SF Gate Column on "You big, fat pile of bacteria"

There is an interesting column on SFGate.com about microbes living in and on people. By Mark Morford, SF Gate Columnist

He talks about eating earthworms as a kid.

Of course, it turns out, biologically speaking, that big, dirty earth-muncher probably did my immune system, my intestinal tract and all the happy bacteria therein a world of good. It’s true.

Furthermore he says

we as an overpampered culture are probably not getting enough nasty buggy immune-system-boosting microbes in our diet, in our meats, in our mouths. And therefore we should probably, you know, eat a bit more crap.

I am not sure I would go as far as suggesting eating crap, but I second the notion that we as a society have to stop being obsessed with getting rid of all bacteria. Bacteria are overall good.

More on the Human Microbiome Program Workshop – Day1

As a follow up to my previous blog I am posting some additional information here about the NIH Roadmap Human Microbiome Project Workshop, which was held in Bethesda, MD.

The general outline of the meeting was as follows:

  • Sunday Night
    • Introduction
      • Welcome by Francis Collins (NHGRI), Hugh Auchincloss (NIAID) and Griffin Rodgers (NIDDK)
      • Comments by Gary Schoolnik
      • Overview of the NAS report on metagenomics by Jim Tiedje
      • Overview of the NIH Roadmap program by Francis Collins
    • Introductory talks on human microbiome
      • Jeff Gordon
      • David Relman
      • Gary Huffnagle
      • Jo Handelsman
  • Monday AM
    • Technological issues
      • Elaine Mardis
      • Jill Banfield
      • Deirdre Meldrum
    • Bioinformatics issues
      • Lior Pachter
      • Rolf Apweiler
      • Peer Bork
    • ELSI Issues Pilar Ossorio
  • Lunch
  • Monday PM – Breakout sessions and discussion
    • Group 1 – Reference microbiome (Claire Fraser and Martin Blaser)
    • Group 2 – Changes in microbiome and human health (Rita Colwell and Martin Rosenberg)
    • Group 3 – Enabling technologies (Bruce Birren and Mary Lidstrom)
    • Group 4 – Bioinformatics tools (Ewan Birney and Owen White)
    • Group 5 – Ethical legal and social issues (Midred Cho)
  • Wrap up

Overall, I found the Sunday night talks very useful to set the stage. The introductory talks by the representatives from NHGRI, NIAID, and NIDDK clearly indicated that NIH as well as others consider the human microbiome an incredibly important research area. Then Jim Tiedje gave a nice overview of the recent NAS report on metagenomics (which was about metagenomics in general, not specifically for the human microbiome). The main points of the report are basically: microbes rule the world, metagenomics is a very powerful tool in studying them, and there is a need for a more coordinated effort among funding agencies to push metagenomics as a tool and a field. (My only complaint about Tiedje’s presentation was he kept using the term “higher organisms” for those multicellular species with nuclei. But otherwise, he did a good job of concicely summarizing the report and the benefits as well as challenges of metagenomics).

Francis Collins then gave an overview of the NIH Roadmap Program. The Roadmap was started in ~2003 as an initaitive to identify projects that would need coordination across multiple NIH agencies. These projects should meet certain characteristics: truly transforming, require all NIH, must need incubator scape, and the outcome should produce material into the public domain. Collins then discussed how, from among hundreds of suggestions, the Human Microbiome was picked as one of five topic areas for in depth consideration for the new round of Roadmap competition. Thus the point of this workshop was to discuss this in more detail and help provide material and ideas for the full consideration of an HMP program.

I should note, I found one thing disappointing in the introduction which was a response to my question concerning whether this project would be limited only to studies of humans or would allow for studies of model systems that inform human work. The answer was basically that this would likely be limited to humans. I think this is a big mistake. The human genome project came to the realization that comparative studies with other species were critical to understanding and interpreting studies of the human genome. The same will be true of the human microbiome program.

Jeff Gordon then gave an overview of human microbiome studies, and focused on what are the key questions that need to be answered. Among the key questions: Do we share a core set of microbes? How should we view differences in microbes between people and over time? How do we relate communities of microbes to health and disease? How should we sample microbial communities to characterize them? What determines robustness of microbial communities in people?

To start to answer these and other questions, he suggested that we have three tiers of data collection: (1) deep draft assemblies of microbial communities and reference genomes, (2) reference microbiome work (deep characterization of individuals including information about the familiy history and genetics) (3) 16s surveys of communities (a global human microbial diversity survey). I basically liked all of his ideas. He did talk about work in model organisms too. His work has shown just how important this is … and I think as I said above it needs to be emphasized more in the HMP.

David Relman, from Stanford, then talked about patterns in human microbial diversity. He talked about some of the challenges in such studies as well as results of his and others work. He discussed many interesting aspects of the diversity of samples, and the shapes of diversity. Some of the patterns he emphasized were that history plays a role in the diversity, that archaea generally seem to have limited presence, that diversity is uneven and complex.

Then Gary Huffnagle discussed in more detail the interaction of microbes with the host immune system. And Jo Handelsman discussed what she calls functional metagenomics, which involves focusing on the functions of genes found in the environment on top of examining the phylogenetic diversity of communities. Unfortauntely, I did not take extensive notes for these two talks so do not have much to base my comments on here. In addition, I confess, the fact that the room in which the meeting was held was incredibly crowded and boiling hot, and the fact that I had flown in from California earlier in the day, made taking notes challenging at this point. However, that did not stop me from going out afterwards for a beer with Julian Parkhill, Ewan Birney, Owen White, and Jacques Ravel. The worst part of going out for the beer – I grew up in Bethesda but I made multiple wrong turns in the two blocks to the brew pub. I am sure from now on Julian and Ewan will never trust my directions. Fortunately, the fact that the pub had the RedSox pummeling the Yankees on TV made up for my direction problems.

I will post more about the second day soon.

A human microbiome program?

I am currently attending a workshop sponsored by NIH in which the participants are discussing whether there should be a Human Microbiome Project, and if so, what that should mean.

First, what is generally meant by the “Microbiome.” In essence the humn microbiome is the sum collection of all the microbes found in or on people. The human microbiome has become an important research field because the microbes that live in and among us play critical roles in human disease and health. An important aspect of this is the idea that microbes can be and are beneficial. For example, in the gut the normal microbes help with digestion and nutrient absorption as well as protect from infection. In addition, a variety of diseases (e.g., IBD, Krohns) seem likely to be caused by disruption in the normal microbial flora. In general, it seems likely that other ailments, like autoimmune diseases, allergies, etc will be found to have a connection to disruptions in the beneficial microbes that live among us.

Because of the importance of beneficial / commensal microbes in human biology, there have been growing efforts to characterize the microbes in various body locations – gut, mouth, lungs, skin, etc. But the efforts so far have simply given a tantalizing taste of how interesting and important these microbes are. So here comes this meeting. Organized by NIH (specifically, Francis Collins at NHGRI), this workshop is geared to discuss the possibility that studies of the human microbiome will be included in the next list of “NIH Roadmap” programs. More on the NIH Roadmap some other time.

Basically, the general idea is – do we need an big scale, organized program to tackle the human microbiome.? To get us in the mood, we had talks by many of the pioneers/leaders in the field (e.g., David Relman, Jeff Gordon, Jim Tiedje) as well as discussion of the NIH Roadmap program. I personally did not need any convincing but it was good to hear some of the ideas presented. In the end, I think there is no doubt that a large scale Human Microbiome Program is needed and would be very beneficial.

One of the reasons that an organized effort is needed is that studies of the human micribome are difficult. Reasons for this include:

1. Many of the microbes in the human system have not, and maybe cannot, be grown in isolation in the lab

2. The key features of the microbiome are determined by by populations of microbes and thus even if a representative of a species could be grown in the lab, it would not represent all the diversity in the population.

3. The best way to sample the populations is via “metagenomic” sequencing which involves isolating DNA and sequencing it directly without culturing.

4. Many of the important sites contain hundreds of species each with significant variation within species.

5. There likely will be ENORMOUS variation in and among people. Within a person, there will be variation over time as well as great variation in different sites. On top of that there will be great variation between people.

Given these and other complications, it seems a no brainer there is a need for a coordinated project to gather background information about the human microbiome that would then be useful to researchers, much like the human genome was useful to many researchers. So what would such a project do? Here are some possibilities

1. Sequence many “reference genomes.” By reference genomes here I mean genomes of cultured isolates that are closely related to organisms known in various human locations.

2. Do metagenomic sequencing of a variety of human mcirobiome samples.

3. Conduct large scale human microbiome diversity studies. This could involve rRNA PCR surveys as well as some amount of genome sequencing.

4. Develop the computational tools needed to analyze the massive amounts of data that will come out.

5. Encourage the development of new methods to aid in studies of the microbiome.

So today I guess we will be discussing what specific things are needed in more detail. But again, even though I do not really work on human microbiome projects much, I think it is pretty clear that the time is right for a Human Microbiome Program. And importantly, the methods and tools and discoveries that could come from this will be of use in all studies of microbes in the environment.

That’s all I have for now … will try to write more later.

Scientist Reveals Secret of the Ocean: It’s Him

Published: April 1, 2007

Maverick scientist J. Craig Venter has done it again. It was just a few years ago that Dr. Venter announced that the human genome sequenced by Celera Genomics was in fact, mostly his own. And now, Venter has revealed a second twist in his genomic self-examination. Venter was discussing his Global Ocean Voyage, in which he used his personal yacht to collect ocean water samples from around the world. He then used large filtration units to collect microbes from the water samples which were then brought back to his high tech lab in Rockville, MD where he used the same methods that were used to sequence the human genome to study the genomes of the 1000s of ocean dwelling microbes found in each sample. In discussing the sampling methods, Venter let slip his latest attack on the standards of science – some of the samples were in fact not from the ocean, but were from microbial habitats in and on his body.

“The human microbiome is the next frontier,” Dr. Venter said. “The ocean voyage was just a cover. My main goal has always been to work on the microbes that live in and on people. And now that my genome is nearly complete, why not use myself as the model for human microbiome studies as well. ”

It is certainly true that in the last few years, the microbes that live in and on people have become a hot research topic. So hot that the same people who were involved in the race to sequence the human genome have been involved in this race too. Francis Collins, Venter main competitor and still the director of the National Human Genome Research Institute (NHGRI), recently testified before Congress regarding this type of work. He said, “There are more bacteria in the human gut than human cells in the entire human body… The human microbiome project represents an exciting new research area for NHGRI.” Other minor players in the public’s human genome effort, such as Eric Lander at the Whitehead Institute and George Weinstock at Baylor College of Medicine are also trying to muscle their way into studies of the human microbiome.

But Venter was not going to have any of this. “This time, I was not going to let them know I was coming. There would be no artificially declared tie. We set up a cutting edge human microbiome sampling system on the yacht, and then headed out to sea. They never knew what hit them. Now I have finished my microbiome.”

Reactions among scientists range from amusement to indifference, most saying that it is unimportant whose microbiome was sequenced. But a few scientists expressed disappointment that Dr. Venter had once again subverted the normal system of anonymity. Recent human microbome studies by other researchers have all involved anonymous donors. Jeff Gordon, at the Washington University in St. Louis expressed astonishment, “I have to fill out about 200 forms for every sample. It takes years to get anything done. And now Venter sails away with the prize. All I can say is, I will never listen to one of my review boards again.”

Venter had hinted at the possibility that something was amiss in an interview he gave last week for the BBC News. He said “Most of the samples we studied were from the ocean but a few were from people.” When the interviewer seemed stunned, Doug Rusch, one of Venter’s collaborators stepped in and said “Collected with the help of other people.”

Venter was apparently spurred to make the admission today that many of the samples were in fact from his own microbiome due to a video that surfaced on YouTube showing Jeff Hoffman, the person responsible for collecting the water samples, performing a tooth scraping of Venter and then replacing the ocean water filter with Venter’s tooth sample.

Venter said the YouTube video was immaterial, “Well, we wanted to wait a few more weeks to have the papers describing the human microbiome published. But in the interest of human health we are deciding to make the announcement today.”

Unlike with the human genome data however, Venter says all of the data from his personal microbiome will be made publicly available with no restrictions. “If there is one lesson I have learned it is that open access is better than closed access. The more people can access my microbiome, the more they will help me understand myself. Plus, unlike Collins and Lander, who publish only in fee-for access journals, we will be publishing our analysis in the inaugural issue of a new Open Access journal that is a joint effort between the Public Library of Science and Nature. It will be called PLoN, the Public Library of Nature.”

In making his microbiome available, Venter has yet again abandoned his genetic privacy as he did when making his own genome available. Interestingly, the microbiome helps explain one of the first findings that was announced regarding his own genome. Venter said that analysis of the samples that came from his intestine reveal that microbes may explain why even though he has an apoE4 allele in his own genome (which is associated with abnormal fat metabolism) he does not need to take fat-lowering drugs. “Apparently, I have some really good fat digesters living in my gut. They make up for what is missing in my own genome.”

Dr. Venter’s reason for having his own microbiome sequenced, he said in the interview was in part scientific curiosity — ”How could one not want to know about one’s own microbes?” As to opening himself to the accusation of egocentricity, he said, ”I’ve been accused of that so many times, I’ve gotten over it.”

The key question that remains is – which of the samples were really from the ocean and which are from Venter. Venter said “Our funding agencies, including the DOE and the Moore Foundation, have agreed that we should not explicitly reveal which samples are which as this will encourage people to develop better methods of analyzing such complex mixtures of different microbes. Next week we will be announcing an X-prize award for the person who can identify which samples are mine and where they came from in me.”

Rob Edwards, a freelance microbial genomics expert says “It won’t be difficult to tell which are which. In fact, we had already identified an anomalous sample from Venter’s previous ocean sampling work, but nobody would listen to us.”

Jonathan Eisen, an evolutionary biologist who used to work for Venter says “I am certain that a few creative evolutionary analyses can reveal which sample is which. In fact, we are starting analyzing the samples already in anticipation of the X-prize announcement.”

Others are not so confident. Ed Delong, an ocean microbiology expert from MIT says “We have spent years carefully selecting our ocean samples to make sure they are not contaminated with sewage from cruise ships or from city drains. And now this – a purposeful mixture of ocean and human. It could take years to clean up the mess.”

Venter does not seem concerned. “If nobody can figure out which sample is from me and which is from the ocean, then we have no hope of making any progress in studies of either human microbiomes or oceans.”

More importantly, many scientists want to know what Venter will do next. Some want to know so that they can make sure to stay out of the way. Others probably relish the potential to go head to head with Venter. In this regard, Venter is not shy. “Biofuels. There is a great future in biofuels.”