Monday, April 16, 2012

Is whole genome sequencing fading? Will it rebound (or relapse)?

There are various informal indicators that funders are losing enthusiasm for human whole genome sequencing.  We've seen discussions of 'genome fatigue' in the media (Carl Zimmer, e.g., talks about this here), and one colleague said there wasn't much enthusiasm for whole genome sequencing because we hadn't found the cure for cancer or made highly useful personalized predictive medicine.  Another colleague on an NIH grant review panel said that particular panel, at least, wasn't going to fund any more GWAS studies.
DNA sequence data, Wikimedia Commons

If this turns out to be more than a few anecdotes or personal opinions, and is actually occurring, it's understandable and to be lauded.  As we think we can truthfully claim, we have for years been warning of the dangers of the kind of overkill that genomics (and, indeed, other 'omics' fads) present:  promise miracles and you had better deliver!

The same thing applies to evolutionary studies that seek whole genome sequences as well as to studies designed to use such data to predict individual diseases.  There are too many variants to sort through, the individual signal is too weak, and too many parts of the genome contribute to many if not most traits, for genomes to be all that important--whether for predicting future disease, normal phenotypes like behaviors, or fitness in the face of natural selection.

There are some traits, especially if close to a specific protein, in which only one or a few genes are important.  There are many genes which, if broken by mutation, can cause serious problems.  And as we've said numerous times, this is where the genetics money should be spent.  But the nature of evolution is that it has produced complexity by involving numerous cooperating genetic elements, and traits are typically buffered against mutations.  Otherwise, organisms couldn't have gotten so complex (try making a brain or liver with just one gene!).  Otherwise, with so many genes and ever-present mutation, nobody in any species would ever survive.

The instances of single-gene or major-mutation causation are numerous and real.  They are already handled by services like genetic counseling in biomedicine, and by evolutionary or experimental analysis.  But the important nature of Nature is its complexity and at present whole genome sequence data provide too much variation for us to deal with on adequate terms.

Nature screens the success of organisms on their overall traits, regardless of what genotype contributed to it.  Many of the contributing variants to a given trait are new mutations or are very rare in the population, and very difficult to detect in terms of assigning 'risk' to them.  Worse, they flow through the population all the time, as individuals die and new ones are born. Since their individual effects depend on their context--the ever-changing environment and the rest of the genome--these effects are also fluid.  Thus, enumerating causal variants may not be a very useful way to understand biological causation.

Of course, rumors of the demise of ever-higher throughput genomics may be greatly exaggerated.  Funding may not actually be diminishing, or may return.  Whether that will be a rebound towards good science, or a relapse of low payoff, is a matter of opinion.


Razib Khan said...

"Is whole genome sequencing fading?"


Jonathan said...

In your first paragraph you conflate whole genome sequencing with GWAS (they're really not the same thing), and then build the rest of this argument on top of it.

Meanwhile there are an ENORMOUS number of whole genome sequencing studies underway or in the pipeline.

I find this entire argument deeply unconvincing.

Ken Weiss said...

There is a lot of instant, or frantic?, wagon-circling going on at the very hint in a remote blog post that genomewide sequencing may be being viewed as not worth its cost.

Our post did not conflate GWAS with sequencing, because the momentum is moving from GWAS to sequencing via a series of rationales (including,by the way, explicit statements of 'what do we need to do in the next mega-genome sequencing project?', that is, to keep the funds flowing).

The current sequencing projects are numerous and diverse, certainly, but that doesn't mean they will remain that way, or in particular that countless humans will have this done.

There are many reasons to do sequencing of different species or for targeted scientific reasons, of course. The issue might become less inflammatory as the cost comes down (except that one can rely on demand being made for at least the same amount of funding for the annotation and analysis).

But anyone who would deny that there are also vested interests of various kinds operating here is just being an ostrich or defending turf. These include all sorts of interests, not worth arguing about here.

It's natural to want to pursue these kinds of data for all sorts of reasons, scientific and otherwise, but the health-care system is heavily stressed, and there a millions of people going without nearly adequate health care. So there are many sides to the investment story.

The GWAS and beyond payoff has been limited, and anyone who's candid knows it. But impatience with slow progress is not always justified. Gene therapy, for example, is a highly technical engineering challenge, and one has to expect it to take along time to bear much fruit (as it may now be doing). GWAS has been clearly at diminishing returns, repeatedly demonstrating what we knew, for the right reasons, long ago. The same can be predicted, based on what we see so far, of whole genome sequencing. Diminishing returns doesn't mean no new knowledge, it means less major payoff per dollar--relative to other ways to invest in science or society.

This post was about things said to us, or rumblings increasingly appearing in the press and elsewhere. We personally see the technology rather than the questions too often driving things in much of this arena, and we explained our reasoning in the post, after saying that we were posting because we have heard that the tide of support may be ebbing.

Nobody need agree with us, but the responses so far have been like Nancy Regan's ("just say no") to the rumor of loss of support. Don't say it, lest a funder hear you!

Counter arguments have not been involved in this reaction, other than the usual vague promises of serendipitous discovery. That's specious, because while serendipity does occur it will occur with other ways of investment as well.

As we concluded, time will tell, especially because of the sequencing cost reductions. We did not predict, but asked, whether there will be a rebound based on scientifically cogent ideas of importance, or a relapse to the often-rote application of technology?

Anonymous said...

I hear this kind of chatter too, but I'm alway disappointed when people take entire areas of research and make overly broad statements about how useless it is. That's just as prejudicial and biased as the folks providing the hype. Some researchers, no doubt, are pushing the boundaries of biomarker development in a good way with genomics as a big part of that. They shouldn't see their funding pulled in tough times simply because the majority couldn't live up to the hype. The scientific sheep should be encouraged to move on, but the serious folks that are in it for the science and not easy funding should be encouraged to stay.

Ken Weiss said...

Yes, I agree. But then people should stop their global promises, and hyping to the media, and perhaps funding for this kind of work should be made more discriminatory relative to whether it's thoughtful or just stabbing in the dark.

This is a two-way street, because it's hard if not impossible to get good funding if you're NOT asking for high-throughput.

To repeat the post, and my comment above, time will tell whether the overall reaction is largely to pull the plug, or whether there will be better or more effective use made.

S.Pelech-Kinexus said...

The identification of disease-causing genes is only the first step in a long road towards successful diagnosis and treatment of illness. Take sickle cell anemia as an example. The common mutation that produces this disease was originally reported by Vernon Ingram et al. back in 1956, after Linus Pauling and his colleagues linked hemoglobin defects to sickle cell anemia earlier in 1949. Today, despite decades of ongoing research, the average life expectancy for victims of this disease is still between 53 to 60 years in North America and Europe.

Recent reports, including findings of the occurrence of typically around a hundred loss-of-function gene mutations in the average healthy human genome (Daniel MacArthur et al.), and the lack of increased risk for 24 different diseases seen when 53,666 identical twins were compared to the general population for the same diseases (Bert Voglestein et al.), exemplify the limitations of disease risk assessment based on purely genomic sequence information. Environmental factors clearly have a major influence on whether most common diseases will materialize, and these can exacerbate or compensate for genetic defects.

Recent genome sequencing studies have yielded hundreds of possible leads for the study of oncology alone. However, most of the major oncogenes were actually identified almost 20 years ago. While thousands of gene microarray studies have been performed to examine changes in gene expression with cancer, it now turns out that gene co-expression data rarely identify direct physical linkage between the protein products of these mRNA. I noticed at the most recent American Association for Cancer Research Meeting in Chicago, an increasing emphasis on epigenomics and micro-RNA research. While interesting from a basic research perspective and this may even have some diagnostic value, these directions are unlikely to translate into improved therapies for most cancers and other diseases. The phenotype for almost any disease ultimately depends on the complex interplay of normal and defective proteins, and for host of practical reasons, proteins remain the best drug targets.

Clearly a myriad of extra levels of control in addition to the genome DNA sequence are exerted inside of cells to maintain their healthy state. These include epigenetic, post-mRNA transcription, post-protein translation, and allosteric regulation. Further complexity arises from hormonal and nervous communications between cells. Our growth in understanding of these processes from biomedical research over the last 50 years has been impressive, but our knowledge is still extremely fragmentary. I remain constantly frustrated by the relatively little support afforded by government and charitable organizations towards looking beyond DNA and RNA. As long as proteomics and metabolomics research continues to be short-shrifted, there will always be a translational gap, and the general public and politicians will become increasingly dubious about their biomedical research investment.

Ken Weiss said...

To some extent the extension of 'omics' is just genomics by another name, that is, it's unfocused, mass data collection--Baconian induction at its best (or worst). There are many ways in which miRNA, epigenetics, GRNs and many others are merely new words for what amount to 'hyper'genes, sill based on the idea of enumerative reductionism.

Indeed, we know now, quite well, that by and large, induction in this area does not lead to its promised emergence of the 'true' theory, because in a sense there is no single such thing in life. We've expounded on the reasons we say this on many prior occasions: life is ad hoc, each gene and trait is different, it is highly probabilistic but without closed prior distributions, and the like.

So while I personally agree that it is time to think differently, and protein biology is at least as important and in an interesting way somewhat causally removed from genes per se, the danger (to me) is that proteomics and metabolomics not be yet another layer of Bacon on the sandwich.

Without going into historical analogies in science, what we see today is to a great extent herd behavior even in science (it's nothing new, and it's only human!). If there is a need, it's for critical thinking about what it means and where to take it, rather than that what we need is more of the same. Unfortunately, one can't order up innovation the way one orders a BLT.

Ken Weiss said...

If we were, for example, to divert funds from mindless rote sequencing of everything that moves or grunts or waves in the wind, and (in human genetics) focused resources on things that are serious, recalcitrant to treatment, and truly genetic (e.g., CF, MS, MD, and, yes, henoglobinopathies, &c), and showed that, as was done with vaccines, figuratively speaking, we could develop targeted therapy that was curative, then nobody would agree to gradually expanding the approach to things that are less 'genetic'.

Instead, genetics has cash and panache, and garners funds even for traits that are rather clearly by far more 'environmental' than genetic. If the media are tiring of Darwin books, they may also be tiring of genomic miracle promises, and rightly so.

Technology opens windows onto Nature. But just opening all the windows doesn't mean that what rushes in will be fresh air.

Ken Weiss said...

Ooops! In the previous comment I meant to say that nobody would DISAGREE with pushing new funds in the genetic direction. And they'd be supportive for the right reasons. But even so, a time would come and it may not be that far into such an extension, when genetic approaches are just too far removed from the relevant causal processes to payoff.

Anonymous said...

Much as all this stuff should be dramatically scaled back, I think you see your desire for that in the words of some individuals. Unfortunately with someone as invested in genomics as Francis running NIH, the near future is doomed to be dominated by continued investment in thought-free engineering approaches rather than real science. I can imagine that smaller groups have trouble getting funded to do it as it really does not work, but the big groups will continue to collect massive amounts of cash through directed support designed to be spent solely on sequencing and other large-scale technology. Such is the nature of our species, to believe that throwing money and technology at a problem will ultimately lead to a solution.... Not likely in this case, however...