So I see that the headlines are that it’s proving difficult to relate gene sequences to specific diseases. (Here's the NEJM, free full-text). I can tell you that the reaction around the drug industry to this news is a weary roll of the eyes and a muttered “Ya don’t say. . .”
That’s because we put our money down early on the whole gene-to-disease paradigm, and in a big way. As I’ve written here before, there was a real frenzy in the industry back in the late 1990s as the genomics efforts started really revving up. Everyone had the fear that all the drug targets that ever were, or ever could be, were about to be discovered, annotated, patented – and licensed to the competition, who were out there fearless on the cutting edge, ready to leap into the future, while we (on the other hand) lounged around like dinosaurs looking sleepily at that big asteroidy thing up there in the sky.
No, that’s really how it felt. Every day brought another press release about another big genomics deal. The train (all the trains!) were loudly leaving the station. A lot of very expensive deals were cut, sometimes in great haste, but (as far as I can tell) they yielded next to nothing – at least in terms of drug candidates, or even real drug targets themselves.
So yeah, we’ve already had a very expensive lesson in how hard it is to associate specific gene sequences with specific diseases. The cases where you can draw a dark, clear line between the two increasingly look like exceptions. There are a lot of these (you can read about them
in these texts
), but they tend to affect small groups of people at a time. The biggest diseases (diabetes, cardiovascular in general, Alzheimer’s, most cancers) seem to be associated with a vast number of genetic factors, most of them fairly fuzzy, and hardly any of them strong enough on their own to make a big difference one way or another. Combine that with the nongenetic (or epigenetic) factors like nutrition, lifestyle, immune response, and so on, and you have a real brew.
On that point, I like E. O. Wilson’s metaphor for nature versus nurture. He likened a person’s genetic inheritance to a photographic negative. Depending on how it’s developed and printed, the resulting picture can turn out a lot of different ways – but there’s never going to be more than was in there to start with. (These days, I suppose that we’re going to have to hunt for another simile – Photoshop is perhaps a bit too powerful to let loose inside that one).
But I've been talking mostly about variations in proteins as set by their corresponding DNA sequences. The real headscratcher has been this:
One observation that has taken many observers by surprise is that most loci that have been discovered through genomewide association analysis do not map to amino acid changes in proteins. Indeed, many of the loci do not even map to recognizable protein open reading frames but rather may act in the RNA world by altering either transcriptional or translational efficiency. They are thus predicted to affect gene expression. Effects on expression may be quite varied and include temporal and spatial effects on gene expression that may be broadly characterized as those that alter transcript levels in a constitutive manner, those that modulate transcript expression in response to stimuli, and those that affect splicing.
That's really going to be a major effort to understand, because we clearly don't understand it very well now. RNA effects have been coming on for the last ten or fifteen years as a major factor in living systems that we really weren't aware of, and it would be foolish to think that the last fireworks have gone off.