Camus enters the clinic: Genome Biology at Genomic Disorders 2013


It is not unusual per se for Nobel laureates to be quoted at genomics conferences, but it is perhaps a little out of the ordinary when the Nobel Prize in question is for Literature. But, then again, the Wellcome Trust's 'Genomic Disorders 2013: From 60 years of DNA to human genomes in the clinic' was not your run-of-the-mill conference; instead, a mesh of current research and historical (and futuristic) perspective paid tribute to the 60th anniversary of Watson and Crick's discovery of the double helix.

So it was not entirely out of keeping with expectations when philosopher (and former candidate for Slovene of the year) Renata Salecl stepped onto the podium and asked:

'Should I kill myself, or have a cup of coffee?'

For those unfamiliar with mid-20th Century Absurdist literature, these are the (translated) words of French-Algerian faux existentialist Albert Camus, taken from the pages of his 1942 novel L'Étranger. Salecl chose the quote as an illustration of the anxiety surrounding ambiguous data generated by modern genetic techniques. Camus' protagonist, Meursault, bumbled through life making choices where the options were clear-cut: with genetic data, we are faced with unknowns, risk factors and grey areas.

Absurd genomics
Meursault ultimately ended up on death row after committing murder, so maybe we should not let him inform the debate too strongly. Salecl reminded us, however, that a real problem of unwarranted certainty exists when handling forensic genetic data in legal cases. And such miscalculations may also result in death row, but for innocent victims of judicial inadequacies.

Salecl offered examples of incompetence and compromised integrity on the part of forensic scientists, and even suggested that a malevolent individual, in the mold of Harold Shipman, might deliberately falsify forensic reports as a form of sadistic power trip. Suffice it to say that the prospect of incompetence is worrisome enough, especially when one considers the number of forensic scientists who put their name to a recently published paper purporting to report the 'Bigfoot' genome sequence.

Genomes2people – but which bits and which people?
A more practical assessment of genetic uncertainty was put forward by Robert Green, of Genomes2People. Together with colleagues, Green has developed a set of recommendations for the reporting of incidental findings in genomic data, one of the main headaches of the personal genomes era that is opening up before us. He discussed studies into how people respond to such findings, and the general trend is an encouraging one: more exercise, more insurance take-up, and so on. Of concern, however, was the large number of people who are unable to accurately describe the risk factor reported to them, even when they can remember the details of what was said.

When experts were canvassed as to which type of incidental finding should be reported, taking into account disease type and the known risk of the variant, very little by way of consensus emerged. Perhaps there really is no right or wrong answer, but this is not an issue with room for neutrality – each finding is either reported or it isn't, and either way you are taking a point of view. Green and his colleagues have at least managed to arrive at a minimal list – encompassing 57 genes in 24 conditions – of risk variants that they recommend should be reported as incidental findings. But they also suggest each clinician should apply personal judgement to individual cases.

Variant-based therapeutics
Green made the point that incidental findings in genetics data seem to be held to a different standard to those derived from imaging data or physical examinations. Perhaps this is because many genetic findings are today not actionable. By conventional approaches (find a druggable target, and then a safe and specific drug for the target), patients have little hope of a successful remedy in the near future.

But Tamar Grossman, of ISIS pharmaceuticals, explained how therapeutic antisense oligos (ASOs) offer a whole new paradigm for rational drug design. One of the exciting features of ASOs is that they not only avoid the need to discover a druggable site (and then a small molecule of high affinity and specificity), but can also target the large number of genes for which no readily druggable site is discoverable.

ASOs can operate by a number of mechanisms, one of which is masking aberrant splice sites, as shown by Jennifer Lentz (Louisiana State University). In a recently published study, Lentz applied ASOs to a mouse model of Acadian-type Usher syndrome, which involves a specific mutation that promotes an inappropriate splicing event.

Lentz is able to prevent onset of the deafness and vestibular symptoms of Usher syndrome mice, although has not yet established whether this is also true of the blindness phenotype. Usher syndrome patients have expressed interest in translating these ASOs to the clinic, but only if it means prevention of blindness. Deafness, on the other hand, is viewed as natural variation – not a 'condition' that clinicians should seek to correct in utero.

Rounding off the meeting with ASOs was fitting, given that they function through complementary base-pairing – the heart of Watson and Crick's double helix discovery, sixty years earlier, in the very same Cambridge streets now playing host to the conference in its honor. The progress made in genetics during these sixty years is really something to behold, and was fully on show at the meeting.

On the anniversary itself, April 25, Genome Biology will publish some special content celebrating sixty years of the double helix, so please do look out for that. We are also hosting a special commemorative bioinformatics challenge, beginning a few days earlier and culminating on DNA day, of which you can read more here.

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