In an excellent post about the vaginal microbiome (the microbes that in the vagina), Dr. Rad asks:
I wonder if the idea of a ‘core microbiome’ came from Lourens Baas Becking’s oft-quoted idea in microbial ecology that ‘Everything is everywhere, but, the environment selects’? Ie putatively similar environments would lead to putatively similar microbiomes. Seems like the alternative to ‘core microbiome’ then would be the neutral theory of biodiversity. That is, if the core microbiome is hypothesized to arise from niche theory. Like I said, I ain’t no microbial ecologist.
I think there are two things going on here. When people began to look at the human microbiome, we had very small sample sizes–if you could generate ~200 sequences per sample, that was a lot–and we had very primitive ways of classifying sequences. So we were only looking at the very common stuff, and we were calling a lot of diverse organisms the same thing. So that led to a belief that there might be a core microbiome.
But the other key thing is the role of the large genomics centers in the Human Microbiome Project (note: until about a year ago, I was deeply involved in the Human Microbiome Project).
That project was developed and led by people who were genomicists, not microbial ecologists (or any other kind of ecologist; note: many moons ago, I was a marine ecologist). One concept that bacterial genomicists use in the notion of a ‘core genome’: the set of genes that are found in all members of a given bacterial species* (for instance, the best estimate for E. coli is around 1,200 out of 5,000). This is often thought of as the set of genes that ‘define’ that organism. By analogy, the core microbiome is the set of species that ‘define’ a body site.
This isn’t supposition on my part: I’ve actually heard this said multiple times.
But, as Dr. Rad notes, that concept seems to have fallen by the wayside–it appears that there are, at the very least, multiple potential core microbiomes. I’ve argued that, in healthy people, for a given body site, there might not even be definable microbiome types, although I haven’t seen the most recent data (Aside: I think with more people examined, we’ll see that, at least among the healthy, it’s a blur. A lot of the claims that microbiomes are distinct seem to fall apart once you get enough samples). It does remain to be seen if, at the functional level (what genes do), whether there is any conservation at any one body site.
To get back to Dr. Rad’s question, I’m fairly certain that the few people involved early on who were familiar with Stephen Hubbell’s The Unified Neutral Theory of Biodiversity and Biogeography did not think there would be a core microbiome. One of the early problems with a lot of the human microbiome work–and which was driven by NIH–is that it was viewed primarily as a medical genomics problem and not a community ecology one**. That’s changed, but the core microbiome concept is a legacy of that way of thinking.
*Given that many genomes or the genes called from them have errors, it’s a little trickier than this, but you get the general idea.
**I’m fairly convinced that it was originally viewed as just another Scary Movie human genome project. However, human genomes do have a finite boundary and are very conserved (compared to a gut ecosystem). And unlike the human genome project, there is a huge ecological component to the analysis.
mikethemadbiologist
Cool! Thanks for the insider view.
I disagree with your characterization of the HMP. It’s unfair to judge in hindsight; and it’s easy to pick apart a project that was conceived and funded at the close of the Sanger sequencing era when the sample sizes and depth of sampling now available were beta-testing. There were many expert microbial ecologists present at the birth of the HMP and concepts from ‘core’ to the infinitely long tail were openly and intelligently discussed. The human ‘core microbiome’ was understood by all as a hypothesis, perhaps even an incorrect one.
However, because the HMP was fundamentally a contract, the goals of the HMP could not be formulated as ‘hypothesis driven’. The goals needed to be stated as deliverables and thus phrases like ‘define the core microbiome’ were invoked. I will also remind the ‘insider’ that a major, and oft forgotten-in-hindsight goal of the HMP was to generate microbial reference genomes to support interpretation of future metagenomic data and, thus, a significant part of the rational for 16S surveys was to identify phylogenies where reference genomes were needed, ie not to define the ‘core’.
I believe that the expert ecologists present, who were more familiar with hypothesis driven proposals, were frustrated by the language of contracts that the sequencing centers are fluent in; and were frustrated by the relatively huge sums of money placed in the service of a non-hypothesis driven contract. Unfortunately, as a result of these frustrations, expert microbial ecologists withdrew their support for the HMP. And, also unfortunately, an organization structure build around medical genomics struggled to adapt to metagenomics without the input and support of experts.
Where am I going? I dispute that the ‘core’ was a legacy of ‘that way of thinking’. It is simply the legacy of a valid hypothesis that is slowly being proved wrong–first with enterotypes and next with something less definable, perhaps. It’s erroneous to blame the HMP for propagating the concept of a core. Better to blame the lack of data and the lack of good analysis. Better to blame a general scientific culture that rewards simplistic black and white conclusions with prestige publications. Certainly individuals associated with HMP championed a core, but so did individuals not associated with HMP. Most associated with HMP were simply trying to produce the best resources possible to enable scientists to address hypotheses.
I don’t disagree with the validity of the project: I’ve defended it multiple times on the blog. But in discussion after discussion by the participants, the core was often referred to, and there was little discussion of ‘non-core’ alternatives.
I’m also confused as your third paragraph is exactly the point I’m making: traditional ecologists weren’t part of the project (for a variety of reasons) and they should have been. Had they been, there would have been a very different take on the data analysis. Nor did I mean to imply that no one else was using the core concept, although, given the data limitations of the early work, that’s understandable.
MIcrobial ecologists were involved in developing the concept for proposal as an NIH Roadmap/Common Funds initiative. NIH actively sought their input. I speculate that this was quickly forgotten as HMP got going and many microbial ecologists became less enthusiastic with their support. I probably over reacted/interpreted your comments as suggesting they were intentionally excluded.
But, you seemed to argue that NIH launched the project with a false perception that it was analogous to medical genomics (as per your footnote **). I disagree for reasons I stated. The goal was to characterize the human microbiome. The design of the study was influenced by competing thoughts and objectives, logistics and budgets, and thus wasn’t ideal for addressing either core or non-core models. All knew that the survey would be insufficient to provide a complete and final description. I’ll back up and comment that there was the center-based survey of healthy individuals to ‘contractually’ define/describe the core microbiome. There were also demonstration projects to associate aspects of the microbiome with health or disease states. Many terrific experts in the field associated themselves with the demonstration projects. My comments are addressing the healthy individual surveys which were largely left to the genomic centers.
On the whole, I think the HMP did a remarkable job of bridging the gaps between genomics, clinical studies, and microbial ecology–the gaps were large and formidable. It would have been nice if all obstacles were met with grace, transparency and efficiency; unfortunately, they weren’t. I agree that if the active involvement of leading microbial ecologists had been maintained, the project would likely have got off on a more solid footing, more quickly. I don’t blame the intent or vision of NIH or the collective participants, however. I’ll blame human nature.