Wednesday, May 5, 2010

First 2010 Misrepresentation of the Year Award Goes to Nature

The first 2010 Misrepresentation of the Year Award goes to Nature magazine for last week's cover story. The caption on the cover is "The MS Genome" and is accompanied by silhouettes of one person standing and her twin in a wheelchair. But is the story about 'the multiple sclerosis genome' (whatever that would be)? No.

Compare the authors' actual title of their report to the cover's:
"Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis."

This is a representative, scientifically responsible title for the paper. There is a difference between genomes from MS patients and 'the MS genome.' What the  authors
report is the complete sequencing of the genomes of one discordant pair of identical twins (where one twin has MS and the other doesn't), and gene expression differences between 3 sets of discordant identical twins. They discuss issues of data accuracy and replicability, and they find no genetic signature that can explain the discordance.

  • Is the story well-done work? Yes, we're not experts but it seems to be
  • Is the science valid? Yes, it seems to be
  • Have the authors explained MS? No, but they don't claim to have done so
  • Have they found the MS genome? No and they don't claim that either
  • Have they identified which genome is 'the' MS genome? No
  • Have they shown that there is such a thing as 'the' MS genome? No
  • Is the story an important contribution to the understanding of MS? That's debatable
Genetic differences between the two twins in each pair were found, presumably the result of somatic mutations that occurred during or after embryogenesis, but none were associated with MS. Because MS has a curious relationship to climate and has sometimes been attributed to viral infection, sequences that weren't identifiable as human from each set of twins were aligned with viral genomes. That was a clever thing to try, and might have identified an MS 'infectome', but unfortunately no differences were found between the viral load of affected vs. unaffected twins.

The twins did not show replicable discordance at the immune system (HLA) genes, or other genes, that previous mapping and other studies had shown are likely contributors to MS risk. The twins varied a lot in terms of DNA sequence (presumably, somatic mutation) and gene expression levels--but in a way that could be attributable to their MS discordance.

This is another installment in the Life is Complex Department. We said above that this may not be an important contribution, because there are so many possible reasons why the authors didn't find what they hoped to find. That would not be their fault, and indeed, their work shows some of the many reasons why these kinds of data are problematic (sequencing errors, difficulty replicating expression levels, and so on). Perhaps they should have known this would have been the case from other similar kinds of studies (such as comparing genomes of cancer and normal tissue from the same person).

They confined their gene expression comparisons to a very confined set of sites -- necessarily, given current sequencing methods -- but that means that in no sense was this study exhaustive. It could be said that this was a premature use of new technology. But that's not our issue here!

The idea was a clever one, but perhaps built too much on hope against what we know about disease complexity. In general, one would be surprised if a clear result had been found, because these twins did not even have the suggested risk genotypes at those candidate genes, and because a genetic signature for MS has been so elusive before now.

Perhaps identical twins are not as good a comparison as they seem on the surface, since we know that stochastic and somatic changes can be responsible for many differences during life (that's what the cancer studies show).

Perhaps twins that did carry the suspected HLA or other risk genotypes, but who are nonetheless discordant for MS, would provide a more cogent comparison. Discordance in them would suggest that something else--perhaps environmental pathogen exposure or somatic mutation in other genes in one of the twins--was responsible.

The etiology of MS remains mysterious and this was one way to take a shot at a discovery.

But multiple sclerosis is no joking matter. The Nature cover is a kind of cruel disservice to those who suffer from MS, or their loved ones, by suggesting that the genetic cause had been found, with the obvious innuendo that a cure is just round the corner. Why else the cover story in Nature??

Their kind of misrepresentation is what diverts resources to inefficient or even lost causes. In fact, in no way has 'the' MS genome been found, nor is it defensible to suggest that there is such a singular thing. And only half the studied people were affected. Maybe the affected twin experienced somatic genetic changes, while the unaffected twin reflected the inherited 'resistant' or 'normal' genome of the pair?

It's not the authors but the journal that is responsible for the misrepresentation. It was a shot in the dark, perhaps, that had no business as a cover story. We hope that research will not be discouraged as a result--that is, that the authors' lack of positive findings does not lead to their work being thought of as 'negative' (if the bait-and-switch of the journal cover leaves hopeful readers deflated when they see the real story).

Nature has been quite successful at its attempt to match the quality standard of People magazine, and we assume that will continue, as they're pros and they know how to reach their market. Their naked savage and 'ancient' Khoisan genome cover of a couple of months ago ran this one a close second, and we wrote about that at the time. Though we're sure they would deserve it, we want to keep these Misrepresentation Awards one per customer per year, so we hope Nature (but not People) will wait for its next one til 2011.


Jennifer said...

MS IS mysterious and devastating. I can see why the cover title would sell the magazine. I agree with Ken that it is a misrepresentation. I also think that this is just one of many studies. Not a start, but a continuation of ongoing studies trying to figure this diseas out. It's very interesting to study the twins, even if nothing is proved. It at least covers some ground. Also, the similaries in people who have MS are very interesting. Be it climate, viral exposure, genetic tendency. I know (anecdotally) a man who has had MS for years, his father died from MS and he knows several people from his small high school who also have it. (Small Vermont town). And any one or more of the above variables could be involved. It's good that they keep studying, whether they come to concrete conclusions or not. At least they keep covering ground. But, it is disgraceful that 'reputable' publications use people's emotions and concern about devasting conditions to sell their magazine.

Anne Buchanan said...

Yes, exactly, Jennifer. The study is important, the journal's treatment of it is cynical and, as you say, disgraceful.