's that respect that leads to my concern for the industry's own health. Some mergers and acquisitions are good ones, of course, but I remain unconvinced that, overall, a few huge drug companies will innovate better than a larger number of smaller ones, even with the help of biotech partners.

The notion that something can be too big to succeed shouldn't be that foreign, because it even applies to people. There's a famous example of an individual who became so big and lumbering that he was easily bested by a smaller, more nimble adversary. You'll find his story in Chapter 17 of the First Book of Samuel. His name was Goliath.

Published: 30 March 2009

Guilt by association

Genome Biology 2009, 10:104

It's a favorite device of politicians who wish to smear a rival candidate. The late, unlamented Democratic Senator Joseph McCarthy employed it, successfully, against leftists whose careers he wished to destroy. The Republicans tried, unsuccessfully, to use it against Barack Obama. In its simplest form, it involves branding someone a Communist, or a terrorist, or a criminal, because they have family or friends, or possibly just casual acquaintances, who are Communists, or terrorists, or criminals. It's called guilt by association.

It's been in the news lately because it's also a favorite tactic of genome biologists, but in this case its purposes are not sinister. Scientifically, it goes by the name of genome-wide association studies, though guilt by association is just as apt. It's an attempt to find connections between simple changes in the coding sequence of genes and the risk for developing complex diseases. A product of the human genome sequence (and, one could almost say, a means of ensuring job security for the hordes of sequencers who were responsible for that project), genome-wide association studies represent the first comprehensive attempt by the genomics community to demonstrate a big payoff, in terms of benefits to human health, for the enormous amounts that were spent on that original project.

If there were world enough and time, as Andrew Marvel (or was it Francis Collins?) would say, we would perform such studies simply by sequencing the complete genomes of large cohorts of people with, say, type II diabetes, or lung cancer, or schizophrenia, or Alzheimer's disease, and then letting the computational folks sift through the resulting reams of data to sort out the varying combinations of simple spelling mistakes in many different genes that give rise to autism, or stroke, and so on - and it's quite likely that, when sequencing costs come down sufficiently, this is exactly what we will do. In the meantime, though, the effort is more restricted.

The current approach relies on data from the International Human Haplotype Mapping (HapMap) Project, which aims to determine the prevalence of common polymorphisms in the human genome, and on the fact that genetic variance at one locus can predict with high probability genetic variance at an adjacent locus, typically over distances of 30,000 base pairs of DNA, making it possible to map the common variability - and, as we shall see, the key word here is 'common' - associated with the risk of a given disease simply by genotyping approximately 500,000 judiciously chosen markers in the genome of several thousand case subjects and comparing the frequency of those markers with genotypes of control subjects. Consequently, it has become relatively routine to identify common variants (for example, those that are present in more than 5% of the population) that confer not a certainty but rather a risk of disease, typically with odds ratios of 1.2 to 5.0.

But now, in a series of articles in the 15 April 2009 online issue of the New England Journal of Medicine, a debate is taking place between proponents of this approach and those who argue that it will never succeed in revealing the genetic basis for complex, polygenic disorders. The reason for this scrutiny is the failure of most of the ongoing studies to find any convincing link with common diseases. It had been expected that the risk of getting cancer, diabetes, and so on would be largely controlled by a relatively small number of common variants, each of which conferred a significant risk, but only a small number of disease-associated variants have been found thus far, and, with a few exceptions, the risk they seem to confer is quite small. As Hardy and Singleton frame the question in one of four papers on the subject, "...discussion has centered on evaluating how far such studies will take us in understanding the risks and causes of disease - and thus the time and resources that should be invested in genotyping more case subjects with any one disease to garner what many see as diminishing genetic returns."

Because they rely on the HapMap, current studies identify loci, not specific genes. Moreover, we currently have haplo-type maps only from single nucleotide polymorphisms (SNPs) present in at least 5% of chromosomes of each of just three groups of defined ancestry: Yoruban, Northern and Western European, and Asian (Chinese and Japanese), so by definition the markers are for rather common variants (present at > 5% frequency) in the human population. Underlying the project at present, then, is the assumption that common diseases are associated with common variations. A further assumption is that, even if individual alleles have only a small effect on one's risk for a disease, each contribution is large enough that a manageably small number will sum to a significant effect. But what if each contribution is very small?

In a companion perspective, Goldstein argues that very many very small contributions is exactly the case and questions the wisdom of continuing this strategy. He points out that there are examples of its successful application: "For example, when exposed to the anti-HIV drug abacavir, a hypersensitivity reaction develops in more than half the carriers of the HLA-B*5701 allele, whereas such a reaction occurs in less than 5% of patients without this allele. Similarly, just three common variants are sufficient to explain 14% of the population variation in HIV-1 viral load." But, he continues, "with traits such as height or type 2 diabetes, it seems that an inordinate number of common SNPs would be needed to account for a sizable fraction of heritability... The apparently modest effect of common variation on most human diseases and related traits probably reflects the efficiency of natural selection in prohibiting increases in disease-associated variants in the population." In other words, common diseases might well be caused by many different combinations of a large number - probably hundreds - of very rare variants, which would even eliminate the utility of the SNP hunt in identifying pathways leading to disease. "In pointing at everything," Goldstein writes, "genetics would point at nothing."

Similar concerns are expressed by Kraft and Hunter in a companion piece (although they favor continuing the common variant hunt). "First, the relative risks that are found to be conferred by common risk genotypes account for only a small proportion of the sibling recurrence risk (or the risk that a sibling will also have the disease of interest). Second, in multivariate analyses of large epidemiologic data sets in which a family history of a disease is a risk factor, the inclusion of data regarding which subjects carry the known associated variants only minimally reduces the risk associated with a family history of the disease. Third, in the case of diseases that have been the focus of several genome-wide association studies, some alleles have been detected more than once, but each study has identified multiple alleles that were not identified in other studies, suggesting that many more alleles remain to be discovered. These factors suggest that many, rather than few, variant risk alleles are responsible for the majority of the inherited risk of each common disease."

One truly surprising result from the studies thus far is that the majority of loci identified as associated with disease risk do not map to the coding regions of individual genes. Instead, they possibly affect either the splicing of the messenger RNA or the sequences of microRNAs that regulate gene expression. Deducing the effects of non-coding changes on the level of active protein(s) in the cell is simply not possible from first principles at the moment; it will require huge experimental efforts in multiple laboratories.

So all this really seems very discouraging, but I have a modest proposal for a somewhat altered approach that I think could yield exciting results rapidly. The problem with most fishing expeditions, which is what genome-wide association studies are, is that one is never sure that one is fishing where the fish are. My proposal is to focus on where we know there are fish (or, to use another analogy, to look for the keys under the lamppost because that's where the light is). That seems unlikely to provide new information, but hear me out. I think the mistake we're making is in looking at the association between SNPs, many of which mean little or nothing, and disease. What we should be doing is looking at the association between diseases.

There are literally hundreds of inherited metabolic disorders, most of which are autosomal recessive - they require mutation in both copies of the gene in question to produce the disease. In many cases there are dozens or even more than a hundred known alleles in the gene in question, any two of which suffice. Carriers for these diseases have just a single variant and are usually free from symptoms of the disease. But it is slowly becoming clear that for at least some of the inborn errors of metabolism, the carriers are at altered risk for something else. It may be that a carrier has a reduced risk for an infectious disease, but often I think a problem with a metabolic enzyme will produce haploinsufficiency in some pathway that is involved in a very different disorder. Thus, carriers for the recessive, lysosomal storage disorder Gaucher disease are almost an order of magnitude more likely to develop Parkinson's disease. Is the connection through lysosomal dysfunction? Maybe, and that's testable: it suggests that carriers for other lysosomal storage diseases such as Niemann-Pick, Tay-Sachs, Anderson-Fabray, and Pompe's diseases should also be at increased risk for Parkinson's and perhaps other neurological disorders.

That's exactly the sort of thing a genome-wide association study could determine, and it would shed valuable light on the causes of a class of common diseases. I think it's almost guaranteed to turn up things, because metabolism is tied into all the other pathways in the cell, and because by definition the carrier alleles for a recessive disorder are mutations that must have some definite effect on the expression or function or stability of the protein in question.

In short, I think we should look at rare diseases for less rare genetic loci (the carrier frequency for Gaucher's is estimated to be 1 in 100 in the general population, and around in 1 in 20 among Ashkenazi Jews) that we know have physiological consequences, and ask whether they are associated with the risk for other, more common diseases. I think that's where the interesting connections are most likely to be found, at least until we can sequence lots of whole genomes very cheaply. After all, in a real criminal case, the police usually focus on suspects they know are likely to be guilty, because they have already been proven guilty of other things in the past. That's guilt by association, to be sure, but it tends to work.

Published: 29 April 2009

Render unto Darwin

Genome Biology 2009, 10:106

You probably haven't encountered a website for something called BioLogos. If you have, you will undoubtedly already have formed a strong opinion about it - it's that kind of site. If you haven't, you really ought to check it out http://www.biologos.org. It's the website for something called the BioLogos Foundation. According to its mission statement, "The BioLogos Foundation promotes the search for truth in both the natural and spiritual realms seeking harmony between these different perspectives." The foundation was established by Francis Collins with a grant from the John Templeton Foundation, a much older organization with a similar mission. And that, apart from its intrinsic interest, is why you should check it out, and why I'm wagering you will have strong opinions when you do. Francis Collins is the scientist who headed the publicly funded Human Genome Sequencing Project in the 1990s. Until last August he was the head of the National Human Genome Institute at the National Institutes of Health (NIH), which continues that work and funds much of the genome biology in the United States. And he just might be the next director of the NIH, the largest scientific research funding organization in the world.

In a public statement, Collins said that he established the BioLogos Foundation "to address the escalating culture war between science and faith in the United States. On one end of the spectrum, 'new atheists' argue that science removes the need for God. On the other end, religious fundamentalists argue that the Bible requires us to reject much of modern science. Many people - including scientists and believers in God - do not find these extreme options attractive. BioLogos represents the harmony of science and faith. It addresses the central themes of science and religion and emphasizes the compatibility of Christian faith with scientific discoveries about the origins of the universe and life. To communicate this message to the general public and add to the ongoing dialog, The BioLogos Foundation created BioLogos.org."

Let's dissect this statement, because if ever there was a statement that needed dissecting, this is one. I completely agree with Collins that there is a culture war between science and faith in the United States. But I do not agree that the war is due primarily to the clash between the extremists on both sides. Take the "new atheists", for example. There are many atheists in the United States, and some of them are scientists. But only a handful would take the extreme - and, to my mind, incorrect - position that science disproves the existence of God. The British scientist Richard Dawkins might, but he doesn't speak for the majority of scientists I know, and his eloquent but strident voice has only served to inflame the opposition by preaching to the converted. There are many more agnostics, who simply believe that there is no compelling evidence to believe in any deity.

Now let's look at that opposition, the "religious fundamentalists" who argue that "the Bible requires us to reject much of modern science". There are a lot more of those, especially in the United States, but - and this is a crucial distinction, as we shall see - they are almost entirely evangelical Christians, not "religious fundamentalists" in general. Evangelical Christians often take the Bible literally, and a literal reading of the Bible is certainly incompatible with many of the findings of science.

One of the missions of the BioLogos website is to advance the idea of theistic evolution, a concept discussed in depth in Collins' book The Language of God, which is also promoted on biologos.org. Essentially, theistic evolution means that evolution is the way God created life. I was first clued into this website by Jonathan Eisen, an evolutionary biologist and open access publishing maven at the University of California, Davis. Eisen, whose blog The Tree of Life http://phylogenomics.blogspot.com/ is a delightful and thoughtful commentary on the worlds of both genomics and scientific publishing, wrote about BioLogos on 5 May. So that you will know where he's coming from, here's his opening statement: "I am all for trying to have discussions about science and religion. But I do not think the two topics are really compatible in the sense of merging them together. Science (and medicine) should be about, well, science. And religion can be about whatever it wants to be. And when we can get religious and scientific leaders together to talk about the implications of each area on the other and on the world, fine too. But merging the two together into one hybrid such as Christian Science and Creation Science? Not for me."

He goes on to make a pointed criticism of the underlying logic - or lack thereof, in his view - behind BioLogos. "The details of Collins' attempt to merge science and religion into a version of theistic evolution are really unclean. Basically, he is trying to argue that on the one hand science and religion are completely separate activities (I support this) but at the same time argues that God can intervene in the setting up of natural laws and in providing some guidance here and there in order to, for example, produce human beings in his image. The website repeats some things from Collins' book that are equally illogical - such as saying that altruism can be explained by science (and even specifically saying that science is the way to explain the natural world) but then turning around and saying that science cannot explain extreme forms of altruism (and therefore implying that actually, the natural world cannot be explained by science). Which is it? Is science for the natural world or not?" Eisen is right that this, and some of BioLogos' other talking points, smack of setting up a straw man.

But in the end, BioLogos aims to show that the findings of science are not inconsistent with the existence of God. And not just any God. BioLogos is all about the Christian God. It even says so: "The creation story of BioLogos is compatible with many faith traditions, and there is no way to give a scientific proof for one monotheistic faith over another. Therefore, this response will simply show the compatibility of Christianity with BioLogos." And again, more forcefully, in their mission statement: "the website is a reliable source of scholarly thought on contemporary issues in science and faith that highlights the compatibility of modern science with traditional Christian beliefs."

Here's another example: "For believers, these [scientific] discoveries must ultimately be compatible with the truth that is revealed in the Bible, and it is the conviction of BioLogos that this compatibility is not only desirable but also possible. The limitation is that our access to all forms of truth, including scientific and religious, is at best partial." The statement that it is Biblical truth that science must be compatible with (and there are other comments that make it clear BioLogos means the Christian Bible, especially the New Testament) marks a clear attempt to link science with one brand of religion.

The creators of BioLogos have every right to make the foundation and website about whatever they want. And I suppose you could argue that, as I see it, because it is evangelical Christians that are the chief opponents of modern science, especially evolution, it is sensible for scientists to promote the compatibility of science with Christian beliefs. But I don't agree. I think it's a huge mistake.

GK Chesterton, a devout Roman Catholic, has his priest-detective Father Brown say, in the superb short story The Sign of the Broken Sword, "When will people understand that it is useless for a man to read his Bible unless he also reads everybody else's Bible? A printer reads the Bible for misprints. A Mormon reads his Bible and finds polygamy; a Christian Scientist reads his and finds we have no arms and legs." I've always liked this quotation, and not just because I agree that one huge problem with putting your faith in the literal reading of a book is that you can find justification in that book for almost any form of behavior, from altruism to genocide to slavery. I like it for a reason that Chesterton probably never intended: it reminds me that there are many more religions than Christianity, and many more people of faith than monotheists. I think if you are going to understand people of faith and try to see how we as scientists can find common ground with them, it is discriminatory - and possibly something worse - to focus on Christians or even monotheists (which, in the modern world, pretty much consists of Muslims, Christians and Jews - Zoroastrians being in short supply nowadays - and I'm pretty sure that the BioLogos folks would not include Islam in their mission, given that faith's denial of the divinity of Christ). If you are going to read the Christian Bible you should also read the Jewish Bible. And the Book of Mormon. And the Koran. And the Bhagavad Gita. If you really care about making contact with people of faith you should not exclude most of them just because they worship different gods from yours.

In some temples in India, during services the priest will read from the Hebrew or Christian Bible and the Muslim Koran as well as the Hindu Gita, moving from one to the other as though it did not matter what precise words were being spoken as long as there was something greater than the individual self that was being worshipped. How can we as scientists find common ground with people of faith unless we recognize the commonalities they share with each other? At its best, all religion is about a love for the natural world, a desire to help other people, and a sense that life is well lived only when it is not lived selfishly and pettily - values that typically underlie most scientific research. At its worst, religion is about unquestionable certainty, authoritarianism, exclusion and discrimination - things that have no place in science either. Scientists can make common cause with people of faith through the values we share, but must reject the extremist, intolerant views that poison both spheres.

And in the end, that's my big problem with BioLogos - at its heart, it strikes me as implicitly exclusionary (plus I agree with Eisen that its logic is shaky). I would have much preferred a clearcut effort to emphasize the non-connectedness of science and faith: that science is about evidence and testable hypotheses, whereas religion is about believing in things for which there is no evidence whatsoever, and cannot be. That would place them in separate realms, but with common ground as I defined it above. The moment you start trying to say that data from science is compatible with the Christian religion in particular, you imply that, for example, polytheistic religions are wrong, and maybe not just as a matter of faith, but as a matter of science.

Nothing is more dangerous than such absolutism. It sets one type of religion as being true and therefore can be used to support the branding of all the others as false. However well-intentioned, BioLogos isn't likely to bring peace to the war between science and religion if it is oriented so strongly towards one religion.

I would have loved to see the resources that the Templeton and BioLogos Foundations spent on biologos.com - both financial and in terms of human effort - devoted to clarifying and promoting the distinctions between science and religion and to a search for a common ground that does not exclude anyone of faith. That's something I could support (and, I bet, something that Jonathan Eisen and possibly Charles Darwin could support, too). But the idea that science provides information that cannot be explained by science alone - and therefore that science 'needs' the Christian God for a complete description of the universe - strikes me as the wrong thing to do. Render unto Darwin the things that are Darwin's, and unto God the things that are God's. But for God's sake (or should that be Darwin's?), don't mix them together.

Published: 01 June 2009

What my genome told me - and what it didn't

Genome Biology 2009, 10:108

Well, it turns out I'm not descended from Genghis Khan. I'm sure that's as surprising to you as it is to me. I mean, according to what we hear from people who use genomics to track human migrations, a huge percentage of the human race is actually descended from Genghis Khan. But not me.

That's one of the things I learned when I submitted a sample of my DNA for genome-wide single nucleotide polymorphism (SNP) analysis by one of the companies that have sprung up to perform such tests for ordinary individuals for a fee. I was curious to see what sort of information they provide, and wanted to know something about my own genomic makeup, to be honest, so I followed the directions of the company I had selected and spat into a plastic container until I produced the required volume of saliva, mailed it in, and awaited the results. Would I have an allele that doomed me to a rare genetic disorder as I got older? Was I at much higher than normal risk for heart disease, diabetes, or any of the other thousand natural shocks that flesh is heir to? Was I descended from Genghis Khan?

The company I sent my saliva sample to doesn't actually do any DNA sequencing or hybridization itself; it contracts this out to a specialist laboratory. Once the lab received my sample, DNA was extracted from cheek cells in the saliva and amplified by PCR to produce enough material for the genotyping step. Next, the DNA was cut by restriction digestion into smaller, more manageable pieces. These DNA pieces were then applied to a DNA chip, which in this specific case is a small glass slide with millions of microscopic beads on its surface. Attached to each bead are the probes - bits of DNA complementary to those specific sites in the human genome where important SNPs are located. There is a pair of probes for each SNP, corresponding to the 'normal' and 'non-normal' version of each SNP. Hybridization to the particular probe, detected by fluorescence just as in the case of any other DNA chip experiment, serves to identify the allele.

The DNA chip that this particular company uses reads 550,000 SNPs that are spread across the entire genome. Although this is still only a fraction of the 10 million SNPs that are estimated to be in the human genome, these 550,000 SNPs are specially selected 'tag SNPs' - because many SNPs are linked to one another, the genotype at many SNPs can often be determined by looking at one SNP that 'tags' its group. This tagging procedure maximizes the information from every SNP analyzed, while keeping the cost of analysis low.

In addition, all the DNA analysis companies have hand-picked tens of thousands of additional SNPs of particular interest from the scientific literature and added their corresponding probes to the DNA chip. These SNPs include risk factors for common and rare human diseases, genetic traits such as color blindness, and so on.

Access to the resulting data is through the company's website, which includes the ability to download the entire set of SNP information. Once I was notified that my results were in, I did that, and being a scientist I performed my own bioinformatics on the data, but the website actually does a pretty good job of providing the customer with specific information about alleles for various illnesses, physical traits, and so on.

Here are a few of the things I leaned about myself, physically speaking:

According to my genome, my eye color is likely to be brown (good guess). I should be lactose tolerant (I am). My cytochrome P450 data show that I would be quite sensitive to the anti-clotting drug warfarin if I ever had to take it (which I hope I never do - it's a nasty drug). The SNPs in my androgen receptor gene say that I am considerably decreased in risk for male pattern baldness (I have news for them; I'm getting rather thin on top). I have a SNP in a dopamine receptor gene that, in one German study, was found to be associated with reduced efficiency in learning to avoid errors (unless I got the facts wrong). According to a single SNP in one gene associated with insulin metabolism, I have increased odds of living to be 100 (that is, if all the mistakes I don't learn to avoid don't get me first). There are a number of SNPs that have, in some studies, been associated with increased athletic performance (faster running, quicker reaction times, and so on). I don't have any of them, which will come as no surprise to any of my gym teachers.

I am at slightly increased risk, relative to the norm, for rheumatoid arthritis and psoriasis (that last one is interesting, because my father suffered from it). I am at slightly decreased risk for Celiac disease, Crohn's disease, type 1 diabetes, and prostate cancer. In all cases, the change is small - less than two-fold difference, and not enough to cause me to consider any lifestyle changes.

But one thing did jump out at me when I looked at my data. I have a guanine at rs1799945, which is located in the gene coding for a protein called HFE. HFE is the protein mutated in hereditary hemochromatosis. Hereditary hemochromatosis, the most common form of iron overload disease, is an autosomal recessive genetic disorder that causes the body to absorb and store too much iron. Excess iron is stored throughout the body in organs and tissues, including the pancreas, liver, and skin. Without treatment, the iron deposits can damage these organs and tissues. There are two primary variants that give rise to this disease.

Genetic variant 1 (C282Y/rs1800562) is in the HFE gene. The HFE gene makes a membrane protein that is similar structurally to MHC class I-type proteins and associates with β2-microglobulin. It is thought that HFE helps cells in the intestines, liver, and immune system control iron absorption by regulating the interaction of the transferrin receptor with transferrin. The C282Y substitution disrupts the interaction between HFE and its β2-microglobulin light chain and prevents cell-surface expression. Pamela Bjorkman's 2.6 Å resolution crystal structure of HFE confirms that, as predicted from its sequence, Cys282 (residue 260 in the mature form of the protein) is involved in a disulfide bridge analogous to those found in class I MHC α3 domains. Loss of the disulfide destabilizes the native fold of the protein. The second most common variant is also in the HFE gene. It is a change of histidine 63 to aspartic acid. In the crystal structure of HFE, His63 (41 in the sequence of the mature form) is involved in a crucial salt bridge, which would be destroyed by mutation to a negatively charged residue, thereby also destabilizing the protein. Thus, like so many other hereditary disorders, hemochromatosis is a protein conformational disease.

In the US, variant 1 is the more frequent. The 'normal' Cys282 allele has guanine in both strands and is found in about 876 out of 1,000 people of European ancestry. The most common form of hereditary hemochromatosis is typically associated with people homozygous for an adenine in both positions; this occurs in about 4 out of 1,000 people of European ancestry (0.4%). However, penetrance is incomplete: only about a third to a half of the homozygotes will show elevated iron levels and perhaps fewer than 10% of the males (and 1 to 2% of the females) will develop the full clinical symptoms of the disease, which include joint pain, fatigue, abdominal pain, liver dysfunction, and heart problems. As Ernest Beutler has pointed out, the hemochromatosis mutation is relatively common; the hemochromatosis disease is rare. Mutation of the HFE gene is a necessary, but not sufficient, condition. The challenge, as in the case of so many diseases in the age of genomics, is to understand what other genetic, epigenetic, and environmental factors determine why a few homozygotes for the C282Y (or H63D) mutations develop severe iron-storage disease, while the majority go through life pretty much unscathed by this genotype.

Heterozygotes for C282Y have an adenine in only one strand and represent about 120 in 1,000 people of European ancestry; they almost never develop clinical symptoms. Heterozygotes for H63D are less common, but also are unlikely to develop clinical symptoms. Like one person in ten in the United States, I am a hemochromatosis carrier. I am heterozygous for H63D.

Now that I know that, what does it do for me? Not much, I guess, but I will remember it, and should I ever develop any of the symptoms of iron overload, I will probably tell my physician to check my iron levels. Maybe that's worth knowing.

But if you go to the website of the company that did my analysis, you will find that the sort of information I've talked about here is actually not that prominently displayed. What is displayed are all manner of data connecting to ancestry. I spoke to the CEO of the company, and she confirmed that, much to their surprise, people who use their service are much more interested in tracing their roots, genetically speaking, than they are in things related to their health or physical condition. The site offers several tools for connecting yourself with others who share your ancestry, genetically speaking. In other words, for the present, the primary use of personal genome-wide SNP analysis is social networking.

My maternal haplogroup is T2b2. Haplogroup T originated about 33,000 years ago in the Middle East, as modern humans first expanded out of eastern Africa. Its present-day geographic distribution is strongly influenced by multiple migrations out of the Middle East into Europe, India, and eastern Africa after about 15,000 years ago. T2 is currently widespread in northern Africa and Europe. My mother's family most recently came from Italy, so I guess this makes sense. You can find famous people with your haplotype on the site: for example, if your maternal haplotype is H4a, you have the same type as Warren Buffet, one of the richest men in the world. You'll be delighted - and perhaps not surprised - to know that the only famous person the site lists as sharing my maternal haplotype is the notorious old-west outlaw Jesse James.

My paternal haplotype is I2. Haplogroup I2 is most abundant in eastern Europe and on the Mediterranean island of Sardinia, where it is found in 40% of the male population. Like its brother haplogroup, I1, I2 expanded northward at the end of the Ice Age about 12,000 to 14,000 years ago. But unlike I1, which expanded from the Iberian peninsula into northwestern Europe, I2 radiated outward from the Balkans and southwestern Russia into the eastern half of the continent. That again makes sense, as my father's family were Cossacks. If my paternal haplotype were the extremely common C3, I would be descended from Genghis Khan. I'm not. If it were type T, I would share paternal lineage with the great American president and founding father Thomas Jefferson. I don't. In fact, the company website doesn't list a single famous person with paternal haplotype I2 (unless you count me, of course).

So now, thanks to my own personal genome SNP analysis, I know that I'm not likely to be exceptionally athletic and that I'm not a blue-eyed balding blonde, neither of which comes as any surprise whatsoever. But I have also learned that I'm not descended from Genghis Khan. So I've got that going for me. Which is something, I suppose.

Published: 29 June 2009

Wimps? What wimps?

Genome Biology 2009, 10:109

They arrive the last week of August on college campuses all over the USA. Accompanied by anxious, hovering parents (indeed, the term 'helicopter parents' has entered the lexicon), they spill out of rented vans and SUVs, looking bewildered and much younger than their years. They are the freshmen, the entering university students who are about to experience, for the first time in their lives, the thrill of independence.

Or are they? Increasingly, American college students are going through their four years of higher education - and often years more beyond that - still firmly attached to the parental umbilical cord. It's an invisible umbilical cord - you probably call it a cell phone - but it's an umbilical cord nonetheless. It's not that unusual for some third- and fourth-year students at university to call or text their parents several times a day. Some of these calls are simply to share the most mundane details of their daily lives, but a large number of them are to ask advice on everything from what courses they should be taking to what activities they should join to what they should do about a roommate who snores.

This is completely different from my college experience and, I suspect, the college experience of practically everyone in my generation. True, we didn't have portable communication devices, but I don't think it would have made any difference if we had. We didn't want to be in constant contact with our parents. We went away to college in part so as not to be in constant contact with our parents. What's more - and this is the key point, I think - our parents didn't want to be in constant contact with us. OK, one time when I hadn't phoned home for more than a week to reassure my folks that I was still alive and spending their hard-earned tuition money, when I finally did call, reversing the charges as usual, my father, on being asked by the operator if he would accept a collect call from his son Greg, replied, "I have no son named Greg. I used to have one, but we haven't heard from him in thirty years" and hung up. But that was an extreme situation. The point is, if I had suddenly started phoning home three or four times a day, my mother would have called the university health service to get them to find out what was wrong with me, and my father would have called the campus police to get them to find out who was impersonating their son. And most of their contemporaries would have reacted the same way.

A few years ago psychologist Hara Estroff Marano wrote an article in Psychology Today called 'A Nation of Wimps'. (You can find it at on the Psychology Today website http://www.psychologytoday.com/node/21819 and I urge you to do so; it's worth reading.) In it she argues that we are in danger of raising a generation of Americans who are unable to think for themselves, who have a distorted view of the world as a dangerous and hypercompetitive place, who are accustomed to playing the system because their parents have bought or finagled special privileges for them throughout their childhood, and whose self-esteem is consequently nowhere near what it should be. Here are a couple of excerpts:

"Behold the wholly sanitized childhood, without skinned knees or the occasional C in history. "Kids need to feel badly sometimes," says child psychologist David Elkind, professor at Tufts University. "We learn through experience and we learn through bad experiences. Through failure we learn how to cope." Messing up, however, even in the playground, is wildly out of style. Although error and experimentation are the true mothers of success, parents are taking pains to remove failure from the equation..."

"No one doubts that there are significant economic forces pushing parents to invest so heavily in their children's outcome from an early age. But taking all the discomfort, disappointment and even the play out of development, especially while increasing pressure for success, turns out to be misguided by just about 180 degrees. With few challenges all their own, kids are unable to forge their creative adaptations to the normal vicissitudes of life. That not only makes them risk-averse, it makes them psychologically fragile, riddled with anxiety. In the process they're robbed of identity, meaning and a sense of accomplishment, to say nothing of a shot at real happiness. Forget, too, about perseverance, not simply a moral virtue but a necessary life skill. These turn out to be the spreading psychic fault lines of 21st-century youth. Whether we want to or not, we're on our way to creating a nation of wimps."

I've taught college freshmen for almost 30 years and, let me tell you, I think for many of our youth that ship has already sailed. During the past couple of decades, I have seen students on average become less independent and more fearful, indecisive and risk-averse. Many of them have been so suffocated by their parents and so insulated from even the slightest disappointment by well-meaning but ineffectual educators that they are likely to be locked in a state of adolescence for years after they graduate. And because they've never learned how to handle defeat and discouragement, they are also prone to depression and acute anxiety when suddenly confronted by difficulties: in school, in relationships and in life choices.

Now, I don't want to fall into the trap of making overgeneralizations, something I think Marano is guilty of in that article. Many students today are well adjusted, capable and independent young men and women. I meet them all the time. What I'm trying to say is that I have noticed an increase in the number who are not, and that increase seems to be correlated with an increase in what I would call overparenting. It's also correlated with a sharp rise in the number of students who are documented to have some sort of learning disability, and who therefore are entitled to - and always request - special accommodations on tests and quizzes. I'm deeply sympathetic to any student with a legitimate difficulty that they are trying to overcome, but I worry that at least some students have been placed into a category in which they don't belong by their parents and educators as a way of helping them do better, and consequently they never develop the confidence in their own abilities that they will need when they face a world that won't make any special accommodations for them whatsoever. So if you allow for the somewhat sensational tone of the article, I think Marano has some important points to make.

Of all the virtues to which I aspire, high on the list would be self-reliance. I take pride in being able to repair computers, fix electrical problems, do basic plumbing and build some of my own furniture. Until cars became rife with anti-pollution devices and overburdened with complex electrical systems, I did a lot of my own automobile work, as did many people of my, and particularly my father's, generation. I like not having to depend on others any more than is absolutely necessary, and I don't mind making mistakes. But I suspect, if Marano is right, that this is one of many respects in which I am about to become as uncommon as a woolly mammoth.

Yet there is one place where, if you want to, you can still find young people who take risks, think for themselves and persevere in the face of numerous setbacks. That place is anywhere you find a junior faculty member in the sciences. We may be about to become a nation of wimps, but the ranks of the instructors and assistant professors constitute a wimp-free zone.

It has become a cliché that, as we get older, we tend to look down on young people as having a much easier time of it than we did. (I've caught myself about to say, to some graduate student complaining about a shortage of pipette-persons, "When I was your age we didn't have pippettemen; we blew our own glass pipettes, and we made the glass from sand as well!") That attitude couldn't be more inappropriate in the case of scientists just starting their academic careers. Beginning investigators have a much more difficult time than we did, in just about every aspect of academic life. It's so much harder to get funding, for one thing. We went through some troughs in federal support for science when I was starting out, but nothing like the doldrums of the past seven years. Competition is fiercer for fellowships, young investigator awards and all the other little things that help make getting one's career going easier. The number of scientists has increased dramatically, but the number of such sources of support has not.

Genomics hasn't made things easier. It's the main reason that biology has become a technology-driven science, which means that, to play at a high level, the cost in equipment alone can be very high. So not only does the aspiring genome biologist have to raise money in an era of tight funding, he or she has to raise more than the average senior faculty member in many other fields.

The bar is also much higher in terms of what is expected in order to gain recognition - and, eventually, tenure. 'Publish or perish' has become 'publish in one of a handful of journals with a high impact factor or perish'. I had the luxury, when I was getting established, of publishing my papers in the places I thought they belonged, which often included highly specialized journals. Heaven help the young biologist who does that now.

Then there are the daily discouragements, which are more numerous, I think, than those we suffered at their age. Because it's harder to get grants today, the average young investigator must endure several rounds, and often years, of failure. Tough enough to get turned down when you've at least had the experience of some success. But to be told repeatedly that your proposal hasn't made the grade when you're just setting off on your own would break many a weaker person. And let's not forget, as I just pointed out, that we are forcing these young people to publish their papers in journals with astronomically high rejection rates, thereby exposing them to regular pummeling from inexperienced editors and misanthropic reviewers.

But, you say, at least they have help from of those of us who have already been through the mill. Not necessarily. I know of many institutions where the senior faculty deliberately take a 'hands-off' approach with younger colleagues - a sort of 'sink-or-swim' philosophy that mandates simply observing whether someone has the right stuff to make it on their own. I believe this distancing is often well intentioned, because inviting a junior faculty member to collaborate can be the kiss of death: at many schools, if an untenured investigator has worked extensively with senior colleagues, when they are brought up for tenure they are tarred with the brush of not really having accomplished anything themselves.

As if that weren't bad enough, I'm not even sure our junior colleagues get enough sympathy from their elders - at least, not in a form that does them much good. At precisely the time they need encouragement, not just about their own work but about the future of profession they are so eagerly trying to join, what they are most apt to hear from us is a litany of complaints about how difficult things are and how bleak that future looks. It's a miracle more of them don't chuck it all and go into a career with better prospects, like selling landline telephones.

So let me offer a few suggestions for things we all could do to make their struggles just a bit easier and their burdens a tad lighter. First and foremost, we should abandon, as a matter of policy, the senseless, haughty and counterproductive belief that they must do everything on their own. Institutions should reward young scientists who collaborate effectively with their senior colleagues for helping to knit departments and programs together, not penalize them for failing to demonstrate some macho-driven concept of 'independence'.

Second, we should be wary of what sort of impression our own carping makes on our young associates. Remember, we are who they want to become, and if they see us as dissatisfied, shrill and constantly frustrated, even the best of them may have second thoughts about getting to where we are. I'm not saying we must give up complaining - at my university that'd be like suggesting that a koala give up eucalyptus leaves. But let's do our complaining to each other, and remember that one of the most important things we have to give to our junior faculty (and eventual successors) is a sense that this is a life worth living and a career worth fighting for. We have to help them keep hope alive.

Third, we must, as a community, condemn the practice of trashing research proposals from beginning investigators as 'overly ambitious'. I've seen this ploy used frequently and it always makes me furious. Being ambitious is what got us where we are. It's what drives much of the great science. It's a virtue, not a vice. I suspect that, when this charge is made, the reviewer actually doesn't have anything negative to say about the substance of the proposal but is merely trying to assert his or her own superiority. It's inexcusable behavior. If you really think the science is exciting but the investigator has proposed far more than they can do in the time allotted on the grant for the money they have requested, fund the damn thing and let them find out by experience how much can be done in four years. To force them to resubmit an otherwise good proposal just to remove some specific aims gives the impression that their senior colleagues are a bunch of nit-picking, supercilious jerks. Which we probably are, but it's nothing to be proud of.

Finally, we should not forget to express to junior faculty everywhere our sympathy and understanding for what they're going through, and our gratitude that they have chosen to endure it. Because without them, our line would be extinct, and the fire of science would die out. Applaud them for their dedication, aspiration, and above all their fortitude. Because they are anything but a bunch of wimps.

Published: 29 July 2009

Nation of twits

Genome Biology 2009, 10:110

I think what finally did it for me was when the Pope got a Facebook page. True, there were warning signs: on 22 July 2009, the crew of the space shuttle Endeavor, orbiting high above the planet, communicated with the earth using Twitter and YouTube. But such minor pandering to youth culture pales into insignificance beside the sight of the smiling face of Pope Benedict XVI, greeting visitors to his unfortunately named website Pope2You.net (I am not making this up), where you can download the application 'Pope2You for Facebook' which, to quote the site, "lets you receive the messages of Pope Benedict XVI through the most important social network of the world. So you can meet the Pope on Facebook, listen to his words, see his pictures, and receive his messages of congratulations through 'virtual postcards'. The postcards can be sent to your 'friends' on Facebook and the application can be shared with anyone. So we can create a close sharing network around our Pope." This, you will recall, is the same Pope who last year issued a well-publicized warning about the dangers of technology.

Social networking is to the latter part of this decade what the Internet was to the 1990s: a technology that both typifies the era and shapes it. In 2000, Harvard University political science professor Robert D Putnam wrote a well-received book, Bowling Alone (an expanded version of an article he had published five years earlier in the Journal of Democracy), in which he sounded the warning that all forms of in-person social intercourse were declining, owing to the technological 'individualizing' of our leisure time via television, the Internet and eventually 'virtual reality helmets'. It's hard to imagine he could have been more wrong. True, the older generation might have viewed technology such as the Internet as leading to increased isolation, but the younger generation has exploited it for exactly the opposite purpose: as a way of building interpersonal ties. The hottest technology companies in the world right now are the ones that create and maintain social-networking sites: namely Facebook, which allows people to advertise themselves on the World Wide Web; LinkedIn, a kind of Facebook for professionals looking to advance their careers; YouTube, a site for sharing videos; and Twitter, a site that basically takes the concept of the text messages so beloved of cell-phone-toting teenagers and allows users to post them as 140-character limit 'tweets', where they can be seen by enormous number of people.

It's easy to see why Twitter has become the social network du jour, at least in the United States. It provides the illusion of human contact without the messy reality. The 140-character tweets are perfect for an age of short attention spans and minimal literacy. And it gives people a glimpse into the daily lives of celebrities and other glamorous folk.

The problem is that, once you actually take such a glimpse, you quickly discover that the daily lives of most glamorous folk are pretty much just like our own: not merely unglamorous but often downright dull. Here, for example, is a tweet from one Chris Cooley, a professional US football player for the Washington Redskins team, sent on the opening day of training camp this year: "Had a six inch Sub for lunch and now I'm headed back to practice number 2. Ugh." Wow. Talk about inside information. Makes you wonder who would waste their time reading this, doesn't it?

Well, the answer, in Chris Cooley's case, is about 12,000 people, who apparently find such 'insights' riveting. That's how many Twitter 'followers' he has, that is, people who have signed up to receive his every tweet as soon as they are posted.

The wrong tweet can get you into all sorts of trouble. Just ask Antonio Cromartie, another US football player (what is it with these guys?) who was recently pulled out of a team meeting and fined $2,500 for the following tweet: "Man we have 2 have the most nasty food of any team. Damn can we upgrade 4 str8 years the same ish maybe that's y we can't win the SB we need." That's right, Cromartie was fined $17.86 for each of the 140 characters of his complaint about training-camp food. At those prices he could have taken out a full-page ad in the local newspaper.

Except, of course, that young people aren't reading newspapers. Instead, they're getting their information from Twitter. And sometimes that's not a bad thing. During the recent political unrest in Iran, most of the authentic news leaking out of that country came in the form of tweets from Iranians and foreigners who happened to be there. (Of course, anything important will quickly be exploited by capitalists, and businesses have already been caught using Twitter and other social-networking sites as a way of spreading sales pitches about their products and misinformation about their competitors, all disguised as 'objective' tweets from disinterested parties.) That's how useful Twitter can be, and it's likely to become more important in the future, as a means of overcoming censorship, for example.

Even US President Barack Obama is getting into the act. His Twitter page, which has 2,045,875 followers, contains observations such as this: History was made today when Sonia Sotomayor took the judicial oath and joined the Supreme Court. Congratulations, Justice.1:31 PM Aug 8th

Still, it is the mind-numbing banality of the activities of virtually every person who tweets regularly that truly impresses. Here, for example, is a tweet from former Vice-Presidential candidate Sarah Palin, posted the day before she resigned as Governor of Alaska: "Wrapped up Anch Gov's Picnic, awesome. Now road trip to Fairbanks for farewell speech/changing of the guard. Camper full of kids & coffee." Where else can her 139,667 Twitter followers get that kind of political scoop?

Do a search for 'genomics' on Twitter and you get a number of genome biologists who tweet regularly. Here are some completely representative tweets from several of them, in no particular order:

The mutt is panting & hiding behind the couch - thunderstorms must be close now....5:46 AM May 16 th

milk was a bad choice 12:22 PM Aug 21 st (I checked to see if there was any follow-up to this one, but there wasn't, so we don't know if the choice was bad because of spoiled milk, some religious prohibition against dairy products, or whatever)

ooooo savin up my moneyyyy to buy a new dishwashaaaa 4:31 PM Aug 19 th

ACLU sues over patents on breast cancer genes - http://bit.ly/KuRBE#cnn 4:32 AM May 13 th (Now this is actually informative, and an example of something that does happen frequently on Twitter: the tweet contains a link to a web page with some information - typically a news story. One function of this social network is for members to alert each other to things of mutual interest.)

Sneezing up a storm, I must have fried a trillion brain cells so far - hope this cold is over soon, I don't have that many to spare! 5:18 AM Apr 29 th

Ontario Institute for Cancer Research (OICR) to Use Helicos' Single Molecule Sequencing Technology http://bit.ly/9n9Mq#genomics#ngs 11:00 PM Aug 20 th

RT @RibogeniX: Yes.. there is an app for that !! calculates Tm, protein, DNA concentrations etc, etc on iphone http://ow.ly/kUWR 6:48 PM Aug 21 st (This is another example of the usefulness of tweeting. RT means 'reply to' and @RibogeniX is the Tweeter ID of someone who apparently asked a question about whether there was an application for the iPhone that performed some calculations they needed. This sort of sharing of advice happens frequently on Twitter.)

Watching election update 9:24 PM Nov 4 th , 2008

new word of the day: Infovore, one that is a voracious consumer of information 8:34 AM Aug 12 th

practicing procrastination. I just don't feel like doing laundry tonight 5:35 PM Apr 10 th

That pretty much sums up Twitter, at least in my experience: occasional flashes of insight or information mixed in with an amazing amount of trivialities. The motto of Twitter is "What are you doing?" and you can see that, even in the case of genome biologists, the answer would often appear to be, "Not much that should interest anybody." Except that, for whatever reason, it does: the average genome biologist has between 50 and 200 followers on Twitter.

Twitter is probably the ultimate example of the triumph of the 'Me' generation. Its very premise, that everybody's most insignificant thoughts or experiences are de facto interesting to someone, and maybe a lot of someones, and therefore are of great intrinsic importance, carries the solipsistic notion that "I am the cosmos" about as far as it can be carried. Twitter also is reducing the English language to misspelled shorthand and is training a generation to substitute emoticons (e.g.: (for sadness) for genuine descriptions of real human emotions. Imagine William Faulkner's great novel The Sound and the Fury written by one who was raised on Twitter. We'd get The Snd & the: {

That said, Twitter, and other social-networking sites, do provide a way for certain communities to make contact and remain connected. Social networking online also encourages brevity, although from my experience, that has yet, on Twitter at least, to become the soul of wit.

But Im L8 4 walkng dogs so no more column 4 now. U can xpect nxt column 2 b about sumthng more important.

Published: 28 August 2009

An issue to remember

Genome Biology 2009, 10:111

Even by that journal's lofty (and frequently self-proclaimed) standards, the 3 September 2009 issue of Nature is likely to be regarded as one of the most memorable in years. Many issues of a general journal have at least one thing in them that is of interest to each reader, but in this case it could be argued that almost everything in this issue is likely to be of interest to practically everybody. Anyone wishing to present evidence of the health of the global scientific enterprise could probably just hold up a copy and then sit down.

Nanotechnology is a field that has sometimes been characterized by more hype than results, but the paper from Nadrian Seeman's lab on page 74 is worthy of all the attention it is likely to attract. It reports the design and synthesis of a triangle of three DNA helices that self-assembles into a three-dimensional periodic array. The authors then prove that the array has the intended structure by crystallizing it and determining its atomic arrangement at 4 Å resolution. As far as I know, this is the first time a well-ordered macromolecular three-dimensional crystalline lattice has been designed and successfully assembled. It opens up the possibility of manufacturing a wealth of nanoscale objects from the stuff that make up the genome, including templates on which other nanoparticles can be assembled. A disclaimer is in order here: Ned Seeman, who is one of the pioneers of biomaterials nanotechnology, has been one of my closest friends for 35 years. I remember when he first described his plans to do this project, over 25 years ago, so this paper is the culmination of more than two decades of effort. But he needs no special favors from me to publicize this work; it is a landmark achievement and if you read nothing else in the article, you should read the last paragraph, in which Ned outlines the possible applications of this technology. It presents a mind-blowing view of a future in which nanoscale fabrication can be done with a precision and versatility that seemed like science fiction not that long ago.

Then there are three papers that represent structural biology at its best, using structure to unveil the details of important cellular mechanisms at the atomic level. They provide the solution of the three-dimensional structure of a mechanosensitive ion channel in its intermediate state, and new insights into the mechanism of action of the molecular motor kinesin, and into the export of tRNA, respectively. In an era when the mindless grinding out of hundreds of structures of proteins of no known function in structural genomics is considered exciting big science and is lavished with support, work such as this reminds us that what structural biologists should be doing is picking important problems and using the power of their technology to probe how things work.

The papers noted so far are enough to make any issue of any journal worth reading, but I haven't even scratched the surface of this one. I will skip over fascinating papers on the molecular basis of the evolution of the heart chamber, and the discovery, in the Andromeda galaxy, of stars and coherent structures that are likely to be the remnants of dwarf galaxies destroyed by the tidal field of this giant one. Two papers stand out as being truly historic. They represent the first reports of the generation of fertile adult mice from induced pluripotent stem cells (iPS cells).

iPS cells are to stem-cell biology what the polymerase chain reaction (PCR) was to cloning. Before PCR, cloning a gene was a hit-or-miss proposition requiring years of work. After PCR, anybody could clone almost anything. Until recently, stem-cell biology was hostage to the technical difficulty, and ethical quagmire, of producing human embryonic stem cells (human ES cells) from human blastocysts. Shinya Yamanaka and his graduate student Katzutoshi Takahashi, from Kyoto University in Japan, changed all that in 2006 when they reported the creation of what they called 'induced pluripotent stem cells'. iPS cells could be generated from a wide variety of differentiated mammalian cells (typically skin cells) by transfection with just four genetic factors. Numerous studies by Yamanaka (who as far as I'm concerned should start booking his flight to Stockholm now to ensure a good seat) and by other workers have confirmed that iPS cells resemble ES cells in morphology, gene-expression profiles, proteomic profile and the epigenetic status of several pluripotency markers. They can also differentiate into a wide variety of specialized cells. But it had not been shown that they could generate viable adult animals.

Until now. On pages 86 and 91 of the 3 September issue of Nature, Qi Zhou's and Fanyi Zeng's groups in Beijing and Shanghai, and Kristin Baldwin and Kristopher Nazor's groups at the Scripps Institute in La Jolla, California, respectively, report the successful generation of healthy, fertile adult mice from iPS cells through tetraploid complementation. A similar result was achieved simultaneously by Shaorong Gao's group at the National Institute of Biological Sciences in Beijing, and was published in the 7 August, 2009 issue of Cell Stem Cell. These data prove conclusively that iPS cells are truly pluripotent and that reprogramming differentiated cells with just the four 'Yamanaka factors' can recapitulate the reprogramming capacity of the oocyte.

So it's been done three times, and if it can be done three times it can be done a thousand times, and it certainly will be. iPS cells are going to change the shape of the biomedical world. In my view, all our existing cell-culture models of disease, many of which are generated with inappropriate cell types such as tumor cell lines, need to be re-evaluated in the light of what iPS cells can do. Given the ability to make pluripotent stem cells from easily obtainable cells of a patient with just about any disease, and the relative ease with which those iPS cells can be converted into neurons or liver cells or just about any cell that is needed, the likelihood is that we are on the cusp of a revolution in how we study a host of processes in living organisms.

But I have to say that none of the papers I've talked about so far is my favorite (sorry, Ned). On page 53 of this remarkable issue is the one I enjoyed the most: 'Early-warning signals for critical transitions' by Marten Scheffer at Wageningen University in the Netherlands and a host of colleagues from other countries. This paper lays out a set of critical signs that a complex system - whether the climate, the brain circuitry of an epileptic, or the financial markets - is about to undergo a dramatic shift from one state to another. If the financial 'masters of the Universe' had only been able to read this paper before the recent financial crisis - well, OK, being a bunch of greedy morons they probably wouldn't have understood it and almost certainly wouldn't have paid attention to it even if they had. Still, for anyone who wants to see when something big is about to happen, the paper is riveting. The authors develop a mathematical model of transitions that provides support for their conclusions, but their essential concepts are easily understood in non-mathematical terms. Basically, systems about to undergo significant transitions experience critical slowing down, increased asymmetry of fluctuations ('skewness'), oscillation between two substates ('flickering'), and the appearance of particular spatial patterns. The authors go on to show that these early-warning signals can predict the onset of transitions in people prone to asthmatic and epileptic seizures, the end of glacial periods, changes in direction of the financial markets, and a number of other real-world applications.

Obviously, I really enjoyed reading this issue of Nature, and the point I now want to make is that I wouldn't have read it at all if I hadn't happened to read it. Let me explain. I knew that Ned had an important paper coming out soon, so I scanned the table of contents of each issue of Nature for a couple of weeks. That in turn caused me to notice the papers by Zhou and Steffen and all the others. But had I instead searched for Ned's paper online, I would have missed them. True, I might have found the iPS cell papers eventually because I am interested in that topic, but I never would have read the early-warning signal paper, or the tRNA export factor paper, or most of the other papers I've talked about here.

Picking up a copy of a journal and thumbing through it - browsing, as we used to call it - has gone out of fashion with the advent of electronic databases and searching the literature with Google or PubMed. That may be more efficient but it's a lot less fun. Creativity is the art of the unexpected, of putting disparate facts together, of connecting the dots between two fields where connections are not known to exist. The more precise our searching, the more specialized our knowledge, the less chance there is of the happy accident from which new ideas almost always spring.

In the rush to do away with paper copies of journals and move towards all-online publication (like this journal), we are in danger of forgetting the importance of finding ways to keep browsing alive. As long as paper copies of journals exist, I will try to find the time to flip through them, hoping for that happy accident. Precise searching within the confines of one's field certainly helps to create experts, but I am willing to bet that those who arrange their intellectual lives so that they only find what they are looking for will forever work for those who browse.

Published: 29 September 2009

The dog days of autumn

Genome Biology 2009, 10:112

In the world which we know, among the different and primitive geniuses that preside over the evolution of the several species, there exists not one, excepting that of the dog, that ever gave a thought to the presence of man. Maurice Maeterlinck

Greg Petsko is tied up with teaching, so, by popular demand - actually, he wonders why there never seems to be a demand for more from him- his column will be guest-written this month by his two dogs, the mixed poodle/spaniel Clifford and the chocolate Labrador retriever Mink (Figure 1). They are not strangers to these pages, having written before, to much acclaim. Precisely how they manage to type their text is unclear.

Mink: Did you see the paper in the issue of Science for 2 October 2009 (326:150-153) by Cadieu and coworkers? It's entitled Coat variation in the domestic dog is governed by variants in three genes.

Clifford: What's a domestic dog?

Mink: I'm not sure. I think maybe it's the opposite of a foreign dog.

Clifford: Are you a foreign dog? After all, you're from Labrador.

Mink: No, I'm from New England. My ancestors were from Labrador. And yours were from France and England.

Clifford: Does that mean I'm not a domestic dog? I don't want to be a foreign dog! I don't speak French!

Mink: Calm down. We're both domestic dogs, I'm sure. But we're getting off the subject here. Did you see that paper?

Clifford: No, I didn't. Was it written in French?

Mink: Will you forget about French! It was written in scientific English, which means it's not easy for a little puppy to understand, but I'll explain it to you. It's about the genes that control different coats in dogs.

Figure 1

Mink (right) and Clifford proudly display their different coats and wish to remind the Editor that, although they don’t work for peanuts, they do work for lamb chops.

Clifford: You mean like how your coat is dark brown and mine is like wheat?

Mink: No, the genes that govern coat color have been known for quite a while. This paper is about the genes that control coat length, growth pattern, and curl. For example, I have a fur coat that's all one color, and it only grows to a certain length and then it stops. I shed in winter -

Clifford: I'll say you do! I've never seen so much brown fur flying around! Why, the carpet in the family room is covered with little mounds of -

Mink: Yes, yes, I know. I can't help it. But as I was saying, I have solid brown, straight fur while you have patchy off-white and beige curly hair. Your coat would just keep growing forever and curl into huge mats if you didn't get taken to the groomer for -

Clifford: I hate the groomer! Hate them!

Mink: Can we stay focused here? I know you hate the groomer. You make that perfectly plain every time Greg tries to take you there. I haven't seen such a performance of suffering since we watched that television broadcast of King Lear with Greg last spring.

Clifford (sotto voce): Hate them!

Mink: OK, we've established that. But the point I'm trying to make is: look how different our coats are.

Clifford: Mine's better. Except for having to go to the groomer. I hate -

Mink (quickly): I'm glad you like your coat. I think mine is perfectly fine, too. And I don't have to go to the groomer. So there.

Clifford (sullenly): What was your point about the paper?

Mink: Oh, yes. The paper. Well, our coats are so completely different, you would think that there would be many genes that were involved in determining those different properties. But the authors of this paper found that's simply not the case. They carried out what are called genome-wide association studies (which is basically just looking for variations in gene sequence that correlate with changes in some property) of more than 1,000 dogs from 80 domestic breeds to identify genes associated with canine fur phenotypes. They were able to take advantage of both inter- and intrabreed variability.

Clifford: What does that mean?

Mink: I think it means that, although dogs' coats vary a lot from breed to breed, like with you and me, they also vary a bit within breeds. Not all poodles have the same kinds of coat, as any groomer can tell you.

Clifford: I hate the groomer!

Mink: Right. Nothing more about groomers, I promise. Anyway, it's an advantage when you have small variations within a breed, because you can use that to find the small number of genes that most likely account for those variations (they stand out against a background that doesn't vary so much since all the dogs are from the same breed), and then you can pay particular attention to those genes when you look for what controls the much larger variations between breeds. That makes genome-wide association studies in dogs much easier and more rewarding than genome-wide association studies in people, where it's harder to find candidate genes, so you have to look at thousands of individuals and it's very expensive.

Clifford (proudly): Dogs are better than people.

Mink: Of course we are. But as I was saying, Greg has talked about this before. He is convinced that, for association studies in people, it would be smart to use the relatively common mutations that give rise to autosomal recessive diseases and examine the carriers for association with other diseases. For example, people with Gaucher Disease are much more likely to get multiple myeloma, so an obvious thing to do would be to see if Gaucher carriers are overrepresented among myeloma patients. Greg thinks that's what the human genome people ought to be doing if they want to make rapid progress on diseases, because the carrier mutations are known to affect the functions of those proteins, so they're much more likely to do something than the common variants that the gene association studies mostly look at. Greg says those people are barking up the wrong tree.

Clifford: Barking up the wrong tree? Why would anybody bark up the wrong tree?

Mink: I have no idea.

Clifford: Can we get back to talking about dogs?

Mink: Sorry. As I was saying, with dogs you can get a good idea what genes to look at as well, from variations within a breed. That's how the people in this paper started their project. The team of scientists, which was headed by Elaine Ostrander of the National Institutes of Health -

Clifford: I've heard of her! She's a genome biologist. We like her. She works on genes responsible for cancer susceptibility in people and dogs. Cancer is the number one killer of dogs. We hate cancer! We hate it almost as much as we hate the gr -

Mink (even more quickly): Yes, she is a great benefactor of the canine race. You may remember that, about two years ago, she headed the team that studied height variation in dogs (Science, 316:112-115, 2007). Dogs have the greatest variation in height of any mammalian species. She discovered that the default for dogs is to be tall, like me, but that a mutation in a single gene, insulin-like growth factor 1, could account for the fact that many dogs are quite small, like Chihuahuas, fox terriers, and, well, like you.

Clifford: I'm not small! I just have short legs for my body height.

Mink: Whatever. The point is, it was a big surprise that one gene could account for such big differences.

Clifford: How did they find that gene? I forget.

Mink: Exactly the same way they found the genes in this study. They first looked at variation in height within a breed where it varies a lot: Portuguese water dogs. That allowed them to home in on the likely gene. Then they checked it across breeds.

Clifford: President Barack Obama has a Portuguese water dog named Bo, doesn't he? I wonder why he didn't pick a poodle/spaniel mix.

Mink: Or a chocolate Lab. Well, nobody's perfect. Anyway, that discovery sort of made sense because insulin-like growth factor is one of the genes that controls cell growth and lifespan.

Clifford (musing): I'd like to meet Bo. Do you think President Obama would let him play with us?

Mink: Can we stay on the topic here? This column'll be over soon.

Clifford: OK. Did they use Portuguese water dogs in this new study about coat variation too?

Mink: As a matter of fact, they did. One of their same-breed groups comprised 76 Portuguese water dogs, because it's a breed that varies a lot in hair curl. They looked at three phenotypes, actually: hair curl, hair length, and the presence or absence of what they call 'furnishings' - you know, that little moustache and bushy eyebrows you have.

Clifford (proudly): I am well furnished.

Mink: Of course you are. Well, after they looked at a few same-breed groups, they then examined genetic variation across 903 dogs from 80 different breeds. They found that distinct mutations in just three genes, RSPO2, FGF5, and KRT71, together account for most coat phenotypes in pure-bred dogs in the United States.

Clifford: You mean my coat is controlled by just three genes?

Mink: Maybe not. They only looked at purebreds, and you're a mixture of two breeds.

Clifford: Are you insulting my mother? I'm just as pure as -

Mink: No, not at all. It's just that, er, uh, more sophisticated dogs like you are too complex for simple genetic analysis.

Clifford: That's me, all right. I'm complicated.

Mink: You can say that again. Anyway, RSPO2 largely controls furnishing, which is interesting, because the gene codes for a protein called R-spondin-2, which is a signaling regulator that synergizes with the Wnt pathway to activate β-catenin, and Wnt signaling is required for the establishment of hair follicles in mammals. The mutation doesn't seem to change the protein sequence; it probably affects the mRNA level. You know, this same pathway is involved in the development of hair-follicle tumors, or pilomatricomas, which occur most frequently in breeds that have furnishings. Recent studies have shown that a mutation in the EDAR gene, also involved in the Wnt pathway, is responsible for a coarse East-Asian hair type found in humans, and as you know, that hair type has some similarity to canine wirehair.

Clifford: Do you think this pathway controls Greg's hair?

Mink: He's a middle-aged man. What hair?

Clifford: How about the other two phenotypes?

Mink: Curl seems to be determined by the KRT71 gene, which codes for one of the forms of keratin, the major protein component of hair.

Clifford: That makes sense. Does the mutation change the protein sequence?

Mink: Yes, it does. It replaces one amino acid, an arginine, with a tryptophan. But why that leads to curly hair is not obvious. The third gene, FGF5, is involved in hair length.

Clifford: What does that protein do?

Mink: It makes one of the fibroblast growth factors. Makes sense, right?

Clifford: It does. Amazing. And if a dog has all three genes mutated...

Mink: He's a wire-hair.

Clifford: Like our friend Max in the park. Cool. But why is this important - besides the fact that it refers to dogs, of course?

Mink: Isn't that enough? Well, I guess one other reason is that it explains how so many different sizes, shapes and appearances of dog could have arisen in only about 15,000 years of accidental and deliberate breeding. If combinations of only a few genes can have a big effect on morphology and so forth, it won't take that many generations to produce a large number of possibilities. In fact, it's thought that most of the breeds we see today originated since about 1800, so it really can happen fast. Dog evolution is much faster than evolution of other mammals in the wild.

Clifford: That's because we're a superior species.

Mink: Obviously. After all, who lies around all day and gets fed, while the other species works to support us?

Clifford: Isn't evolution wonderful?

Mink: It is, but in our case, I prefer the term intelligent design.

Published: 4 November 2009

Advice and dissent

Genome Biology 2009, 10:113

Former US President George W Bush was not a man given to irony. Yet, asked where he got his information, he replied, "The best way to get the news is from objective sources. And the most objective sources I have are people on my staff."

Sadly, for the United States and for the world, he was not being ironic - he actually believed what he said. The notion that people close to the king typically try to remain close to the king by telling the king what he wants to hear does not seem to have occurred to that remarkably unreflective man.

Woe betide the courtier who troubles his or her monarch with unpleasant realities. Professor David Nutt must now understand this principle better than anyone. Until a few weeks ago he was the chairman of the UK's Advisory Council on the Misuse of Drugs (ACMD) - an independent expert body that provides scientific advice to the British government on drug-related issues, including recommendations on how to classify the dangers of cannabis (marijuana), ecstasy, and other drugs of abuse. On 30 October 2009, David Nutt was summarily fired by the British Home Secretary, Alan Johnson, for giving the government advice and then criticizing it for not taking it.

That advice concerned the thorny issue of reclassification, of cannabis in particular. Few subjects illustrate the divide between conservatives and liberals more starkly than drugs, and cannabis is the drug that provokes the most heated debate. People may argue about whether all drugs should be legalized, but they generally agree that heroin and cocaine are dangerous substances that can have severe psychotropic effects. Cannabis, however, is viewed so differently by liberals and conservatives that one's opinion on its harmful effects could serve as a shibboleth for distinguishing the two philosophies. Most liberals consider marijuana a relatively harmless recreational drug, along the lines of alcohol but less addictive and not so socially damaging, whereas most conservatives regard it as a tool of the devil - a drug that, in addition to producing all manner of terrible side-effects, is guaranteed to lead its user down a slippery slope to more dangerous drugs.

In Britain, cannabis was originally classified in 1971 in The Misuse of Drugs Act as a Class B drug. The category was created specifically for cannabis and some other drugs (such as amphetamines) as a compromise between those who thought cannabis was as dangerous as heroin (Class A) and those who thought it was a 'soft' drug like the benzodiazepines (Class C). After several abortive attempts to reclassify it, marijuana was officially downgraded to Class C in 2004 after a recommendation by the ACMD. These classifications can have significant consequences: if cannabis is a Class B drug, people convicted of possessing it could, in principle, face up to 5 years in prison, compared to a maximum of 2 years if it were Class C. In 2008, however, the then Home Secretary Jacqui Smith rejected the advice from the ACMD to keep cannabis at Class C and moved it back to Class B, despite the council's extensive review of evidence concerning its long-term effects, including any link to mental illness.

David Nutt, who was appointed chair of the ACMD in 2008, reacted angrily to this decision. In October, in a lecture given at Kings College London on a briefing paper prepared for the London-based Centre for Crime and Justice Studies, he publicly accused ministers of "devaluing and distorting" the scientific evidence over illicit drugs by their decision to reclassify cannabis to Class B against the advice of the ACMD. In deciding to speak out, he was probably also stung by the government's decision, in February of this year, to veto another ACMD recommendation, following a review of 4,000 papers on the subject, that the drug ecstasy be downgraded from Class A. His public criticism of the government was rapidly followed by his dismissal from the ACMD by Alan Johnson, a government action that has ignited a firestorm of editorials and comment, including predictable references to the Catholic Church's prosecution of Galileo in 1633 (for a set of links, see http://www.guardian.co.uk/uk/david-nutt).

No one questions the government's legal right to sack someone they appoint; at issue here is the cause. It cannot be a question of competence: David Nutt is certainly well qualified. A professor at both the University of Bristol and Imperial College, London, he is a specialist in the psychopharmacology of depression, addiction, insomnia and other psychiatric disorders. The stated reason for his dismissal was that, by going public with his dissent, he made it impossible for the government to send a clear and consistent message about drugs to the public.

A number of people agreed with that decision. In an opinion piece in The Telegraph on 7 November, Alasdair Palmer wrote, "Prof. Nutt isn't a martyr to science who lost his job merely for confronting the government with incontestable facts. He was sacked because, as Mr Johnson insisted, 'he cannot be both a government adviser and a campaigner against government policy'." He goes on to say that "Prof. Nutt's views on policy matters ... are not straightforward inferences from the scientific facts ... the harm that cannabis can cause in teenage brains is a good reason for, as the government says, 'erring on the side of caution' and classifying cannabis as a Class B drug, with heavy penalties for those convicted of possession. The science does not force you to that conclusion - but then it does not force you to the conclusion that cannabis should be downgraded to Class C."

But many scientists were appalled by the government's actions. Two members of the ACMD immediately resigned in protest, and three more have resigned since, raising the possibility that the committee might no longer have enough expertise to do its job. And a week after Nutt's dismissal, more than 20 academics, including Martin Rees, the President of the Royal Society, sent the government a set of guidelines that they say "would enhance confidence in the scientific advisory system and help government to secure essential advice." The guidelines assert that "disagreement with government policy and the public articulation and discussion of relevant evidence and issues by members of advisory committees can not be grounds for criticism or dismissal." When scientific advice is rejected, they said, the reasons should be described explicitly and publicly.

Ironically, Nutt's sacking took place just days after the British government had issued a statement about the importance of independence in scientific advice that said, in part, that scientists should not be criticized for publishing scientific papers or making statements as professionals, independent of their role as government advisers. So why was David Nutt sacked, really?

My guess is that it had relatively little to do with the issue of scientific independence and a lot more to do with the peculiar nature of drugs as a political and social lightning rod. Few issues, short of abortion, raise the moral outrage of the Right as reliably as a suggestion that we should go softer on those who use certain drugs. Governments advocate such positions at their peril. Facing a hostile electorate because of the financial crisis, together with a strong challenge from a reinvigorated Conservative Party, the Labour government of Gordon Brown probably felt it could ill afford to be seen as being anything but hard-line on any drugs issue at this time. Not firing Professor Nutt, they obviously thought, would send a mixed message to the voters about their confidence in their drugs policy.

Regardless of the underlying motives, this case should have a powerful resonance in the United States. For 8 of the past 9 years, the American government deliberately misrepresented and ignored scientific advice whenever that advice contradicted the ideology of those in power. It routinely put poorly qualified scientists and even non-scientists in 'scientific' advisory positions, so long as they passed the litmus test of political and religious attitudes. The government edited scientific data and conclusions out of reports, and persecuted government scientists who questioned its policies. So bad was the situation that, when he was elected, President Barack Obama felt the need to address this problem publicly in both his Inaugural Address on 20 January 2009 ("We will restore science to its rightful place") and in a speech he gave before the National Academy of Sciences on 27 April ("...we have watched as scientific integrity has been undermined and scientific research politicized in an effort to advance predetermined ideological agendas").

Ignoring and marginalizing science has a long, sorry history in the United States. One of the main reasons for the failure to develop a firm policy on the climate crisis can be seen in the persistent tendency of several administrations to find that handful of scientists who disagreed with the majority opinion and listen only to them. Confronted with scientific evidence that one of his cherished beliefs was simply not supported by the facts, President Ronald Reagan would simply dismiss it by saying, "Oh, I don't think that's true." The Eisenhower and Truman administrations stocked their scientific advisory boards with physicists who shared their militaristic, cold-war anti-communist philosophy, and in some cases persecuted those (J Robert Oppenheimer, for example) who begged to differ.

The tension between scientific advice and policy advice remains strong. I believe that it is the function of a scientific adviser to any government to provide advice purely on scientific matters. Your job, in other words, is to tell your bosses what the data say. If the data are relatively unambiguous and there is good consensus on their interpretation, that needs to be said. If there are reasonable opposing conclusions that are supported by reliable measurements, it is important to see that those views are aired. But a scientist has to be careful about advocating a particular policy in response to the science. If science can say that there is a probability that a particular policy would have severe negative consequences, it is essential that governments be told that. But in general, policy is a matter not for scientific advisers but for politicians.

Politicians, we are constantly told, acquire and retain power by deceit and salesmanship, and frequently are contemptuous of the people they profess to serve. But, true as that cliché might be (and happily there are some notable exceptions), it is their job to get something done, and getting something done frequently requires making compromises that appall or offend the scientist. A good politician usually keeps his or her options open. I agree completely with the guidelines proposed by the 20 academicians in Britain, which state that scientific advisers should not be dismissed for public criticism of policy decisions - but I would issue a caution to those advisers who contemplate doing so.

Scientific advisers should be free to air their views, and not just on matters of science. But they need to understand the consequences. Politicians are naturally suspicious of anyone with an agenda, and not being reluctant to spin the facts if it serves their purpose, they are quick to believe that others will do so as well. If scientific advisers seem to be advocating particular policies, their scientific objectivity will come into question, regardless of the solidity of their conclusions. David Nutt was right to criticize a policy decision that he felt went against the science. But it led to his being removed from a position where he might have been able to influence such policies in the future. If we want governments to learn to trust scientific advice, we have to ensure that such advice is seen to be objective, as well as actually being so. In his position, would I have done what Professor Nutt did? Probably, but with one significant difference: I would have resigned before going public with my criticism, thereby establishing the separation between my duties as a scientific adviser and my duty as a concerned scientist to speak out about a flawed policy. I also think the Labour government overreacted, and in so doing turned a debate about drug safety into one about the independence of scientific advice and the limits of dissent. Instead of looking tough on drugs, they came across as being afraid of the truth.

We as academics cannot give the advice governments need to hear if we are seen as just another political faction with its own (usually liberal) agenda. The great strength of science is that its conclusions are evidence based. Scientific advice, like Caesar's wife, must be above suspicion. If we appear to stray, we lose.

Published: 24 November 2009

A harsh climate

Genome Biology 2009, 10:115

I might as well come right out and say it: I don't care whether global warming is caused by manmade greenhouse gas emissions. And neither should you.

Before you start reaching for your laptops, iPhones, and BlackBerrys to fire off scathing emails, give me a moment to explain why I made this statement and what it really means. I bet that, when I'm through, you will agree with me.

This column is being written because of the confluence of two events. One is a meeting in Copenhagen of representatives of most of the world's nations, aimed at formulating a new global strategy for dealing with the climate crisis. The talks have ground to a halt as I write this because the group of developing countries, known as the G-77, has accused the United States and other industrialized states of forsaking the Kyoto Protocol, the current climate agreement that imposes greenhouse gas emissions on nearly every developed nation.

The second event is 'Climategate', the release of illegally hacked emails between climatologists. As an example of giving aid and comfort to the enemy, Climategate could hardly be improved on. In late November, a computer file including more than 1,000 emails either sent from or to members of the University of East Anglia's Climate Research Unit (CRU) was stolen and released on the Internet. The emails contain language that opponents of emission curbs have seized on as alleged examples of data manipulation and outright fraud on the part of climate researchers. For example, one email apparently sent by the head of the CRU, Professor Phil Jones, refers to using "Mike's Nature trick of adding in the real temps to each series for the last 20 years ... to hide the decline". The CRU is one of the leading research units on climate change, and their data had a major role in the Fourth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC), released in 2007, that provided unequivocal evidence for global warming (see Figure 1).

Figure 1

Unequivocal evidence for a warming planet. Global surface temperature trend from three global datasets: NOAA (NCDC Dataset), NASA (GISS dataset) and combined Hadley Center and Climate Research Unit of the University of East Anglia (UK) (HadCRUT3 dataset). The data clearly indicate a dramatic, and accelerating, warming trend over the past 150 years. Reproduced from the World Meteorological Organisation [http://www.wmo.int/pages/index_en.html].

Of course, scientists use the word 'trick' all the time as a shorthand term for a method or algorithm, but professional skeptics rarely bother themselves with the way scientists work. It seems likely that the files were stolen in an attempt to undermine the Copenhagen talks, but my assessment is that there are so many other contentious issues in that meeting that this is a relatively minor matter for most of its participants. Nevertheless, Professor Jones has stepped down as head of the CRU pending an internal investigation. In my view, he should instead have been made to write on the blackboard 1,000 times: "I will never put anything into an email or text message that could be embarrassing to me or to my organization if it were read by someone else, and if I don't believe this I should ask Tiger Woods."

One of the most sensible things I have read about the climate debate is an opinion piece by Stewart Brand in the 15 December 2009 edition of The New York Times. He argues that the popular depiction of the combatants as belonging to two camps, the alarmists and the skeptics, is fallacious. There are actually four sides: denialists, a group consisting of people with a right-wing political agenda who assert that the claim that global warming is caused by manmade emissions is a lie and is not based on sound science; skeptics, a group largely comprising scientists who argue that climate science, particularly large-scale modeling, is far too imperfect to form the basis of a consensus; warners, another group of scientists who believe that the best climate models accurately predict a looming planetary disaster and that human production of greenhouse gases is the primary cause; and calamatists, a collection of environmental activists whose agenda, like that of the denialists, is ideologically driven, but in the opposite direction: they have a neo-luddite view of industrialization, and believe the denialists are evil. As Brand, a self-described warner, points out, understanding from which of these camps any given argument springs is useful in distinguishing propaganda from science, and appeals to emotion from evidence-based assertions.

Yet even Brand misses what I think is the crucial point, the point I want to make in this column, which is that you can't win a war if you are fighting in the wrong field. And in the war over climate change, which should be fought in the field of science, the denialists and the calamatists have dragged us into battle on their turf.

When you're in a fight with an opponent who is not above using invective and illogic, the worst mistake you can make is letting the other side define the terms of the debate. That's exactly what has happened in the argument about climate change. For decades the denialists insisted that the earth was not getting warmer. Short-term fluctuations were meaningless, they asserted. Climate modeling was worse than useless. The doomsayers were just trying to push a liberal political agenda, and so on. But after massive amounts of data were collected and analyzed by the Intergovernmental Panel on Climate Change, it became clear, on the release of their report in 2007, that no sensible person could deny that a dramatic rise in the planet's average temperature had been occurring for at least a century (see Figure 1). Largely thanks to Al Gore, this information also reached the general public, whose reaction even the staunchest denialists could not ignore.

So they did what clever, unprincipled losers often do: they changed the issue. Of course the earth is getting warmer, they said (blithely ignoring the fact that they had said exactly the opposite the day before), but human activities have nothing to do with it. It's entirely due to natural causes, and people who assert that manmade greenhouse gases are causing the problem are employing flawed science, deliberately distorting the facts (Climategate), and are using fear to advance the same old, tired environmental activism. Because global warming is not a manmade phenomenon, there is no scientific or political reason to limit manmade greenhouse gas emissions. Sarah Palin (why am I not surprised?) is one of the leaders of this chorus, stating recently that climate change occurs naturally "like gravity", while warning that reducing greenhouse gas emissions will mean "job losses" and "economic costs". (This is the same ex-Alaska governor Sarah Palin who, before becoming a national political figure, said in July of last year, "Alaska's climate is warming. While there have been warming and cooling trends before, climatologists tell us that the current rate of warming is unprecedented within the time of human civilization. Many experts predict that Alaska, along with our northern latitude neighbors, will warm at a faster pace than any other areas, and the warming will continue for decades." I don't know whether to laugh at that kind of soulless opportunism or just cry.)

This strategy is actually working, to some extent. It's much harder to establish the cause of something than it is to prove that something is happening, and the data supporting manmade emissions as the leading driver of climate change are not nearly as persuasive, or as immune to challenge, as the data demonstrating the fact of global warming. And scientists, foolishly, have allowed that to become the center of the climate crisis debate. I say foolishly because, in so doing, they have given up the victory that they already won.

The denialists have conceded the fact of climate change. And here is my central point: once you admit that the earth is warming rapidly, it does not matter in the least whether that trend is due to manmade causes or not.

Regardless of its origin, a rapidly changing climate is a very bad thing. We have built an entire civilization on the assumption of long-term climate stability. We grow wheat in Kansas rather than in the Yukon because Kansas has an ideal climate for growing wheat and the Yukon is too cold, and we assume that will still be the case 10 years from now. We build our cities on the coast because that is convenient for shipping goods, and we assume the coastline won't suddenly move 10 miles inland. We don't have air conditioning in many homes in northern California because we assume the average temperature won't suddenly rise by several degrees, making summer unbearably hot. We assume that England won't have a yearly climate like Lapland, even though its position on the globe might lead one to expect otherwise, because the Gulf Stream will always be there off the west coast, keeping things moderate. Every one of these assumptions fails in the event of significant global warming. One reason I prefer the term 'climate crisis' to 'climate change' or 'global warming' in discussing this problem is because our dependence on stable long-term climate patterns means that any change in those patterns represents a potential catastrophe on a planet-wide scale.

It doesn't matter what the cause of that crisis is; once you accept the fact that the crisis is coming, the only thing that matters is how to prevent it or slow it down. And the only way we have of doing that at the moment is to reduce our greenhouse gas emissions. Put another way, human activity may not even be causing the earth's temperature to rise, but human activity is the only means we have of doing something about it.

A simple analogy may make this point clearer. Suppose we learned tomorrow that there was one chance in ten that a huge asteroid, recently discovered, was going to crash into the earth in 5 years, killing a billion people and raining debris in such amounts as to blot out sunlight significantly for a year. (A similar event is thought to have led to the extinction of the dinosaurs.) Would anyone in his or her right mind argue that, because we couldn't prove that human activity was responsible for the asteroid, there was no reason to hurt our economy by spending hundreds of billions of dollars firing nuclear-tipped rockets at it to destroy it or alter its course? Yet that's exactly what the denialists are trying to argue now, in the case of a climate crisis that has at least an equal probability of globally devastating consequences.

True, our climate models can't predict with certainty that the steps being considered in Copenhagen will retard, halt or reverse the current warming trend. But they represent all we can do at the moment. If global warming is being caused primarily by greenhouse gases, as many thoughtful scientists believe, then they will do a lot. If global warming is actually caused by, say, sunspots or something similar, reduction of emissions may not do so much. But everyone agrees that they will do something, and my point is that something simply has to be done.

I hope you see now why I started this essay as I did. We should not be debating whether human activity is responsible for global warming or not. Given that even the denialists and skeptics have conceded the fact of global warming, the debate should be over the most effective means of doing something about it. This means, I am afraid, not just limiting our discussion to controls on CO_2 emissions. We need to look seriously at developing technologies for carbon sequestration, alternative fuels, and carbon-neutral technologies for transportation and energy production. Much of this will involve engineering microorganisms and plants, so genomics is going to be very important in enabling these technologies as we grapple with the crisis. I also see no escape from at least investigating ideas for geoengineering - solutions involving deliberate changing in sunlight absorption, carbon capture and temperature reduction on a continent- or planet-wide scale. My gut reaction to geoengineering is that it is a terrible idea, born as much of hubris as desperation, that should be shelved permanently because we will never have the kind of models that would guarantee beforehand that it could be done safely. But the fact is, we don't know what we don't know when it comes to such projects, and, given the severity of the climate crisis, if someone wants to propose that we should at least begin to study such solutions to determine the extent of our ignorance and the possibility that we might someday be able to employ them, I wouldn't say no.

So, the next time you find yourself in a debate with someone over the climate crisis, and they say that we shouldn't reduce CO_2 emissions because there is no definitive proof that manmade greenhouse gases are the cause of global warming, respond by saying, "Then if an alien race were threatening to exterminate mankind, you wouldn't do anything to try to stop them because human activities weren't the cause of the alien invasion, is that right?" And they'll reply, "Of course not! But this is completely different." And you'll say, "No, it's not. Let me explain why."

Given the harsh climate that has developed around the subject of global warming, you probably won't convince them that they're wrong. But at least you'll be having the right argument.

Published: 30 December 2009

Rising in the East

Genome Biology 2010, 11:102

The publication of the complete genome sequence of the giant panda, Ailuropoda melanoleuca, is a watershed moment for genomics, and not just because of the technology used. Before I explain, let me say a few words about that technology, because it is worth commenting on. The sequence, which was published in the 21 January issue of Nature (Li et al., Nature 2010 463:311-317, with a nice News and Views piece by Kim Worley and Richard Gibbs on pages 303-304; see also the minireview by Shaun Jackman and Inanç Birol in Genome Biology http://genomebiology.com/2010/11/1/202), was determined largely at the Beijing Genomics Institute (more on that later), which is not actually in Beijing, but never mind. It's an important genome, in part because the giant panda is a highly endangered species (only a few thousand are known to exist), in part because on the tree of life the panda sits between the human and the dog, but also because it is the first reported mammalian genome sequence to be determined using so-called 'next-generation' sequencing methods.

NGS methods, as they are widely called, use machines that produce very short sequences at very high speed. Compared with more traditional sequencing methodologies, they also cost much less per base pair. Some tests of NGS sequencing have been reported, but none involved the de novo assembly of an entire mammalian genome. Only the human genome sequence (2001-2003) and the mouse genome sequence (2002) have been completed with high redundancy and few gaps. Other large genomes, such as those of the dog, rat and monkey are basically drafts (approximately sevenfold coverage).

Genome sequencing is done in stages. After the genome is fragmented, the fragments are sequenced by machines that typically read 1,000 bases at a time. The reads are assembled by merging overlaps at the ends to form continuous sequence fragments (contigs). Traditional mammalian genome sequences contain contigs 100 kilobases long, so that often a complete gene is contained in one, providing reasonable accuracy. Contigs are then ordered into larger semi-continuous stretches, called scaffolds, using a variety of bioinformatics tools. A scaffold will contain a number of contigs separated by gaps. Larger gaps separate the scaffolds from each other. A good draft sequence of a mammalian genome will have perhaps a hundred scaffolds, or even fewer. Some people have wondered whether NGS machines, which typically read less than 100 bases at a time, would ever give comparable accuracy.

The Chinese team has answered that question, with a loud affirmative. The giant panda sequence has 73-fold average redundancy and a median contig length of 40 kilobases. Those are not typographical errors. The high redundancy offsets the assembly error problems that would compromise the quality of the sequence if the coverage were 10-fold or less. However, because of the short fragment read length, there are 3,805 scaffolds. That is not a typo either.

Illumina machines were used for most of the sequence, and the total cost of the sequencing itself has been estimated at less than US$1 million - at least 10 times less than that of a comparable genome done by, say, Sanger sequencing machines. While we are still a way off from the $1,000 human genome sequence, the $100,000 human genome sequence is essentially here.

To me, however, the real import of this paper lies in its geographic origin. The Beijing Genomics Institute (BGI) has its sequencing facility in Shenzhen, near the border with Hong Kong. It is a new but unremarkable building whose 11 floors of relatively plain decor belie the state-of-the-art science going on. It is the brainchild of Yang Huanming, a US-trained scientist who founded BGI in Beijing in 1999 as a private, non-profit research organization. Yang quickly got his fledgling institute involved in China's contribution to the Human Genome Project. Three years later, they made the cover of Science by winning the race for the sequence of the rice genome. Using Sanger sequencing machines, they completed that project in just 74 days. The giant panda sequence took 6 months.

In 2007, the BGI made two momentous decisions. They made a huge investment in NGS technology, focusing on the Illumina Solexa machine, and moved their headquarters to Shenzhen. The director is now a home-grown genome biologist, Jun Wang, who is only 33 years old. He is the last of the 123 authors of the giant panda genome sequence paper.

The goal of the BGI-Shenzhen is to sequence informative genomes from all branches of the tree of life. In 2008, they completed the sequence of the genome from a Han Chinese individual, only the third published complete personal human sequence. Their intention is to sequence at least 100 more individuals within a few years, to explore the enormous ethnic variation in the Chinese population.

The BGI has about 30 Illumina Genome Analyzers, and can produce tens of Gigabases of sequence per day. The institute is exploring the use of other technologies, such as the SOLiD system developed by Life Technologies. It has a supercomputer center comprising 500 Linux nodes to do the assembly and analysis, and it needs it: the sequencing generates 10 terabytes of raw data every 24 hours. The computer center alone has an annual budget of about $9 million; the annual budget of the institute is $30 million.

I know what you're thinking: "I could do the same thing here if I had that kind of support from my government." The only problem with that is that you're mistaken. The BGI is a totally private organization, and doesn't derive a single cent of its budget from direct appropriations. It exists entirely on competitive contracts and grants, income from some spin-off companies, plus some private donations.

And this is just one institute of many in the exploding Chinese scientific landscape. I could instead have told you about the National Institute of Biological Sciences in Beijing (China's version of the legendary MRC Laboratory of Molecular Biology in Cambridge, UK), where scientists have successfully produced fertile mice from induced pluripotent stem cells. Or the 10 different Institutes of the Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences, China's version of the intramural research program of the National Institutes of Health.

But instead, let me tell you about the Kungming Institute of Botany, which is located in the capital of Yunnan Province, close to Tibet. In addition to doing first-rate botanical work, this institute contains the State Key Laboratory of Phytochemistry and Plant Resources of West China, which focuses on the search for bioactive molecules from natural sources. In this unique research facility, teams of chemists screen the vast biodiversity of the region and local ethnobotanical knowledge to discover compounds that can be developed into new drugs for unmet therapeutic needs and agrochemicals that do not harm the environment, and then synthesize them and make analogs of them. I toured the institute with an American synthetic organic chemist, and every other poster he would grab my arm, point to something, and say, "I've never seen anything like that [molecule or reaction] before!" In other words, the Kungming Institute of Botany, an institute you've never heard of in place a thousand miles off the beaten track, is one of the great centers of natural product chemistry in the world.

At a time when the United States is talking about three years of level government spending and an anti-intellectual movement I once thought was fading looks to be stronger than ever (more on that next month), China is beginning to tap the vast resource of its enormous population. Chinese culture has a strong work ethic, the government is pouring money into science, higher education is trying to emulate that of the United States, and living conditions have improved to the point that many foreign-trained Chinese scientists are going back home instead of remaining abroad permanently. Their research system, which is less hierarchical than that of Japan or Korea, is much better than either of those two countries in allowing young scientists, women as well as men, to be independent and advance. I could say something as well about the more gradual, but nonetheless impressive, rise of science in India, or its rapid rise in Singapore. The Far East, once a scientific backwater, is becoming a powerhouse.

In 1854 the American Indian Chief Seattle, considering whether to sign an unfavorable treaty, uttered these words:

But why should I mourn at the untimely fate of my people? Tribe follows tribe, and nation follows nation, like the waves of the sea. It is the order of nature, and regret is useless. Your time of decay may be distant, but it will surely come, for even the White Man whose God walked and talked with him as friend to friend, cannot be exempt from the common destiny.

I have always believed that not only was he right, but that sometime during my lifetime would be the time where future historians would draw their imaginary line and say, here marks the beginning of the fall of Western civilization and the rise of the East. I don't actually know if that's true, of course, but this much seems certain: Western scientific hegemony is fading fast. If you doubt it, just look at how many of the interesting and important papers in the leading journals are starting to come out of China, Korea and Singapore, and still come out of Japan. You could start with the 21 January issue of Nature. You can't miss it - it has a pair of giant pandas on the cover.

I feel sorry for those scientists who published other papers in that issue. They probably spent a fair amount of time and effort making illustrations they hoped would be selected for the cover. They never had a chance.

Published: 29 January 2010

Lost in translation

Genome Biology 2010, 11:107

Francis Collins, the current director of the NIH (who, I might add, has got off to an excellent start), made a somewhat provocative remark after assuming his new position last year. Interviewed for The New York Times last October (5 October 2009; http://www.nytimes.com/2009/10/06/health/06nih.html?pagewanted=all), Collins is quoted as saying, "We're not the National Institutes of Basic Sciences, we're the National Institutes of Health." This remark came in the context of Collins' declared wish to encourage academic researchers to consider commercializing their ideas or pursuing drug development in universities, given the increasingly barren state of pharmaceutical company labs.

This reminded me of an article I read some time ago, which I largely agreed with but which made me hopping mad at the same time. It was 'Big biology is here to stay' by Steven Wiley, a Pacific Northwest National Laboratory Fellow and director of PNNL's Biomolecular Systems Initiative, which appeared in the The Scientist http://www.the-scientist.com/article/display/54854. Subtitled 'Why R01-funded biologists should throw their support behind large-scale science projects', the thesis of the article was that, "The business of the National Institutes of Health (NIH) is to fund research that improves people's health, not fund our personal research projects." In the article Wiley confesses that he originally thought the Human Genome Project would be a waste of money, but now thinks "we were all wrong". He goes on to say that, "Starting new, large-scale research projects was a clear demonstration that NIH was willing to try new approaches to accelerate biomedical research... trying to shift funds away from these large projects will ensure that they do fail, and will be self-defeating in the long run. We'd better hope these projects are successful, and we should do all we can to help them."

Now, given my well known views on the ascendancy of big science over little science, and the increasing tendency to direct research from the top down by bureaucratically initiated programs, you may be wondering why I say that I largely agree with Wiley's sentiments. The reason is that neither Wiley's column nor Collins' remark was really about big science in the sense that I mean it. I dislike large-scale, top-down programs; they are referring to projects aimed at translating the findings of biomedical research into therapies for human disease. Many of the big science projects that I regard as not worth continuing, like the structural genomics initiative, aim to advance fundamental knowledge rather than produce direct health benefits, and many of the others, like the effort to associate common genomic polymorphisms with risk for disease, are simply not likely to produce significant health benefits no matter what their intention was.

I have no problem with good science, whether it's large or small, although I do believe we must always have both sizes, and that research driven by the curiosity of the individual investigator should be the predominant kind we support. I agreed with Wiley (and Collins) because they were in fact making a case for good science aimed directly at finding cures versus science aimed at expanding our basic knowledge of biology - in other words, translational research versus basic research. And that is also precisely why the Wiley article (and the Collins remark) made me angry. It wasn't what they said. It was the way they chose to talk about it.

I hate translational research. Now, before you either applaud or burst a blood vessel, you should know something else: I also hate basic research. Or, to be precise, I hate the terms 'translational research' and 'basic research'.

If there's a theme, besides the transformative nature of the age of genomics, that runs through the columns I've written for the past 10 years, it's that the words we use to describe something are incredibly important, and often get us into all kinds of trouble. We should never have used 'therapeutic cloning' to describe somatic cell nuclear transfer; having the word 'cloning' in there allowed religious fundamentalists to define the terms of the debate about embryonic stem cells. We should not have let the term 'chemical' become a pejorative. 'Global warming' is a poor phrase to rouse people to change their way of life - 'climate crisis' might have been much better (and also would have had the virtue of being alliterative). But of all the poorly chosen words in recent scientific history, few are as bad as 'translational research' and 'basic research'.

How did we allow this purely artificial distinction to dominate our discussion of funding priorities? It's everything we should avoid. It sets up a dichotomy that is bound to confuse the lay public; it divides us into two warring camps, competing for attention and resources; and it implies, falsely, that there may be a difference in value in the kind of work that we do based on its intent.

We should make this our mantra as life scientists: there is no such thing as basic research and no such thing as translational research. There is only research, period. If we must put an adjective in front of it, then let's use 'biomedical'. But we simply have to stop talking about our science as though there were different versions of it, with different objectives and different implicit worth.

Do you really think that what is called basic research could exist if the public, and its elected officials, did not believe they would ultimately derive some benefit from it? And what would translational research have to translate if no new fundamental discoveries were made? These two feuding city-states need each other, and ought to be united in common cause against the invading empire of ignorance, superstition, and anti-intellectualism. But more than that: they shouldn't be separate states in the first place.

We simply have to stop talking about research as though there were two kinds. There aren't. When we start to use those divisive terms, we have to check ourselves. When a scientific official like Francis Collins uses them, we have to urge him not to. And we have to make peace within our own community, with both sides in the current dispute recognizing not only that they need each other to survive, but that our enterprise is seamless - a continuum from the most basic discovery to its most practical application. If Barnett Rosenberg hadn't wondered what would happen to Escherichia coli cells when they were placed in an electric field, we would never have known that cisplatin, which doesn't have a single atom of carbon in it, was a drug that could block cell growth and division. But if a number of other scientists hadn't worked with him to follow the implications of that observation and test cisplatin on cancer models in animals, and then to fight for its eventual testing on people, testicular cancer would not be a curable disease, and Lance Armstrong would probably be dead. There is no basic research and no translational research; there is only research, in all its frustrating, expensive, confusing magnificence. Why should we take one of the greatest monuments to the human spirit and turn it into the Balkans?

But if you agree with me, and I hope you do, you are probably wondering, "Well how, then, can we explain to the public that you have to support the Barney Rosenbergs of the world doing things just to satisfy their own curiosity in order to get the cures you want? At least the way Collins and Wiley talk about research, you can piggyback support for basic research onto the flood of money coming in for translating discoveries into therapies. If you can't talk about the two parts of the enterprise that way, how do you get support for it at all?"

The answer, I think, is that we haven't been making the argument for the support of biomedical research as well as we could. Wiley is wrong when he says, "The business of the NIH is to fund research that improves people's health, not fund our personal research projects." The business of the NIH is to fund both, because they are the same thing. But how do we get that point across? Next month, I'll tell you.

Published: 26 February 2010

No stone unturned

Genome Biology 2010, 11:112

Last month, I wrote about what I consider to be one of the most serious problems facing the life sciences in the age of genomics: the increasing polarization between those who do what they call 'basic research' and those who do what is termed 'translational research' http://genomebiology.com/2010/11/2/107. I argued that we have created this problem ourselves by accepting this divisive terminology and using it in everyday discourse. And I asserted that we should abandon, forever, what I think is an artificial and inaccurate distinction.

But such a change raises a potential problem. Support for what we will no longer call basic research has, for quite some time, piggybacked on the support for what we will no longer call translational research, which was what scientific leaders presented to governments and laypeople as the raison d'etre for public support of biomedical research. Generally, they didn't talk much about basic research at all, believing that the public wouldn't understand it very well and therefore wouldn't support it. They understood its importance themselves, so they paid for it, but they didn't advertise it. National Institutes of Health (NIH) director Francis Collins's now-famous remark that "We're not the National Institutes of Basic Sciences" is but one example of this mentality. If we now are to talk about all research using the same language, how do we justify the support of projects that don't have an obvious clinical relevance, and may never have one?

This problem is becoming more acute because we have oversold some big science projects in order to gain the huge financial support they require. The human genome sequencing effort, which was really a basic research project, was presented as a faster route to diagnosis and cures for a host of diseases, although it typically takes decades for research results to lead to clinical advances. Congress and the public, having bought the original sales pitch, are now asking, "So where are the cures?"

Three articles in the 17 March issue of the Journal of the American Medical Association (JAMA) highlight this increasing impatience. They concern the War on Cancer, a huge increase in both funding and responsibilities for the US National Cancer Institute (one of the institutes that make up the National Institutes of Health) that was started by President Richard Nixon in 1971. Ignoring the fact that the language of the legislation implied that cancer was one disease, which it most assuredly is not, and therefore should have one cure, which it most assuredly does not, the war has led to $100 billion dollars in research funding in the past 40 years, much of which has been spent on 'basic' research in cellular and developmental biology. Now, as Susan Gapstur and Michael Thun point out 1, the cancer war has become a lightning rod, even for some who support its goals. "Frustration about the pace of its progress," they write, "has led some critics to dismiss advances that have been made," and "nearly 1 in 2 men and more than 1 in 3 women will be diagnosed with cancer given the current lifespan." The annual cost to the United States of all cancers, as given by Elena Elkin and Peter Bach in an accompanying article 2, is more than $90 billion a year (by comparison, the entire NIH budget is just a little over $30 billion). As more families face cancer-associated medical costs that can wipe out a lifetime of savings in a single year, the demand that scientists deliver on their promises is growing from a rumbling to a chorus.

Of course, there have been many successes in the cancer war, most of them resulting from fundamental discoveries about how cell growth is regulated and how cancer starts. Miracle drugs have turned testicular cancer and gastrointestinal stromal cancer and chronic myelogenous leukemia, to name but a few, into treatable diseases in many cases. But there are over 100 different forms of cancer, and most of them still have no cure if the disease is not caught at its earliest stages. Faced with this reality, the instinct of many scientific administrators and researchers is to make even more promises, and to push even harder for more applied research. Writing in the same issue of JAMA, John Niederhuber 3, the current Director of the National Cancer Institute, does exactly that: "To realize a future of personalized medicine, the translation of genomic and functional biology discoveries into clinical practice is essential."

So you see what we're up against. We should talk about research as a seamless whole, a continuum of effort that flows from fundamental discoveries with no obvious application inexorably to the prevention and treatment of human diseases. Yet in order to justify it to the public, we have created a distinction that could ultimately tear the biomedical community asunder. How do we make people understand why it is in their best interest for us to do things that have no apparent connection to their concerns?

An old joke encapsulates the problem. A drunkard is looking for his lost car keys at night under a lamppost. A passerby offers to help and asks exactly where he lost them. "Over there," he replies, pointing off into the darkness. "But then, why are you looking for them here?" says the puzzled samaritan. The drunkard explains, "Because the light's better here."

If the only kind of research we do is based on what we already know, we are looking where we already have light. If it turns out that's where the keys are, fine. But we usually aren't sure where the keys are, so we also need to go looking in the darkness. "Basic research" is the light that shines in that dark.

Now, I realize that basing support for all forms of research on a joke may not be the most politically astute of ideas - although I bet it would be a pretty good tactic if you have to explain biomedical research to a gathering of laypeople. Besides, in this age of 10-second sound bites, we need something more immediately memorable, and digestible. But the metaphor of hunting for what is lost provides the answer.

The greatest reassurance we can offer people with life-threatening or crippling illnesses is that we are leaving no stone unturned in our efforts to find them a treatment. If we only do research that applies discoveries we already have made, we are only looking under stones that have already been turned. That we must do, but if it's all we do, it's not enough. We also need to turn over new stones, because we have no idea where the answers lie. I think anyone can understand that, and appreciate it. This metaphor makes clear the value, and continuity, of all forms of scientific research. And it allows us to discard the 'basic' and 'translational' dichotomy once and for all.

When I go onto the web site of the National Institutes of Health http://www.nih.gov, which includes the National Institute of General Medical Science (that's 'Basic Sciences', in fact), I notice that this gigantic human endeavor has no motto (it says "The Nation's Medical Research Agency" as a subtitle, but any marketing expert would turn his or her nose up at such a dull and unmemorable phrase). I think it needs one. It should be something that any layperson can immediately grasp, something that speaks to the dedication, commitment, passion, and effort of biomedical scientists to do everything in our power to better their lives. It should be not just NIH's motto, but our motto. What could be better than "No Stone Unturned".

References

1. Gapstur SM: Progress in the war on cancer. JAMA 2010, 303, 1084-1085

2. Elkin EB: Cancer's next frontier: addressing high and increasing costs. JAMA 2010, 303, 1086-1087

3. Niederhuber JE: Translating discovery to patient care. JAMA 2010, 303, 1088-1089

Published: 29 March 2010

The devil's in the details

Genome Biology 2010, 11:117

The Health Care Reform Bill that was recently passed by the US Congress and signed into law by President Obama has admirably simple goals: to provide health care benefits to some 30+ million Americans who currently have none, and to begin to control the spiraling cost of health care, which is threatening to make a shambles of the US economy. But, as my mother was fond of saying, the devil's in the details, and at 2,562 pages of almost unreadable prose, there are a lot of details for the devil to hide in. This shouldn't detract from the extraordinary achievement of President Obama and the Democratic Party leadership in Congress; by simply getting the bill passed, they accomplished something that presidents since Theodore Roosevelt have failed to do.

Still, there is one particular detail that is worth scientists in general - and maybe genome biologists in particular - paying some attention to. It goes by the rather unglamorous name of SA 2688, and it's an amendment to the bill. It was inserted into the final package by Pennsylvania Senator Arlen Specter, a longtime champion of biomedical research and increased funding for the US National Institutes of Health (NIH). The amendment is 8 pages long, so I can't quote it in detail, but here's a summary of what it says.

The amendment creates a program called the Cures Acceleration Network (CAN) within the Office of the NIH Director (with a 24-member oversight board). CAN is to "award grants and contracts to eligible entities… to accelerate the development of high need cures, including through the development of medical products and behavioral therapies". A high need cure is defined as a product that "is a priority to diagnose, mitigate, prevent, or treat harm from any disease or condition; and for which the incentives of the commercial market are unlikely to result in its adequate or timely development". CAN's functions include: conducting and supporting revolutionary advances in basic research; translating scientific discoveries from bench to bedside; awarding grants and contracts to eligible entities; providing the resources necessary for government agencies, private companies, academic institutions, and investigators to develop high need cures; reducing the barriers between laboratory discoveries and clinical trials for new therapies; and facilitating review in the Food and Drug Administration (FDA) for the high need cures funded by CAN.

The board consists of 24 members, serving 4 year terms. At least one individual eminent in each of the following fields will be appointed: basic research; medicine; biopharmaceuticals; discovery and delivery of medical products; bioinformatics and gene therapy; medical instrumentation; and regulatory review and approval of medical products. In an unprecedented move, an additional four individuals from private venture capital firms will also be appointed, as well as eight representatives of disease advocacy organizations.

Finally, ex officio members will include a representative from each of the NIH, the Department of Defense Health Affairs office, the US National Science Foundation, and the FDA, the regulatory body that oversees the safety and effectiveness of medicines and treatments. The Board is to advise the NIH Director on 'significant barriers' to successful translation of basic science into clinical application. The Board will provide recommendations to the Director if such a barrier is identified. If the NIH Director does not accept such a recommendation, he must explain to the Board why he has not done so.

The CAN sets up a series of grant programs designed to facilitate the development of high need cures that are in compliance with FDA standards on the drug development and approval process. Eligible entities include private or public research institutions, academic institutions, medical centers, biotechnology or pharmaceutical companies, disease or patient advocacy organizations, or academic research institutions.

There are three types of awards: first, the Cures Acceleration Partnership Awards, which provide up to $15 million per project for the first year, in one lump sum. It seems that additional increments of up to $15 million can be applied for in subsequent fiscal years (but it is not clear whether more than one additional year of funding is allowed). The recipient must also come up with non-Federal matching funds in a ratio of $1 for each $3 of Federal funds received. The matching-fund requirement can be waived by the director. Second, there are the Cures Acceleration Grant Awards, which are also funded at up to $15 million the first year, with at least one follow-up funding cycle of up to an additional $15 million possible. There is no matching requirement for this type of award. Finally, there are the Cures Acceleration Flexible Research Awards, which allow the NIH director to use 'other transactions' besides contracts, grants, or cooperative agreements to carry out the goals and objectives of the award program. No more than 20% of the total funds available for the CAN program can be spent in this manner. The CAN is authorized at $500 million in 2010, with additional funds as required for each of the next 10 years.

On the surface, this sounds like a great idea, and one that might help improve the image of federally-funded scientific research with the general public. But the devil is in the details, and to understand that, I need to take a moment to explain a peculiarity of American civics to my non-US readers.

There are two major kinds of legislation that Congress can pass when it wants to establish new programs: authorizations and appropriations. Authorizing legislation is that "which authorizes the appropriation of funds to implement" laws that create agencies, programs or government functions. It does not give a government agency permission to write a check or enter into a contract. Rather, its purpose is to set parameters for government agencies and programs. An appropriations act, on the other hand, confers budget authority on federal agencies to incur obligations. In other words, authorizing legislation sets policies and funding limits for agencies/programs, whereas appropriations legislation is what a department or agency needs to obtain new money from the government to actually fund that agency or program. In the absence of an appropriation, agencies must find the money they need to satisfy an authorization by taking it away from other funded activities: this is the dreaded 'unfunded mandate' that drives administrators to distraction.

SA 2688 is - you guessed it - an authorization without an appropriation. It requires the NIH to spend $500 million a year for 10 years (about 1.7% of its current $30 billion budget), but it does not provide any new money to pay for it. So the money must come from somewhere, and the big fear among many in the scientific community is that it will come from the pool of individual investigator-initiated research support, which has no single large political constituency to fight for it, rather than, say, some of the large, disease-focused programs that are closely watched over by the patient advocacy organizations. This is a particular problem right now, because the NIH is facing a potential 'budget cliff' in fiscal year 2011, when the stimulus funds that Congress appropriated in response to the financial crisis expire, and the base NIH budget becomes flat again. Bleeding $500 million - or even a fraction of it - from the individual research grant pool would turn that cliff into an abyss.

There are various alternatives for 'finding' the money that the community should urge the NIH Director to look into. One would be to allow each of the disease-oriented Institutes and Centers of the NIH to designate grants and programs they are already funding as CAN programs - provided, of course, that they meet the general parameters of the authorization. That would allow CAN to coexist peacefully with the existing research that NIH supports.

But, whereas I like that idea, I'd like to see another one debated first, because there's a chance that I'd like it even more. It involves transforming the RoadMap program, which is already administered out of the NIH Director's office, into CAN.

The RoadMap was the brainchild of Elias Zerhouni, the former NIH Director (the agency is now headed by Francis Collins, a genome biologist). The purpose was to identify major opportunities and gaps in biomedical research that no single institute at NIH could tackle alone but that the agency as a whole needed to address, to make the biggest impact on the progress of medical research. Doesn't that sound exactly like what CAN is also concerned about? The RoadMap has never received the unqualified support of the biological science community, chiefly because they saw it as taking money and attention away from important fundamental research and channeling it into lower-quality, clinically oriented studies that often didn't go anywhere.

The CAN authorization provides a golden opportunity to reinvent this program in a way that Congress and the disease advocates would both love, while doing some very useful work. What's wrong with that? Well, nothing, but the devil's in the details. Read the wrong way, CAN could turn first-rate biomedical research programs at NIH and elsewhere into third-rate pharmaceutical endeavors. That would be a disaster, because the Bill greatly underestimates the cost of bringing a therapy to the clinic (almost $1 billion for a small-molecule drug, a third to a half of that for a biopharmaceutical), and risks promising the public cures that will take over a decade to materialize. Such an approach would also set the advocates for different diseases in direct competition with one another for this pot of money, which is the major reason I oppose focusing CAN on any one disease or set of diseases.

Why not, instead, take CAN at its word? It wants to accelerate the finding of cures, so let's focus it on the major bottlenecks to going from fundamental scientific discoveries to actual cures, for all diseases.

There are many of these. I think CAN should pick, say, two or three of them and make those its focus for the next 10 years. These should be what those three types of grants should be asked to address, and the money should be the money that is currently being spent on the RoadMap. Here are my personal favorites, but there are a few more that could also be imagined:

A major bottleneck is the inability to make analogs of complex organic molecules rapidly, especially those containing more than one asymmetric center. NIH still funds some research on the development of new synthetic methods in organic chemistry, but it used to fund a lot more. This is an opportunity for it to get back into that very important business.

Natural products are still very important sources of drugs, but they are hard to separate from the complex mixtures found in the wild and even harder to characterize and synthesize. CAN could throw some serious resources at the development of better methods to do these things.

Our animal models for toxicity are pretty good, but our animal and cell culture models for many diseases are terrible (this is particularly true for the major neurological disorders). Comparative assessments of all existing disease models, followed a program to fund the development of better ones where needed, would have a major impact on the pace of drug discovery, because such improved models would allow therapeutics to fail much earlier in the drug development pipeline, before expensive clinical trials are initiated.

The blood-brain barrier is one major reason that many pharmaceutical companies are abandoning their programs in central nervous system (CNS) diseases. It is very difficult to predict the CNS availability of a compound in humans without doing actual trials. The blood-brain barrier is a combination of restricted permeability of the brain to compounds in the blood with specific efflux pumps that export many drug-like substances. We need ways to design CNS-available compounds from first principles if we really wish to accelerate the development of cures for disorders such as Alzheimer's disease.

Most biopharmaceuticals are immunogenic, even when they are human proteins, and some of them are seriously so. One of the main reasons is that misfolded or aggregated proteins break tolerance, and the manufacture, storage and delivery of therapeutic biological macromolecules contains numerous opportunities for proteins to denature. Development of improved methods to form and maintain the native structure of these molecules would remove a significant obstacle to their increased use.

There's one more I would strongly suggest, but I don't have room to discuss it here. I've written about it in a commentary in our sister publication, BMC Biology, the flagship journal of the BMC series. The main point I am trying to make is that we should use CAN as an opportunity to energize the biomedical research community to tackle some of the major roadblocks to the development of therapeutics in general. That is, we need to make major improvement to the details of how we do such development, after all, when it comes to such development, the devil is in the details, and if we're going to beat the devil, those details are where we need to focus more effort.

Published: 30 April 2010

And they said it wouldn't last...

Genome Biology 2010, 11:121

As years go, 2000 was an eventful one. It was, of course, the beginning of a new millennium (I know, strictly speaking that should have been 2001, but no one seriously considered doing it that way). The dreaded Y2K bug that was supposed to shut down half the world's computers proved to be nothing but a bonanza for computer consultants. George W Bush was about to be elected President of the United States, thereby proving that in my country, an ordinary bloke can grow up to be president (provided that their father had been president, they came from one of the richest and most powerful families in the land, and had been handed virtually everything they ever got on a silver plate). The most popular songs included 'It's gonna be me' by a group called 'N Sync and a rap song called 'The real Slim Shady' by Eminem. The most popular baby names for boys were Jacob, Michael, and Joshua, which might make you wonder if the whole country had been converted to Judaism, except that the most popular girls' names were Emily, Madison, and Ashley, which suggested that if it had, it had been converted to Jewish WASPs. The most-watched television show in the US was a program called 'Survivor'. It was the first example of new concept called reality TV - a genre that was going to represent the nadir of the medium for the entire decade to come. In the movie theatres, the most popular films that year were 'Spider-Man', 'The Lord of the Rings: The Two Towers', 'Star Wars: Episode II - Attack of the Clones', and 'Harry Potter and the Chamber of Secrets' - fantasy adventures, every one. As the summer of 2000 approached, no one realized that, whereas they were immersing themselves in fake reality on television and fake unreality at the cinema, their real world was about to change forever.

On 9 June 2000, the first edition of Genome Biology appeared, both online and in print. It included a column by yours truly called 'The grail problem' [1]. The second issue, on 28 July, contained a second opinion column by the same author, this one entitled 'Dog eat dogma' [2]; it discussed how genomics was changing the Central Dogma of Biology from 'DNA makes RNA makes protein' to 'Sequence determines structure determines function.' You might have thought that this one-to-one mapping would have frightened most readers off, but that doesn't seem to have happened: almost 120 issues later, both the journal and this column are about to celebrate their 10th anniversary.

Genome Biology was the brainchild of many people, and I don't know who all of them were. My own dealings at that time were primarily with Miranda Robertson, Theo Bloom, and Vitek Tracz. Vitek was the founder of the open access publisher BioMed Central, and in the year 2000, open access publishing was regarded by many as a fool's dream and by many others as a threat to their way of life. Vitek, Miranda, and Theo were convinced not only that it was a viable business model, but that it was the wave of the future.

And if open access publishing was considered either heretical or ridiculous, the idea of a primarily online scientific journal was considered suicidal. Yet Genome Biology was conceived from the beginning as primarily an online publication; the print edition that went out to subscribers for the first few years was an afterthought and, frankly, looked like one.

Content was another potential problem. In January 2000, there were still a relatively small number of complete genome sequences, and nearly all of them were of prokaryotes. The founding editors and publisher of Genome Biology were betting on a revolution that really hadn't started yet in the minds of many people.

In retrospect, however, the timing couldn't have been better, because something else happened in June of 2000 besides the launch of this journal. At a gala televised press conference that featured US President Bill Clinton and UK Prime Minister Tony Blair, the publicly funded Human Genome Project and the privately funded Celera Genomics Corporation announced their simultaneous completion of the draft sequence of the human genome. And nothing in biomedical research would ever be the same again.

Yes, Genome Biology was in on the ground floor of what has been one of the greatest transformations in the history of science. What molecular biology promised, genome biology has delivered: the maturation of biology into a truly molecular discipline. Because now, at last, we have the parts list. In principle, we can know all the molecules that a cell can make. Of course, the magnificent irony of this knowledge is that it does us very little good without a simultaneous change in thinking that goes beyond the molecular and back to a time when whole pathways, organelles, cells and organs and organisms were studied. Thus, genome sequencing, the ultimate tool of reductionist thinking - which gave birth to metabolomics and transcriptomics and a host of other data gathering 'omics', welcome or not - has led, inevitably, to systems biology (whatever that is), and to a rebirth of the noble discipline of physiology. Like it or not, biology has become Big Science, and the Pandora's Box that genomics has opened cannot be closed again.

I have been trying to offer my personal take on this sea change in an opinion column that has appeared in every issue since the first one. The editors have allowed me free rein to do this any way I wish: satire, imaginary dialogs, even short dramas. In turn, I've tried to be provocative, imaginative, and entertaining. Whether I've succeeded or not is not for me to say. But what I can say is that I have had, thanks to this publication, a front-row seat for the kind of change in a field that comes along only once or twice in a lifetime.

Genome Biology has chronicled this metamorphosis with style and insight. The first of its kind, it remains the best of its kind in my opinion. Other journals will follow its ascent (or is it descent?) to exclusive online content with the inevitability of a sunrise. They may also imitate its unique blend of commentary, review, humor, peer-reviewed science, and series. But they can't say that they saw what was coming, because few did. I think it's completely appropriate to engage in a few self-congratulations, to which I will add mine: well done, gang.

So where do we go from here? Biology is still changing, and a journal that aims to be at the cutting edge will have to change with it. My own guess is that biological research in the age of genomics will move inexorably towards more human biology, and more direct relevance to human disease. This is partly a natural progression, but it is also driven by the increased demand that big science deliver on the promises made to convince the public to support it. Genomics was born of a promise that understanding the workings of the cell would lead to faster cures, and that promise hasn't been kept. Funding agencies and government officials and patient advocacy groups are going to hold us to that promise, and their impatience will be the prime driver for the field. To continue to be au courant, Genome Biology will need to increase its coverage not only of research related to the human genome, but also of disease-related research that makes use of both the tools and the discoveries of genomics.

The scientific changes have been amazing, and will continue to be so, but equally amazing, I think, are the changes in the culture of science that genomics has wrought. These are even harder to predict, but a good guess would be an increased rewarding of collaboration rather than an insistence that one's reputation be built entirely by one's own hands. Another might be an almost complete blurring of the lines between traditional disciplines, such that academic departments are outmoded and allegiances become fluid. Biology will also become more data-driven, quantitative, and computational than ever before, which will mean a very different sort of scientist will probably become king in this new world.

Anyway, I intend to keep writing about it all, for as long as Genome Biology exists, or until they get sick of me. Sorry about that.

References

1. Petsko GA: The grail problem. Genome Biol 2000, 1, comment002.1-002.2

2. Petsko GA: Dog eat dogma. Genome Biol 2000, 1, comment1002.1-1002.2

Published: 5 May 2010

Hand-made biology

Genome Biology 2010, 11:124

But tonight, we shall hurl the gauntlet of science into the frightful face of death itself. - Young Frankenstein (1974)

It's alive! It's ALIVE! … Oh, in the name of God! Now I know what it feels like to BE God! - Frankenstein (1931)

Craig Venter would never be Central Casting’s first choice to play Dr Frankenstein. And I can’t see Hamilton Smith as Igor, either. But when these two genome biologists and their coworkers announced, in the May 20th issue of Science, that they had ‘created’ a bacterium, one would have been forgiven for thinking, based on the language they used and the turgid - even hysterical - reports in the press, that they were auditioning for the parts. Here is the opening paragraph of the account of their work in The Economist, a publication not customarily given to hyperbole:

In the end there was no castle, no thunderstorm and definitely no hunchbacked cackling lab assistant. Nevertheless, Craig Venter, Hamilton Smith and their colleagues have done for real what Mary Shelley merely imagined. On May 20th, in the pages of Science, they announced that they had created a living creature.

But did they? Is their achievement ‘creation’ in the literal, and Frankensteinian, sense of the word (the action or process of bringing something into existence), or is it something else entirely? And if it is something else, is it still as monumental as some people, and the authors themselves, claim?

In case you were in a coma and missed it, here’s a brief summary of what they did. They took a ‘host’ strain, that of the small, free-living bacterium Mycoplasma capricolum, and deleted the genes for its own restriction enzymes (this would correspond to the cadaver in the Frankenstein tale). The restriction enzyme genes were deleted so that the host would not cleave the ‘foreign’ DNA they planned to insert. (The equivalent to this procedure would be immune suppressing a transplant recipient so that they would not reject the foreign organ.) Venter, Smith and colleagues then inserted into this strain a completely synthetic chromosome (the ‘brain’) for the related strain Mycoplasma mycoides. In synthesizing the 1.08 million base pairs of this genome, the team at the J Craig Venter Institute deliberately deleted 14 genes that might have conferred pathogenicity on the new strain, and also inserted into the DNA sequence a set of watermarks: specifically designed segments of DNA that spell out words and phrases. The watermarks prove that the genome is synthetic, and identify the laboratory of origin. Encoded in the watermarks is a new DNA code for writing words, sentences and numbers. In addition to the new code there is a web address to send emails to if you can decode it, plus the names of 46 authors and other key contributors to the work, and these three quotations: ’To live, to err, to fall, to triumph, to recreate life out of life’ - James Joyce; ‘See things not as they are, but as they might be’ - from the book, American Prometheus; and ‘What I cannot build, I cannot understand’ - Richard Feynman. After about 30 generations, there was no trace of the original bacterial genome in the new organism (presumably, it had been destroyed by the restriction enzymes encoded by the synthetic chromosome), and the proteins and other macromolecules in the cell were entirely those from the inserted DNA. That’s the achievement. What does it mean?

First, can we all agree that there is nothing surprising here? No one should have been amazed that this worked. Not only was it likely to work; it HAD to work if it was done properly. The surprise would have been if it HADN’T worked. In an interview given at the time of publication, Venter, a truly great scientist whose genius extends to a talent for self-promotion, said, ‘Really, it has changed my view of the definition of life and how it works.’ Which makes me want to ask him just what his view of the definition of life and how it works used to be, because it must have been remarkably naïve. This is no conceptual breakthrough, no matter what language is used to describe it.

Venter, who headed the private team that sequenced the human genome 10 years ago (along with the public effort headed by Francis Collins), calls the result a ‘synthetic cell’, but it isn’t one. It’s no more a synthetic cell than Frankenstein’s monster was a synthetic human. ‘Synthetic’ means a substance that is made by chemical synthesis, often in imitation of a natural product. The genome that Venter and Smith inserted into their cadaverous host was synthetic, but the host was not. It was an actual bacterial cell, produced naturally. To have made a synthetic cell, Venter and Smith would have had to synthesize abiotically not only the DNA, but also all of the proteins, carbohydrates, lipids and other molecules that make up the cytoplasm and shell of the organism. They are a long way from doing that.

The closest analogy to what they did is not Mary Shelley’s fictional mad scientist and his unfortunate creation; it is a technique called somatic cell nuclear transfer (SCNT), and it has been used for years. In SCNT (sometimes referred to as therapeutic cloning), the nucleus of a somatic cell is removed and the rest of the cell discarded. At the same time, the nucleus of a host egg cell is removed. The nucleus of the somatic cell is then inserted into the denucleated egg, and after many cell divisions, a blastocyst (early stage embryo) forms, which is a clone of the original somatic donor organism. This is the process used to clone Dolly the sheep, and nearly all other animals that have been cloned. The success of this procedure guaranteed that the Venter team’s procedure of reprogramming one bacterial cell with the DNA from another would work if done properly. The major difference is that they used a synthetic genome and carried out their experiments in a bacterial host rather than a eukaryotic one. For me, what they did is not creating life. It’s making chromosomes and letting the machinery of an already evolved life form read the sequence and produce the desired output.

So now that I have, I hope, convinced you that this is no big deal, let me convince you that it is actually a very big deal. No, Venter and Company did not create life - at least not in the sense that the phrase is normally used. But what they did do is pretty monumental nonetheless.

For starters, they have shown that it is possible to synthesize functional chromosomes. That’s a formidable technical achievement. M. mycoides has a very small genome, but the method they developed, of making the sequence in fragments and using the high rate of homologous recombination in budding yeast to assemble them, is clearly applicable to much larger genomes.

Second, they have single-handedly made Systems Biology into a viable intellectual discipline. It is now possible to design organisms to test the predictions and models from that ambitious field - organisms simple enough that the assumptions that go into the models may actually not be too bad. If I were the Systems Biology community, I’d be buying Venter and Smith a drink. Maybe lots of drinks.

But it’s the third thing they’ve done that impresses me the most, because I think it is going to be a game-changer for all of us. In taking the first step towards the construction of a truly synthetic cell, Venter and colleagues have also taken the first step towards making biology into an engineering science.

Engineers design things and then build them out of pre-made, usually standardized, parts. Smith and Venter didn’t quite do that, but they came closer than anyone has before, and they and others will come closer still, very soon. It won’t be long until simple organisms can be designed and constructed, if not fully synthetically, then semi-synthetically as was done here - organisms with novel and useful properties. The Systems Biology folks will learn how to do the designing, and the Venters of the world will then make organisms to order. To facilitate such engineering, it would be nice to have reliable software to design the collection of genes and pathways needed for a particular set of desired properties, plus a set of premade, standardized parts (genes and prepared host cells), and there are people already starting to make both. In the end, designed organisms could churn out drugs like artemisinin (an antimalarial compound currently isolated from willow extract), or gobble up oil spills. Their uses will be limited only by our imaginations and our ability to predict what output a given set of parts will produce.

Engineers are problem-solvers and when engineering comes to biology (or is it the other way around?), we should be able to solve a number of very important ones. Unfortunately, some problems are military, and the solutions to these often involve making weapons. That’s just the way it is. The fear that this new science of hand-made biology will be used to make bioweapons is overblown for now - the technology is too complex and expensive, and terrorists can, unfortunately, manage quite well with much simpler instruments of death - but doubtless at some point in the future some group, or rogue nation-state, will try. Prohibiting synthetic biology, or strangling it with regulations, is not the way to deal with this threat. Experience teaches that information cannot be confined, and in the end it is better to know what the forces of evil might do, so that we can plan our countermeasures from the beginning.

Something very much like this happened to chemistry in the past century. Using the science to make molecules became as important as fundamental discoveries in the structure and reactivity of matter. That change didn’t diminish the centrality of chemistry as a discipline; it enhanced it. Of course, along with the plastics and the new drugs came nerve gas and high explosives. This loss of innocence can happen to biology, too. It probably will. But in the end, we will accept the risks in order to reap the benefits, like we did with atomic energy, and synthetic chemistry.

No, Venter and Smith aren’t playing Frankenstein, and they aren’t playing God either. What they’re really playing is Thomas Edison. There is no divinity in this work; quite the opposite. It’s being done for practical, commercial reasons, and partly because of that there will be a lot of safeties built in, especially in the early days. The religious right and the ethicists and the neo-Luddites and the average concerned citizen shouldn’t worry too much about synthetic biology, at least not yet.

The ones who should worry are the synthetic chemists, because living organisms can make many polymers and drugs and novel materials faster, cheaper, and with more complexity and variety than chemists can. And what does the future hold for process chemistry when we can design our organisms to fit our manufacturing technology, instead of the other way around?

Yes, if I were a synthetic chemist or a chemical engineer, I’d be worried. Actually, if I were a synthetic chemist or a chemical engineer, I’d be learning how to do synthetic biology.

Published: 30 June 2010

When the pie is too small

Genome Biology 2010, 11:127

Thirty-two billion US dollars is a lot of money. It's more than the gross national product of Kuala Rokat, a non-existent but real-sounding country. If it were in pennies the resulting stack of 3.2 trillion coins would be roughly 5 billion meters high, tall enough to reach from the surface of the earth roughly a tenth of the way to Mars. In one dollar bills, which don't weigh more than a gram, it would weigh about three times as much as the Eiffel Tower. Any way you express it, it's a mighty big pie. Unfortunately, it's not big enough.

The Congress of the United States is currently debating the budget for the National Institutes of Health (NIH), the world's largest provider of research funding for biomedical science in general (and genome biology in particular), and $32 billion is the figure they are currently recommending for fiscal year 2011. If that is the number ultimately awarded, the biomedical science research community in the US is going to face some agonizing choices.

Before the stimulus funding of 2009-2010, the NIH budget was $30 billion. $32 billion would represent an increase, but one substantially less than the level of scientific inflation, which has been averaging about 6% a year over the past few years. And the base budget was too small already back then, because of years of declining funding (in inflation-adjusted dollars) under George W Bush. The Federation of American Societies for Experimental Biology (FASEB) estimated that $37 billion would be needed to bring the budget up to where it should be, and to avoid what some are calling a 'cliff' in funding as the $10 billion in stimulus money that was added to the base budget last year runs out. My personal view was that we needed something as close to $40 billion as we could get. $32 billion isn't close at all.

Things could change before the final budget is passed, but I doubt it. Congress is scared to death about the burgeoning US deficit, which is stupid because we are in a deep recession with close to double-digit unemployment and a real interest rate close to zero. Keynesian economics tells you that in such a situation, where monetary policy is useless because interest rates cannot go negative, the government should be spending more, not less. And spending money on scientific research is particularly smart, because it has been estimated that every dollar spent that way rapidly produces 2.0-2.5 dollars of economic output, one of the highest multipliers for any form of government investment. But the US Congress has been remarkably spineless of late, and in the face of calls for fiscal restraint by the political right, it seems unlikely that we will see an increase in the proposed amount for the NIH.

There's another reason not to expect much, and that's because the Democrats are in power. I know, it seems ridiculous that Barack Obama's administration, which actually respects science and listens to its advice, would leave biomedical research high and dry, but I think they will. Democratic administrations usually do. The problem isn't that they don't love science, it's that they love their favorite social programs more, and there simply isn't enough money to fund both at the level they are clamoring for. The odd thing about US politics (okay, one of many odd things) is that, with the exception of the anti-intellectual, science-phobic Bush administration, Republican governments have been friendlier to scientific research, in terms of funding, than their Democratic counterparts. Republicans have largely bought the idea that funding research, including 'basic' research, helps the competitiveness of the country and jump-starts new businesses. There will be a lot more money under Obama for energy research (the Democrats have completely accepted the idea that global warming is a huge problem), but that may well be at the expense of money for the life sciences.

What, then, does a $32 billion NIH budget mean for American science? If present trends in funding priorities continue, it means that the number of individual investigator-initiated grants (called 'R01s' in NIH-speak) is going to shrink dramatically, as the bureaucrats in Washington use the precious dollars first to maintain - and possibly expand - their pet big science programs. Keeping the cancer genome program and the structural genomics program and the genome-wide association studies afloat will require that the R01 pool shrink, and it is already, in percentage terms, dangerously low.

Kyle Brown, public policy fellow at the American Society for Biochemistry and Molecular Biology, has put together some initial data that illustrate this looming crisis. Using the total number of R01s and investigators in a given year, he has calculated the average number of R01 grants per investigator from 1965 to 2005. The data were obtained from the NIH RePORT website (http://report.nih.gov/index.aspx; specifically http://grants2.nih.gov/grants/new_investigators/New_Invest_Grants_and_Numbers.xls).

In 2005, the average number of R01-equivalents per investigator was 1.35. This average has climbed steadily since 1970, when it was 1.12, and its rate of increase has become steeper since the 7-year NIH budget doubling began in the late 1990s. One interpretation of this trend is that proportionally more principal investigators (PIs) are able to obtain more than one grant than they were in 1970. This trend accelerated during the doubling. Taking this further, it suggests that as the budget has increased, the NIH is putting more of its money into proportionally fewer labs.

The distribution of grants per investigator looks exponential and has a mode of 1 (the most investigators have one grant, the second most have two, the third most have three, and so on). But perhaps even more important is the dollar amount, because it is the finite pie that we're talking about here. During the past 10 years, a small number of laboratories and groups of laboratories have been receiving an increasing share of that pie, as big, expensive data-gathering projects and programs have increased at the expense of single-investigator hypothesis-driven research grants.

These numbers show why all scientists should fear for the R01 pool in a time of disastrously small budgets. I am not sanguine that most of the directors of the NIH institutes and centers, who control their individual budgets, are going to be able to resist the temptation to protect the most visible, glamorous, and disease-related work while letting the number of 'basic' science projects shrink. It is, therefore, incumbent on us to offer them solutions to the small-pie problem that keep that from happening. Here are some ways that have been suggested of cutting the pie into more slices, predicated on the assumption - which seems entirely reasonable to me - that it is better to give an investigator with a good idea some money than no money at all.

(1) Impose a cap on the maximum dollar amount per R01 grant for direct and, more importantly, indirect costs. The former are the dollars that actually go to the investigator(s); the latter are the dollars that go to the institution to cover the costs of administering the grant. Indirect cost rates range from around 20% of total direct costs to over 100% (and yes, that's not a typo), so a $1 million grant spread over 5 years can actually end up costing the NIH $1.5 million or more. The problem with this strategy is that most research universities, and medical schools in particular, live on indirect costs, and an abrupt shutoff of the pipeline could starve them.

(2) It may be necessary to make people with special long-term sources of funding, such as those with research chairs that supply large amounts of research dollars, or Investigators of the Howard Hughes Medical Institutes, ineligible for more than one R01 grant on top of their other funding. An exception could be made if they were in the 3-year transition period after being dropped as a Howard Hughes Investigator, or were about to lose the special funds for any reason. How to determine whether there is enough special funding to trigger such a restriction is not obvious to me.

(3) Impose a cap on the maximum number of R01 total dollars per PI. I have no idea how to set that figure fairly given the vastly different costs of clinical and non-clinical research, but maybe someone else will.

(4) Reduce the maximum duration of an R01 grant (currently 4-5 years) to perhaps 3-4 years. The burden this will place on scientists will be considerable, given that they already spend a huge percentage of their time writing grants now.

(5) Impose a limit of no more than one R01 equivalent per PI from any one NIH institute. That would have the advantage of forcing scientists to become more interdisciplinary, and the disadvantage of flooding, say, the National Cancer Institute with applications from people who know nothing about cancer.

(6) Award percentages of recommended budgets according to how highly a proposal was rated by the grants review panel. Thus, the top 5% of proposals would receive 100% of their recommended (not requested) budget; the next 5% would receive 75%, the next 5% 65%, and the next 5% 50%. This is the solution I prefer, as it rewards quality while stretching the research dollars to cover more investigators.

Any of these provisions would need to be reversible pending a better funding climate. Given the difficulty in ending any government program, that may be harder to carry out than the actual spending restrictions, which is another reason I prefer solution 6 above; it would have the least severe long-term consequences. The commitment for each institute and center could be to aim for a payline of, say, 20% of recommended R01 proposals receiving funding, which they would achieve by cutting and/or modifying spending using some combination of these provisions as necessary. (My friend John Kyriakis owlishly points out that the political climate is just right to get such ideas implemented. NIH could claim it is contributing to 'reducing big government'.)

Of course, an even better solution would be to terminate some of the pie-hogging big science programs and put the savings into the R01 pool. That's what we should in fact do, so I guess there really isn't a hope in hell that we will.

By the way, $32 billion is exactly the sum that BP has been forced to pay by the US government as a penalty for the Gulf of Mexico oil spill. I don't know whether to laugh at that coincidence or just cry.

Published: 30 July 2010

The past is a foreign country

Genome Biology 2010, 11:131

'When I was your age,' my father was fond of telling me, 'I used to walk 5 miles through a foot of snow just to go to school.' I was impressed for a while, until I noticed that, as he got older, the distance got longer and the snow got deeper. Eventually, he claimed to have walked 20 miles through 6 feet of snow. I became even more suspicious when I found out from my grandmother that they had lived three blocks from school.

In an age of school buses and car-pooling parents, such stories, whether believable or not, conjure up visions of a world almost beyond the imaginations of today's children. I was reminded of that today by an email from my friend and Brandeis colleague Tom Pochapsky, who directed my attention to a fascinating article on the website of Beloit College (http://www.beloit.edu/mindset/2014.php). Each August since 1998, Beloit College has released the Beloit College Mindset List, which provides a look at the cultural background of the students entering college that fall. The creation of Beloit's Keefer Professor of the Humanities Tom McBride and former Public Affairs Director Ron Nief, it was originally created as a reminder to the Beloit faculty to be aware of dated references. As the website notes, 'it quickly became a catalog of the rapidly changing worldview of each new generation.'

So what's the worldview of the class of 2014? According to the latest list, here are a few of the things these 18-year-olds, born in 1992, have experienced - and not experienced:

- Few in the class know how to write in cursive.

- They find that email is just too slow, and they seldom if ever use snail mail. They text. Oh, God, do they text.

- To them, Clint Eastwood is better known as a sensitive film director than as vigilante cop Dirty Harry.

- For them, Korean cars have always been a staple on American highways.

- They've never recognized that pointing to their wrists was a request for the time of day.

- In their world, Czechoslovakia has never existed. There was no Berlin Wall, the Iron Curtain is a meaningless phrase, and Russia has never had a Communist government.

- There has never been a world without AIDS.

- The Beatles and the Rolling Stones are classical music.

- Toothpaste tubes have always stood up on their caps.

- There have always been women priests in the Anglican Church.

- Having hundreds of cable channels but nothing good to watch has always been the norm.

- The US public has never approved of the job the US Congress is doing.

- Most of them have never seen a long-playing record, or even a tape drive. If they have ever seen a typewriter, it was in a museum, possibly alongside a dial telephone.

- They have never lived in a world without personal computers, the Internet, CD-ROMs or laser printers.

There are, of course, many things they have experienced that we also experienced at the same age. Among these are automobiles, jet airplanes, color television sets, and the Chicago Cubs not having won the World Series. Another commonality has been the enduring hostility between the English and the French.

But they couldn't imagine life without PopTarts, juice boxes, and movies you can have on your home TV, and they have no idea how we could have survived in a world that required carbon paper.

All of which got me wondering: what would the scientific worldview be like for someone, let's say, just starting graduate school today (and therefore about 22 years of age)? Born in 1988, how would their scientific lives differ from the lives of the generations preceding them (including mine, which is the only one I really care about)? It makes for some interesting speculation:

- For today's budding biologists, DNA fingerprinting would have always existed. Actual fingerprinting would have been a recent invention, used primarily to secure laptop computers.

- Protein crystal structure determination would for them never be anything but a routine tool.

- Molecular biology would never have been a discipline in its own right. Instead, it would always have been a set of techniques, introduced to students in better high schools.

- They cannot imagine a world without kits to make experiments virtually automatic.

- Since the first free-living organism had its genome sequenced when they were 7 years old, they have grown up in the age of genomics. They have had access to the complete sequence of the human genome since they were in middle school.

- They have never attended a lecture given with slides from a carousel projector, and they may not have ever seen one given from overhead transparencies either. PowerPoint has been in use for virtually their entire lives.

- In their lifetime, no one has ever pipetted anything by mouth.

- DNA sequencing, peptide synthesis, chemical analysis, and gene synthesis have always been farmed out to specialty companies rather than done in one's own lab.

- They have almost certainly never seen anyone blow glass. In fact, many of them may not know that test tubes were ever made of anything but plastic.

- They have always had the option of going into the biotechnology industry.

- The term 'enzyme' has always referred to both protein and RNA.

- Evolution has always been under attack, and science and religion have largely been seen as incompatible.

- There have always been 'big science' projects in biology.

- Chemistry has always been a declining field in terms of student interest, and physics has always been the province of a small number of practitioners.

- Believe it or not, they have never known a world without cDNA microarrays.

- For them, 'Xerox' is a verb, Polaroid makes LCD TVs, and every piece of equipment is computer-controlled.

- They have never requested a reprint. They probably don't know what one is.

- They believe that no science was done before 2000. Any science not indexed on PubMed was not done either, even if it was done yesterday.

- They cannot imagine that there once was only a single Cell journal, and just one Nature as well.

I'm sure you could think of lots more. I know I could, but we had 10 feet of snow last night, and that 50-mile walk to school is going to take me a while.

Published: 27 August 2010

About the author

Gregory Petsko studied chemistry and classics at Princeton University, before attending Oxford University as a Rhodes scholar where he received his D. Phil. in molecular biophysics in 1973.

Petsko is a renowned structural biochemist, and is currently the Gyula and Katica Tauber Professor of Biochemistry at Brandeis University, where his research with Professor Dagmar Ringe focuses on the three-dimensional structures of proteins and their biochemical functions. He is also an adjunct professor in the Department of Neurology and Center for Neurologic Diseases at Brigham & Women’s Hospital, Harvard Medical School, in Boston.

Petsko was the president of the American Society for Biochemistry and Molecular Biology 2008 - 2010, was elected to the National Academy of Sciences in 1995, the Institute of Medicine in 2001, the American Academy of Arts and Sciences in 2002 and the American Philosophical Society in 2010.

About Genome Biology

http://genomebiology.com/

Editor: Clare Garvey PhD

Genome Biology serves the biological research community as an international forum for the dissemination, discussion and critical review of information about all areas of biology informed by genomic research. Key objectives are to provide a guide to the rapidly developing resources and technology in genomics and its impact on biological research, to publish large datasets and extensive results that are not readily accommodated in traditional journals, and to help establish new standards and nomenclature for post-genomic biology.

Genome Biology publishes research articles, new methods and software tools, in addition to reviews and opinions, from the full spectrum of biology, including molecular, cellular, organism or population biology studied from a genomic perspective, as well as sequence analysis, bioinformatics, proteomics, comparative biology and evolution.

Open access

All research, method and software articles in Genome Biology are published under BioMed Central’s Open Access Charter: they are freely available online and archived in full in PubMed Central, and all users may download, store, or redistribute them in their original form as long as the original citation and bibliographic details remain with each article. BioMed Central is committed to maintaining open access for all research articles that it publishes, both retrospectively and prospectively, in all eventualities.

Table of Contents

Cover Page

Title Page

ISBN/Copyright Page

Quotes

Contents

Foreword

2000

The Grail problem

Dog eat dogma

The dark side

Perpetual motion of the worst kind

Seek and ye shall maybe find

Count me out

2001

The buckyball effect

Homologuephobia

Size doesn't matter

The slide rule and the calculator

The Rosetta Stone

Location, location, location

Model behavior

Design by necessity

Hell is a karaoke cruise

September 11, 01

Winter, plague and pestilence

A piece of the action

A Christmas Carol

2002

If you can't take any more of this, please press two

The father of us all

What's in a name?

Grain of truth

Our own petards

No place like Ome

Summer reading

Fish tale

An Asilomar moment

The guards themselves

Banana republic

Everything I need to know about genomics, I learned from Yogi Berra

2003

Funky, not junky

Still no flying cars

Judgement call

War and peace

Ira

A new recruit for the army of the men of death

Galileo's stepchildren

The road worrier

The usual suspects

Sleeping dogs

For the good of the state

Live and let diet

2004

Bad chemistry

Good chemistry

Doctor Dunsel

The Ascent of Man?

Pharmacogenomics arrives

Powerless to stop myself

A drop in the bucket

Fame is a bubble, but not for some

Twilight of a hero

The emperor's new shibboleth

Color blind

Identity crisis

2005

Tsunami

Feet in mouth disease

Who owns the data?

A matter of life and death

How may you help me?

Eighty years ago

The life aquatic

Trinity

Half right

H5N1

Who steals my identity steals trash

Foxes and hounds

2006

Let's get our priorities straight

Sweden has the right idea

The system is broken

Instructions for repair

The next epidemic

The ninth wave

Facts and figures

Senior moments

Fly's time

Transformation

Do the math

A model worth considering?

2007

Jumping the shark

And the second shall be first

A day in the life of a genome biologist in the not-too-distant future

It can't happen here - can it?

Inconvenient truths

An idea whose time has gone

A truly titanic figure in science

My worries are no longer behind me

Strange days

They fought the law and the law won

What if Watson had said "Apes evolved from man"?

Medicine man

2008

The story they missed

The right to be wrong

Going to the dogs

Not debatable

The new Manichaeans

It is alive

Having an impact (factor)

Biodefense versus bioterrorism

When bubbles burst

Meta-morphosis

The wisdom, and madness, of crowds

A seat at the table

2009

Life is a Ponzi scheme

Many happy returns

Too big to succeed?

Guilt by association

Render unto Darwin

What my genome told me - and what it didn't

Wimps? What wimps?

Nation of twits

An issue to remember

The dog days of autumn

Advice and dissent

A harsh climate

2010

Rising in the East

Lost in translation

No stone unturned

The devil's in the details

And they said it wouldn't last...

Hand-made biology

When the pie is too small

The past is a foreign country

About the Author

About Genome Biology