BioMed Central blog » BMC Biology

Antibiotic resistance – Can we avert the apocalypse?

Penelope Austin — Fri, 17 May 2013 12:53:11 +0000

The problem of antibiotic resistance, recently described as “apocalyptic” by Sally Davies, Chief Medical Officer of the UK, is getting worse and cannot be expected to get better quickly. In a Question and Answer article in BMC Biology, Gerard Wright explains the reasons for the worsening situation, and why, despite the acute need, there are few new antibiotics on the horizon.

Antibiotic resistance is a natural and ancient phenomenon, and the emergence and spread of resistance in human pathogens inevitable, he argues, though widespread clinical and agricultural use of antibiotics makes it much worse; and the problem can only be met by the development of new drugs.

The point that antibiotic resistance predates our development of antibiotic drugs was made in an earlier Q&A in which Wright explored the mechanisms and origins of antibiotic resistance – it is prevalent in bacteria that live in the environment, for example in the soil microbes from which almost all of our antibiotic products are derived. He can now cite a more recent study confirming that the resistance genes we see in human pathogens are the same as those found in environmental bacteria, presumably as a defence against antibiotic products of their microbial neighbours – the very same products that are exploited by us for antimicrobial drugs. And the antiquity of resistance is illustrated by his own recent finding of resistance genes in the microbial community of a cave sealed from the surface 4 million years ago. The news that multi-resistant bugs have been found on American supermarket shelves thus clearly does not necessarily (as pointed out by the US FDA) imply a disease outbreak in the making – pathogens do not have a monopoly of resistance genes.

So if antibiotic resistance genes are everywhere, and can spread easily – what can we do about it? Wright’s answer, to which he has effectively devoted his career, is to keep discovering new antibiotics, or new ways to make old ones effective again. The problem here, he explains, IS manmade. Not a shortage of good ideas, or new compounds with drug potential, but a regulatory and incentive structure that is ill adapted to support the development of these drugs and get them quickly to the pharmacy. Perhaps most important is a bias towards the development of broad spectrum drugs, which has served the industry well in the past, but which limits the number of suitable lead compounds and – it can be argued – has helped promote both the spread of resistance and undesirable side-effects such as antibiotic-induced colitis, due to an indiscriminate effect on the patient’s microbiome.

Despite his conclusion that things will get worse before they can get better again, Wright points to some glimmers of hope. The Generate Antibiotic Incentives Now (GAIN) Act passed in in the US in 2012 has special provisions for antibiotics against resistant bacteria as well as measures designed to help fast-track new drugs. More recently, further reforms to clinical trial requirements have been proposed by the pharmaceutical industry. There are already some drugs that are benefiting from the GAIN Act, including two new drugs that will treat Clostridium difficile, bacteria that are notoriously causing complications after treatment with broad-spectrum antibiotics in a hospital setting.

Seventy years after antibiotics were first brought to market, it is hard to imagine where we would be if they cease to be effective. The erosion of their efficacy is ongoing, but Wright gives us reason to believe that the inevitable problem of resistance can be successfully met.

A quantitative map of immune cells in mosquitoes

Penelope Austin — Tue, 30 Apr 2013 15:55:09 +0000

Inside insects there is an open cavity called the hemocoel, in which fluid and cells known as hemocytes circulate due to the pumping of a heart. The hemocytes have a primary role in immune defense, killing pathogens by phagocytosis and via the production of anti-microbial factors. A study by Jonas King and Julian Hillyer published in BMC Biology adds to our understanding of insect hemocyte biology in three ways. First, it provides a quantitative map of their anatomical distribution, and shows that hemocytes attached to tissues (i,e sessile rather than circulating) form a major component of the mosquito immune system. Second it finds that their numbers diminish with age, but increase in response to infection. Third, it captures circulating hematocytes that are undergoing mitosis, showing that hemocyte proliferation in adult mosquitoes does not require a discrete organ or progenitor cell type.

Sessile phagocytic hemocytes are found everywhere except inside the antennae and halteres. The vast majority are attached to the abdominal wall, particularly around the trachea, and in the region of the heart valves, where they are well placed to trap and phagocytose any circulating pathogens. When labeled E coli are injected it is the circulating hemocytes and those attached around the heart valves that increase in numbers, whereas the decline in hemocyte numbers seen with age occurs in both sessile and circulating compartments. In young mosquitoes there is an even dispersion of sessile hemocytes throughout the abdominal wall and at 1-2 days post emergence, some had internalized muscle fibers and nuclear materials that were likely remnants of larval swimming muscles, suggesting a role in shaping the internal architecture of the developing adult.

These informative observations should prove a valuable reference for future work on hemocyte function, particularly in mosquitoes, whose immune response may affect the transmission of human parasites such as malaria.

How can you tell if an arrow is polarized?

Ann Le Good — Mon, 29 Apr 2013 17:32:19 +0000

This was the opening question Lewis Wolpert posed at the Royal Society’s conference on Cell Polarity in London on April 15. If you think the answer is obvious, check the end of this blog. The conference, organized by Human Frontier Science Program collaborators Rafael Edgardo Carazo Salas, Attila Csikasz-Nagy and Masamitsu Sato, focused on what regulates cell polarity in the context of the oocyte, Drosophila, C. elegans, the gut, skin and T cells – with the main question of how does a cell break symmetry?

Asymmetric cell division is one answer, but that immediately raises the question of how and where microtubule spindle formation is regulated: we still don’t know how the centrosome knows where to position itself in the cell. We do know that formin 2 is part of the signal bringing chromatin to an asymmetric location in the cortex in the oocyte (Rong Li), and Asako Sugimoto reported that in C. elegans, Aurora A kinase is important for this, but it is not understood why: there is no need for the kinase activity per se.

Once cells are polarized, what drives cell changes? W. James Nelson and Cecile Sykes presented in vitro models to show that tension on cells can cause changes in polarity, and all agreed that it is actin at the leading edge of a polarized cell that causes movement, pushed by a myosin motor at the back. But what triggers polarity: external polarity cues or intrinsic determinants? Several participants spoke on the role of the apical cell determinants for polarity, including the PAR complex (PARs 3 and 6/aPKC/Crumbs), but how other molecular players, for example LGN/Pins, Inscuteable, NuMA/Mud, regulate apical polarity is not yet clear.

What are the consequences of the loss of cellular polarity? Whilst around 85% of cancers arise from epithelial cells, the speakers were divided on whether the cause is loss of polarity triggered by a mis-orientation of spindles or the subsequent loss of the definition of the epithelial monolayer. Daniel St Johnston reported that inducing a mis-orientation of spindles in the follicular epithelium of flies does not produce tumor-like epithelial disruption. But using a mammary transplant model Ian Macara showed that disruption of cell polarity by mislocalization of aPKCs/loss of Par3 and Inscuteable in mammary glands causes epithelial cell disorganization and he believes this will be one of the keys to understanding breast cancer cell metastasis.

Several speakers asked how we can model polarity. Over 60 years ago, Alan Turing proposed a chemical basis for morphogenesis modeled on reaction-diffusion equations, and more than half a century on, Leah Edelstein-Keshet discussed how she had used similar principles, with local perturbation analysis to model cell polarity.

Will the answer to what regulates cell polarity come from mathematical modeling or ingenious experiments? It will almost certainly be both. – Oh, and the answer to Wolpert’s question is: it’s not polarized – if you cut an arrow along its length, there is no difference between one end and another of the bits without the arrowhead.

Peer review of peer reviewing

ruthfrancis — Wed, 24 Apr 2013 14:29:09 +0000

Often referred to as the ‘the worst system imaginable except for all others’, peer review itself was under review on Monday 21 April, at the Experimental Biology conference in Boston. A panel, organised by BioMed Central and energetically chaired by Gregory Petsko, took on the issues faced by academics and editors in peer review.

The Oxford English Dictionary definition of peer review is ‘the evaluation of scientific, academic, or professional work by others working in the same field’. Participants in the panel discussion painted a rather more vivid picture of the painful reality of that evaluation, with its consequences for funding and careers.

Commentaries highlighting the inefficiencies, even failings, of peer review have seemingly been on the increase since Martin Raff, Alexander Johnson and Peter Walter protested about ‘painful publishing’ in Science in 2009; panellist Hidde Ploegh, whose comment in Nature two years ago called for an end to the ‘tyranny’ of reviewer experiments, represented a widely shared feeling among academic scientists. By way of an introduction to the issues the panel would hope to address, Petsko summarised other commentaries here.

Problems include lengthy review processes that do not ultimately benefit the quality of research or its presentation, detrimentally holding up publication, an insistence that each paper presents a ‘complete story’ – as one discussant put it: “The one thesis one paper problem.”, and requests from journal Editors for reviewers to assess a manuscript’s impact or significance (which may not become apparent for years after a paper’s publication).

Given that most authors and also reviewers, and most reviewers are also authors, this is a problem for the whole scientific community – as Petsko says ‘we have seen the enemy and it is us’. But what is the solution?

It is clear that there is no single panacea, and encouraging that journals are addressing the problem in a variety of ways. Miranda Robertson explained BMC Biology’s policy of re-review opt out, intended to relieve the pressure on reviewers and minimize delays to publication: once a paper has been revised in response to reviewers, the authors may choose whether it is seen again, or a decision is simply made by the editors. Emilie Marcus explained how Cell sets standards and carefully discusses each decision under the traditional reviewing process.

The eLife approach is different: all academics involved in editing are well known scientists and the aim is to encourage communication between reviewers and reach a consensus view. Not only does this make the rogue reviewer problem less likely but it makes possible a collective decision about what is reasonable. This does make substantial demands on the time of the academics involved, for which they (though not the reviewers) are paid by the three major funding agencies that publish eLife; and some felt it was not clear how generalizable this model is.

Elsewhere open peer review is proving successful. Biology Direct, now in its 8th year, aims to increase the responsibility of reviewers by including both their names and reports in the published article. As stated in the launch Editorial, why hide the “priceless discussions often… providing us with new perspectives and fresh ideas for our research” behind closed doors?

Perhaps open review and new platforms of communication will provide a solution. Laurie Goodman, Editor in Chief of Gigascience referred to the review of one manuscript late last year when a reviewer blogged his review – something that would traditionally be a cause for alarm. The paper was on preprint server and already available for comment, and contrary to the expected negative effects, the ensuing discussion of the paper and review by the author, editors, tweeters and bloggers added to the paper significantly. Goodman says: “In 20 years of peer review, this was the first time where the review process was an absolute blast.”

Category award winners announced for BioMed Central’s 7th Annual Research Awards

Rebecca Fairbairn — Thu, 18 Apr 2013 08:50:39 +0000

Each year BioMed Central’s Annual Research Awards celebrate excellence in scientific research made freely available through open access publishing within our portfolio of biology and medical journals. Now in their 7th year, they are intended to recognize the achievements of particular research teams in ten diverse subject-specific award categories spanning all areas of Biology, Medicine and Health Services Research. We also have an Open Data award recognizing leadership in the sharing of data and a Case Report of the Year Award for the best case report recognized for its originality and significance to clinical practice.We are pleased to announce the winners for the ten subject-specific award categories:

The winning articles, selected by internationally respected scientists, will automatically be shortlisted for the overall BioMed Central Research Award, sponsored this year by antibodies-online.The winner of the overall BioMed Central award will be announced at a presentation on Sunday, 21^st April, at the Seaport Hotel in Boston, USA, as part of an evening celebrating the tenth anniversary of publication of BMC Biology, the flagship biology journal of BioMed Central. The evening includes a panel discussion on the hotly-debated topic of how to avoid the ‘tyranny’ of current peer review practices.

The panel will include Hidde Ploegh, the author of a widely read article on peer review, Emilie Marcus, Editor of Cell, John Timmer, Science Editor at Ars Technica and Miranda Robertson, Editor of BMC Biology, whose re-review opt-out policy is intended to address some of the problems faced by academics.

If you will be in Boston on April 21st and would like to attend, please email us for a formal invitation by April 19th.

Open access and the need to turn data into knowledge

Kester Jarvis — Mon, 15 Apr 2013 16:27:42 +0000

BMC Biology began ten years ago, and BioMed Central three years earlier, right at the beginning of open-access publishing in biology. As part of BMC Biology’s 10-year anniversary, Editorial Board member Pat Brown (right) talks about the origins of open access and the circumstances that led him to become one of the early open access agitators. The rapid growth of the internet and the possibility of publishing without print is one obvious enabler of open access, but Brown also discusses another driver whose growth has accelerated along with open access publishing. As much as it is a product of the internet age, open access is also a product of the dawn of the high-throughput era in biology, with the jump from analysing a handful of genes on a Northern blot to the thousands of genes interrogated in early microarray experiments resulting in a strong need to connect experimental results to a broader swathe of the existing literature. Brown describes the frustration he encountered in trying to do exactly this, and how his original vision of open access was so radical that much of it still has yet to happen – in particular, immediate data-sharing and reuse, with analytic tools to exploit the data to the full.

Curating data

Mike Tyers and Kara Dolinski share this concern. In an anniversary update on their 2006 paper describing the BioGRID database – originally holding information on a multitude of protein and genetic interaction data for the baker’s yeast Saccharomyces cerevisiae, and now expanded to more than 30 species – they discuss the urgent need for curation to make the best use, and indeed sense, out of the huge interaction datasets that make up a significant part of modern biology. The volume of data is overwhelming, and while BioGRID now contains comprehensive curation and annotation of interactions for a number of species, the literature is growing at such a speed that it is impossible for manual curators to keep up – and computerised curation isn’t yet sophisticated enough to represent a viable alternative. So what’s the answer? Tyers and Dolinski suggest that three things may be particularly important: deposition during publication of structured experimental data records in a standardised format that can be easily linked to and combined with other data; the addition of meta-data that reconciles contradictory data in the literature and gives investigators an estimate of its reliability; and a unified database of human and model organism interaction data that allows for inference across species to conserved but poorly understood human genes. None of these is trivial – but no one ever said turning data into knowledge would be easy.

Is the centrosome necessary?

Ann Le Good — Fri, 12 Apr 2013 14:46:30 +0000

Edouard Van Beneden and Theodor Boveri first described the centrosome as “the organ for cell division” in the 1880s, so you might think it is an essential component of cells. Not so, according to Monica Bettencourt-Dias in her Question and Answer article in BMC Biology, where she assembles accumulating recent evidence that despite its apparent ubiquity in animals and classical appearance at the poles of the mitotic spindle, it’s optional. This is particularly surprising because in the course of the hundred-plus years since Beneden and Boveri, it has become clear that centrosomes also function in the positioning of the microtubule cytoskeleton in non-dividing cells in which they play a part in motility, signalling, protein traffic and other important activities. So what do we now understand of the function of the centrosome?

Critical to the answer are the two microtubule-based centrioles at the structural heart of the centrosome, which otherwise consists of an amorphous matrix known as the pericentriolar material, or PCM. It is well known that the centrosome acts as a microtubule organizing center, with its textbook role in forming mitotic spindles in dividing cells. So in many cells, the centrosome with its centrioles is indeed essential to ensure correct cell division, and in these the PCM ensures the distribution of the right number of centrioles to each daughter cell. But there are exceptions – which include somatic cells in fruit flies and some fungi – where no centrioles are needed; and centrosomes in some differentiated cells, including neurons and muscle cells, are inactive.

Centrioles, on the other hand, are essential in almost all organisms, at least if they need cilia (which most do) or flagella. Centrioles form the basal ‘unit’ of cilia and flagella, and there is no organism that has cilia or flagella but no centrioles. Flatworms (planarians), which have no centrosomes, assemble centrioles de novo in cells with cilia. Is the nucleation of cilia the ancestral function of the centriole, from which centrosomes secondarily derived? Read the article and see what you think.

Many other questions remain. We have yet to understand the role of the pericentriolar material, in which many different protein components have been identified, without yet yielding clear understanding of the part they play. How component proteins regulate the striking “cartwheel” structure of the centriole that gives rise to its nine-fold symmetry is also a puzzle yet to be solved.

How is the length of a centriole limited? What happens when centrosome-related structures do not form properly? This is the last question tackled by Bettencourt-Dias in her Q&A article, giving insight into diseases of the brain and cancers, as well as developmental defects.

This Q&A forms part of BMC Biology’s series on cell geometry. BMC Biology welcomes submissions that may help to answer these outstanding questions.

Painful publishing – whose fault?

Miranda Robertson — Fri, 01 Mar 2013 17:30:06 +0000

In the five years since the publication of the ‘Painful publishing’ letter in Science by Martin Raff , Alexander Johnson and Peter Walter, and the four since we (then Journal of Biology, now BMC Biology) started our experimental re-review opt-out policy, many voices have been raised in protest at the tyranny (sic) of reviewers, and solutions of various kinds have been offered – among the recent ones perhaps most prominently by eLife, and most radically by F1000Research.

The editorial leash

The aim of all of them, whatever their approach, is to reduce the frustration of authors who find current peer review practices obstructive to the point of being destructive. Our approach, inspired by the personal experience of Peter Walter with a submission that became particularly badly mired in editorial delays, is to offer authors the opportunity to opt out of re-review once their manuscripts have been revised (even if substantively) in the light of referees’ comments. In the course of the four years since its inception, our policy has been refined – though not significantly modified – in the light of experience, and we have answers to some important and interesting questions: for example, whether referees are still willing to assess papers if they may not be asked to sign off on revisions (yes they are), and what proportion of authors opt out (about half). To summarize the current operation of our policy, we have published an overview in Q&A format that provides the answers to some obvious questions, including the two posed above, as well as the central one of whether the policy increases the risk of publishing unsound papers (we think not, obviously, for reasons explained in our editorial).

The pit-bull reviewer

Not unnaturally, the focus of the complaints about editorial procedures, and of attempts at optimizing them, has been on reviewers and editors. But a broader perspective would greatly help what is, after all – or at least should be – the common interest of reviewers, editors, and the authors themselves. Virginia Walbot, in one of our most popular Comment items (and the origin of the pit bull metaphor), set out guidelines for PIs in training postdocs in fair and judicious refereeing…

…but what about the author?

When we first mooted our own policy, Robert Horwitz remarked that ‘…what is in the paper is fundamentally the responsibility of the authors, not of the reviewers’ – but otherwise, so far as I am aware, the only comment to address the responsibility of the authors is Leslie Vosshall’s in The FASEB Journal last year. Everything she says is eminently intelligent – aim your paper at an appropriate journal, don’t start at the one with the highest impact factor and work down until you exhaust the pool of competent referees (and lose time in the process); and write your paper clearly and succinctly, take care with the graphics, and proofread the whole thing properly before submitting it, so that reviewers and editors don’t have to struggle to extract the salient information.

Portability of peer review

On the issue of exhausting (sensu lato) referees, one purely procedural manoeuvre that clearly makes sense is to make referees’ reports from highly selective and/or general journals available to other journals to which rejected authors of ultimately publishable papers might want to submit. BMC Biology has the luxury of an extensive family of subject-specific sister journals with whom referees’ reports can be shared to expedite the progress to publication of those papers that turn out not to meet its criteria. We are also open to refugees bringing referees’ reports from other publishers’ journals – on a formal basis in some cases (PeerJ, And under negotiation with EMBOJ and eLife), or informally from anywhere. In the latter case, of course, we can’t use the same referees to check revisions, but we can often make a decision quickly on the basis of advice from an Editorial Board member.

Parting remarks

It is notable that all the publishers recently to offer new strategies of enlightened peer review are open access, a movement that BioMed Central is proud to have pioneered.

A flick of the tongue and the chemistry of predator-prey interactions

Shannon Harper — Fri, 01 Mar 2013 11:08:26 +0000

The evolution of predator-prey interactions yields interesting adaptations, resulting in some quirky phenomena. Snakes are a commonly-feared predator and people are familiar with (and dread) the venomous ones. There are two ways in which snakes have evolved to utilize their venom to capture prey. One method is to strike and hold, whereby the snake maintains its grip on the prey after biting and injecting its venom. This seems a perfectly reasonable strategy on the part of the snake. Alternatively, some snakes use a strike and release process: once envenomation occurs, the snake releases its prey, which seems on the face of it less reasonable but can be explained as a way of reducing the chances of retaliation. However, this method presents the problem of relocating the prey once the venom has taken effect.

It has proved remarkably difficult to establish how snakes achieve this feat. It is known that snakes use rapid tongue flicking to assay their environment and locate their prey, and that chemical cues in the tongue provide information to a snake’s vomeronasal organ, enabling them effectively to sniff out the envenomated animal. This lead to the development of a behavioural assay based on SICS – Strike-Induced Chemosensory Searching – which is used for various animals that employ their tongue as a chemosensory detector, such as viperid, elapid and colubrid snakes, as well as some lizards. Utilizing this assay, researchers sought the specific molecules given off by a struck prey that reveal its location. Testing cues such as prey urine, scent and alarm pheromones proved fruitless, as snakes did not respond to these obvious smells. So the mystery remained of how an animal, once bitten and injected with venom, produced an odor that provided an olfactory locator for the snake.

Now however, in a series of experiments reported in BMC Biology, Stephen Mackessy and colleagues have found evidence that it is a molecule in the venom itself that is responsible for prey relocation in vipirid snakes. They applied crude venom to euthanized mice and used the SICS assay to show a clear preference on the part of rattlesnakes for envenomated prey. The authors then fractionated and purified the whole venom into its component parts. They found that only one fraction could reproduce the preferential tongue flicking response which, surprisingly, was not an enzyme or other such catalyst. Mass spectrometry revealed that the molecules responsible were the disintegrins- crotatroxin 1 and crotatroxin 2. Disintegrins are proteins that bind to and antagonize beta integrin receptors; the finding that they play a part in prey location seems entirely unexpected.

Perhaps the Chinese year of the snake will herald greater insights into these predators’ hunting senses.

Open questions from a tax-paying homeotherm

Miranda Robertson — Wed, 27 Feb 2013 14:32:23 +0000

Biologists have become wary of claiming that any cellular system is now understood but for the odd t left uncrossed, or i undotted, at least since the discovery of introns in the late 1970s opened up a new world of questions undreamed-of in the philosophy of the time.

So Sean Munro opens his contribution to the BMC Biology 10^th anniversary collection ‘Open questions in biology’ by declaring firmly that there is no danger that cell biologists will become bored for the duration of the century. He does risk predicting some of the questions that may be answered in that time frame, though we note that as we are still quite close to the beginning of the 21^st century, and Sean is already well into adulthood, he is unlikely to be around to be proved wrong. (Unless, of course, current research on aging…)

Remarking (benignly) on a few cell biological mysteries whose resolution seems irreversibly obstructed by the intransigently polarized views of those working on them, and (wistfully?) on the likelihood that we shall never have the resources to explore fully the extraordinary diversity of (non-tax-paying) life forms, he settles for five questions that might fruitfully be tackled in the next 87 years.

I’m not going to tell you what they are, because if I did this blog would be almost as long as Sean’s short Comment, and I couldn’t possibly put the questions better than he does. But I will say that diversity is a keynote, and two of his questions are ones that are widely ignored. This title of this blog contains a clue to one of them. His title is ‘What is there left for cell biologists to do?’ If you want to know his answers, read the piece.