Here’s a strongly opinionated look at where the “precision medicine” field is these days, and I think that this is just the sort of article that the field (and the journalists covering it) need to see, whether you agree with it or not:
In 1999 Francis Collins published a foundational document of precision medicine entitled “Medical and Societal Consequences of the Human Genome Project,”(1) which made predictions about the ways the human genome would be used to predict, prevent, and treat disease in 2010. In 2000, he suggested that “Over the longer term, perhaps in another 15 or 20 years, you will see a complete transformation in therapeutic medicine” (2).
The vision described in the article became the aspirational template for the precision medicine movement (Figure 1). We have passed the 2010 deadline and are rapidly approaching 2020, yet the “complete transformation in therapeutic medicine” has not occurred. Using the framework of the predictions made nearly 20 years ago, we argue that the foundational assumptions of precision medicine are unsound.
It was indeed clear by 2010 that the expectations from the original human sequencing were not being met, and that part of the reason was that some of those expectations were a bit too grandiose. That doesn’t mean that the whole thing was a bust, by any means – the push towards fast, cheap sequencing has had profound effects throughout the biomedical sciences, certainly up at the R&D end. I would have to think that the drop in sequencing cost/base pair would have taken place anyway, but it surely would have taken longer without the impetus of the Human Genome Project. But talk of “complete transformation” in medicine, yeah – that’s not quite the case. To get our definitions straight, this paper defines “precision medicine” or “personalized medicine” as “the view that incorporating information encoded in the human genome as the dominant factor in the prediction, diagnosis, and treatment of human disease will lead to marked improvements in human health“.
We’ve long known about the genetic contributions to many rare diseases. One of the hopes for the new era was that we’d be able to discover some genetic variants or combinations with relevance to many of the more widespread ones (diabetes, Alzheimer’s, etc.) But that’s not the case. What you find is a cloud of dozens or hundreds of genes that put together explain only some fraction of the disease landscape. And it’s not like the rest is lurking in the genome somewhere – we’re studying the whole genome already, so that excuse, which was very popular at one time, is no longer operative. Nope, the rest of it is in all the things that aren’t in the gene sequences: epigenetic markers, to be sure, but more generally the uncounted effects of environment and development. Now, it’s true that you can do a pretty good prediction of height from gene sequence these days, with a model that blends in a whole heap of gene variants, each of which contribute a bit up or down. But that’s only if you stipulate good nutrition, in that case, since that can override things pretty thoroughly. And for so many other traits, we don’t quite know what nongenetic influences to control for, or how much genetic influence is left once you’ve done that. As this paper puts it, “Extensive analyses of thousands of potential gene-health outcomes often fail to match, let alone exceed, the predictive power of a few simply acquired and readily measured characteristics such as family history, neighborhood, socioeconomic circumstances, or even measurements made with nothing more than a tape measure and a bathroom scale.”
So if you had to boil down the lessons of the “genomic revolution”, I’d suggest “Sequence isn’t everything”. You might think that cancer would be an exception to that, since there are certainly specific molecular mechanisms that tumors use to become (and remain) tumors (although we don’t know them all, to be sure), and since these are often driven by gene mutations. The problem is, as anyone in the field can tell you, that tumor cells also tend to be genetically unstable. Any given solid tumor is almost certainly a mosaic of dozens, hundreds of mutated cell lines, with more being thrown off all the time. So even in the cases where we would expect a benefit, it’s elusive, except for some gene variants with exceptionally high penetrance.
The authors sum up:
However, nearly two decades after the first predictions of dramatic success, we find no impact of the human genome project on the population’s life expectancy or any other public health measure, notwithstanding the vast resources that have been directed at genomics. Exaggerated expectations of how large an impact on disease would be found for genes have been paralleled by unrealistic timelines for success, yet the promotion of precision medicine continues unabated.
The problem is partly with the results, and partly with the predictions. Expectations were raised too high. The general public got the idea that Genes Are Destiny, which viewpoint is being exemplified (and reinforced) by the popularity of the consumer-sequencing companies. Those might be interesting to figure out your ancestry (although there are a few little tiny uncertainties here and there), and some folks have definitely found out more about their immediate ancestry than they realized there was to know. But as far as predicting disease or overall health. . .not so much. That’s a tangle of environment and heredity like you’ve never seen. Unless you hit one of those rare-disease genes with huge penetrance (where genes really are destiny), your gene sequence is just part of that tangle, and good luck unraveling it.
All those clinics advertising “precision cancer treatment”? Same problem, and worse because of that genomic instability mentioned above. It would be great if we could dial in a personalized treatment for each patient based on tumor sequence, but that’s not where we are yet, outside of very rare cases. Earlier attempts to treat the general run of oncology patients by such techniques have not worked. The current effort in this line is NCI-MATCH, a comprehensive effort to line up targeted therapies versus genetic signature, and it has shown a mixture of potentially promising and not as promising results so far. We do have the first approvals for oncology drugs (larotrectinib and pembrolizumab) on the basis of gene signature regardless of tissue, so there’s progress. But if you’d told Francis Collins back in 1999 that we’d have the first two approvals of that sort only in the fall of 2018, he would have wondered what the heck went wrong.
The authors of this new paper end by saying that “it is urgent that the biomedical research community reconsider its ongoing obsession with the human genome“, which is strong language. We’ve learned a lot from genomic studies, and we’re still learning more, and it’s not going away. But if by “obsession” they mean trying to apply genomic viewpoints to every problem regardless of suitability, or promising success in some of these programs once we can do just a bit more sequencing – because that’s all they’re lacking – then they have a point. The genome is great, the genome is huge, the genome is important. But it’s not the only great huge important thing out there.