Thursday, June 30, 2011

More hype. The microbiome. Sigh.

For the last two decades, the answer to why we get sick, and how to prevent it was said to be in the genome.  The answer may have been elusive, always just out of our grasp, but once we had the whole genome sequence, or understood what non-coding DNA did, or had catalogued all common variants, or when we discovered variable copy number or epigenetic mechanisms like methylation, or had catalogued all rare variants, we'd have the answer.  And the hundreds of millions spent on the search would be justified, and we'd all live forever -- even if all the ethical and societal implications of this consequence were never thoroughly explored.

Some people understood pretty quickly after the human genome sequence was announced in 2003 that the promised answers were unlikely to be there, and so they broadened the search.  Maybe we'd be done if we understood the function of gene networks or everything in the cell or if we thought in terms like systems biology -- or any omic you cared to come up with, from the nutriome to the connectome to the microbiome.

And it's interesting about that microbiome, the cataloging of which is now well under way.  The BBC World Service radio program, Discovery, explores the issue this week.

The Human Microbiome Project webpage explains the project's mission:

  • This initiative will begin with the sequencing of up to 600 genomes from both cultured and uncultured bacteria, plus several non-bacterial microbes. Combined with existing and other currently planned efforts, the total reference collection should reach 1000 genomes.
  • The initiative will continue with metagenomic analysis to characterize the complexity of microbial communities at individual body sites, and to determine whether there is a core microbiome at each site. Pilot studies will implement shallow and then deep 16S rRNA sequencing, progressing into deep metagenomic sequencing. Several body sites will be studied, including the gastrointestinal and female urogenital tracts, oral cavity, naso-pharyngeal tract, and skin.

The second stage of the project will explore the relationship between the microbiome and disease, and at the risk of sounding like a broken record, we have to say, the leaders of the project interviewed by the BBC sound a whole lot like the leaders of the Human Genome Project did at the inception -- microbes are likely to explain everything, from heart disease to asthma to cancers and autism, arthritis, Alzheimer's and much more, even aggression (we wrote about that particular issue here, and here's a list of the demonstration projects already funded and underway).  And once we've got the microbiome from those 5 different tissue layers sequenced, we'll understand how.  And we'll be able to prevent the 'microbiome imbalance' that makes us sick.  Or, presumably, aggressive or whatever other undesirable behavior that imbalance might cause.  (Hmmm, that sounds like Galenic medicine in which you are well unless your humours are out of balance--only it's your microbiomic contents!)

Yes, of course some diseases are caused by single genes, and some diseases are caused by microbes, in any sense of the term, and more are sure to be found.  And those can be legitimate targets of technical medicine (or, we note, non-technical environmental or lifestyle modifications)  The problem is the way the hype machine is yet again rolled out to generate the promise that has gone into getting this project funded, and keeping it going.  Microbes are as unlikely to explain all disease -- and unwanted behavior -- as genes are, but the promises must be made so the money can be gotten and the work can go on.

To see that this not (just) another rant on our part, one can consider that the microbes that matter are those that interact directly or indirectly with our cells.  Pure fellow travelers neither hurt nor harm us. That means that their genomes are in many ways our genomes as well (and vice versa). We know empirically that our phenotypes are by and large complex--and we know that whether or not some of the genes that are contributing are in our cells or our microbiome's.  The major thing that can happen with the latter is that a nasty bacterium can reproduce (much like a cancer precursor cell), to have a major effect.  But for that same reason, we already know the ones that do that (bad E. coli strains, cytomegalovirus, etc.).  We have active, successful, major research programs to track them, look at their pathogenicity, and evolution relative to us as hosts.  There are real battles ahead in this area, and regular science will work--if we're lucky--in this context.  Otherwise, just as with GWAS, what we're promising to find is mainly likely to be the shifty complex of minor contributors.

We have allowed a Battle of the Omics to be waged by almost unrestricted acceptance of each omics claim.  Bloating and puffery are the current way of life.  Of course, the dust will eventually settle, but nobody will know what better might have been done with the money than waging this kind of unrestricted warfare.

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