Jonathan Eisen's Lab

More (you know you wanted it) on fecal transplants and the microbiome

There is an interesting mini review in the Journal of Clinical Gastroenterology’s September issue that may be of interest to some out there. It is entitled “Fecal Bacteriotherapy, Fecal Transplant, and the Microbiome” by Martin Floch and well, the title is indicative of the article.

Yes, the fecal transplant meme is here to stay. Sure, the cognoscenti already knew about fecal transplants. Perhaps they had read Tara Smith’s discussion of it in her Aetiology blog in 2007. Perhaps they had pondered it when they read the article from my lab on intestinal transplants. Perhaps they had seenthis discussion on MSNBC, or various other stories out there such asthis or this post from Angry by Choice. Or, maybe you just learned about it from Bora’s Carnival of Poop.

But the meme on fecal transplants really spread and many may have first heard about fecal transplants from Carl Zimmer’s New York Times article a month or so ago “How microbes defend and define us“

In the article Zimmer discussed how Dr. Alexander Khoruts used a fecal transplant to treat a woman with a persistent and severe Clostridium infection. And Zimmer discusses how, thought such transplants had been done before, this was the first time that the microbial community was carefully surveyed before and after. (Note, my favorite part of the article is this part, where my friend Janet Jansson describes her reaction:

Two weeks after the transplant, the scientists analyzed the microbes again. Her husband’s microbes had taken over. “That community was able to function and cure her disease in a matter of days,” said Janet Jansson, a microbial ecologist at Lawrence Berkeley National Laboratory and a co-author of the paper. “I didn’t expect it to work. The project blew me away.”

Anyway Zimmer’s article, as with many of his, garnered a lot of response and got many people discussing the poop on fecal transplants.

Well, this issue of the Journal of Clinical Gastroenterology may now be the biggest pile of information about fecal transplants around. That is because, in addition to this little review mentioned above, there are in fact three articles in this issue relating to fecal transplant. Alas, most of you out there will probably only be able to read the review since the other articles are behind a pay wall.

But the review is good. And I think this is not the last you will hear about this. (Though I note that, even though I think fecal transplants have some major potential, they seem to be being oversold a bit by many as some cure all — fodder for a future “Overselling the Microbiome Award” I am sure).

I will end with this line from the review which raises some other issues about fecal transplants:

Probably one of the major problems is to define how this therapy can become socially accepted. (Can you imagine the Food & Drug Administration discussion?)

Floch, M. (2010). Fecal Bacteriotherapy, Fecal Transplant, and the Microbiome Journal of Clinical Gastroenterology, 44 (8), 529-530 DOI: 10.1097/MCG.0b013e3181e1d6e2

Grehan, M., Borody, T., Leis, S., Campbell, J., Mitchell, H., & Wettstein, A. (2010). Durable Alteration of the Colonic Microbiota by the Administration of Donor Fecal Flora Journal of Clinical Gastroenterology, 44 (8), 551-561 DOI: 10.1097/MCG.0b013e3181e5d06b

Khoruts, A., Dicksved, J., Jansson, J., & Sadowsky, M. (2009). Changes in the Composition of the Human Fecal Microbiome After Bacteriotherapy for Recurrent Clostridium Difficile-associated Diarrhea Journal of Clinical Gastroenterology DOI: 10.1097/MCG.0b013e3181c87e02

Yoon, S., & Brandt, L. (2010). Treatment of Refractory/Recurrent C. difficile-associated Disease by Donated Stool Transplanted Via Colonoscopy Journal of Clinical Gastroenterology, 44 (8), 562-566 DOI: 10.1097/MCG.0b013e3181dac035

Overselling the microbiome award: Stephen Barrie on pre and probiotics at the Huffington Post

Yes, I think the microbes that live in and on people are important, interesting, cool, and worthy of lots and lots of attention. However, I am getting sicker and sicker of the ways in which the effects of these microbes are, well oversold. So today I am starting a new series here on the Tree of Life – the “Overselling the Microbiome and Probiotics Award.”

And, we have a winner today. The winner is Stephen Barrie who has posted something at the paragon of high quality science – the Huffington Post (for more on the dubious science at Huffington Post, a good place to look is Bora’s Blog Around the Clock). Well, Barrie really takes the cake on this one

Stephen Barrie, ND: The Keys to Maintaining a Healthy Gut

He starts off OK – referring to the number of microbes in the human ecosystem and even quoting Jeroen Raes, who does some great work.

Then he mentions how

“These bacteria have a profound influence on human physiology, your immune system, your nutrition, and are crucial for human life.”

OK I can go with this — maybe an exaggeration but still within reasonable confines. Then the woppers begin

“The health of your body and mind is largely tied to the health of your gut”.

Wow- that is one serious jump – from these microbes have a profound influence to the gut driving health of body and MIND.

Then he goes back to some OK territory again, discussing some functions known for gut microbes, like vitamin production, preventing infection, etc. But just after this he switches to the woppers again claiming that out of balance microbes can cause allergies, inflammatory bowel disease, eczema, arthritis, irritable bowel disease, obesity, autism and personality changes including paranoia, hostility, aggression and so on. Completely ludicrous actually. What we know about these issues is that researchers have found that microbial populations may be altered in people with these maladies. But that does not mean the alteration in the microbes caused these maladies. It could be that other factors cause both the malady and the microbial alteration or the malady itself could lead to altered microbial populations.

But wait, it gets a bit better. Now that he has established that microbes cause all these problems, he tells us how to

“avoid one of the emerging causes of both obesity and food allergies? Lower your risk of inflammatory bowel disease, irritable bowel disease, eczema, colon cancer (15) strengthen your immune system? All this while reducing any levels of paranoia or hostility (and retaining your Jon Stewart sense of humor).”

The recipe for prevention is as follows:

Eat a low fat diet rich in vegetables, fruits and complex carbohydrates

Limit consumption of animal protein

Reduce sugar consumption

Increase pre-biotic and probiotic intake

Consume enough soluble and insoluble fiber to maintain a daily bowel movement. A slow bowel transit time leads to increased exposure of your body to toxic bowel contents.

Reduce dietary sulfate consumption.

Again, I am all for more research into the microbiome. And I think microbes that live with us must have all sorts of positive and negative effects on our health. And yes, I understand why “probiotics” and “prebiotics” are getting lots of hype. But because Barrie has gone from what must be a gut feeling (sorry) to making medical claims without evidence and prescribing treatments to cure ailments that probably don’t exist, he is the recipient of my first “Overselling the microbiome award”.

If a picture=1000 words, what is sound worth? #burrowingowls

Well, my brother Matt is visiting and he has in one fell swoop opened my ears to a whole new world. We went for a walk on this trail near my house in Davis, CA where a massive number of burrowing owls live. I have spent the last few months, on and off, trying to take some good pictures of these amazing owls. Here is a slideshow of some of my favorites.

http://picasaweb.google.com/s/c/bin/slideshow.swf

Anyway, while going on this walk, Matt brought an extensive collection of giant strange looking sound equipment.

You see, he is a sound engineer in his spare time and this is, well, what he does. And when we found some owls he told us to mosey on down the trail so he could record. And here are some of his recordings – completely changing my view of these owls.

http://player.soundcloud.com/player.swf?url=http%3A%2F%2Fsoundcloud.com%2Fmattrglenn%2Fburrowing-owls&secret_url=false Burrowing Owls by mattglenn

He has more detail about this on this blog.

Bad omics word of the day: adversomics h/t @jennifergardy @mentalindigest

Well, I guess the bad omics blogger in me is back. The bad omics word of the day today is adversomics. First pointed out to me by Jim C at from MentalIndigestion and now reintroduced to me by Jennifer Gardy.

This one is so awful I had to write it up. The first I know of it is here in an article by Gregory Poland et al. entitled “Adversomics: The Emerging Field of Vaccine Adverse Event Immunogenetics”. And now in a new article by the same authors: Application of pharmacogenomics to vaccines where they say

Another area of importance is genetically determined vaccine-associated adverse events, which we have called ‘adversomics’

I note this is the same group that brought us a previous bad omics word of the day winner in “vaccinomics“. So they are double winners. Hooray for them.

Quick blog post: interesting piece on the evolution of ecology by Simon Levin

There is a very interesting piece in the Chronicle of Higher Education by Simon Levin on the “Evolution of Ecology.”

See The Evolution of Ecology – The Chronicle Review – The Chronicle of Higher Education

In it Simon, who I consider both a friend and colleague and who has been an inspiration to me for much of my work, discusses the history of the concept and the field of ecology. He repeats a key phrase he has used elsewhere:

Ecology, the unifying science in integrating knowledge of life on our planet, has become the essential science in learning how to preserve it.

I like this phrase and plan to use it a bit here and there, with attribution of course.

Levin also discusses how Darwin’s Voyage of the Beagle helped launch the field of ecology because it

defined a new and synthetic way of looking at nature—in which the patterns characteristic of particular regions found explanation in a unifying, dynamic framework

It was only after Voyage of the Beagle and Wallace’s work and others that the term “oekologie” came into being.

I particularly like the end where he connects ecology to study of other complex adaptive systems like economic ones and medical ones.

The article is really really really worth a read.

Lack of neutrality in bacteria and where pseudogenes go when they die

Pseudogenes, which are in essence regions of the genome that used to be genes but no longer able to produce a functional unit, have long been considered to be models of the genetic equivalent of Switzerland’s neutrality. With this assumption of neutrality in hand, researchers have used studies of pseudogenes to better understand what happens to DNA when it is not visible to any form of natural selection. That is, pseudogenes have been thought to be neither harmful (as in, they are not under negative selection) or helpful (i.e., they are not under positive selection).

And from this assumption we have supposedly learned about mutation rates and patterns (because if they are neutral then the changes in pseudogenes should be reflective of mutational processes, not selection) as well as all sorts of other features of genome evolution.

Over the years, some have challenged the assumption of neutrality of pseudogenes (e.g., see here) like many have questioned whether Switzerland is really neutral. But overall, the feeling that pseudogenes were mostly neutral seems to have stuck. However, that may change a bit with a new paper from Chih-Horng Chu and Howard Ochman in PLoS Genetics (PLoS Genetics: The Extinction Dynamics of Bacterial Pseudogenes).

In their paper they report: (this is their authors summary)

Pseudogenes have traditionally been viewed as evolving in a strictly neutral manner. In bacteria, however, pseudogenes are deleted rapidly from genomes, suggesting that their presence is somehow deleterious. The distribution of pseudogenes among sequenced strains of Salmonella indicates that removal of many of these apparently functionless regions is attributable to their deleterious effects in cell fitness, suggesting that a sizeable fraction of pseudogenes are under selection.

Basically, what they did was the following

1. Compare Salmonella genomes. Identify putative pseudogenes and trace their evolution onto a phylogeny of the species.

Figure 1. Distribution of pseudogenes among Salmonellagenomes.

The phylogenetic tree was inferred from 2,898 single-copy genes shared by all fiveS. enterica subsp. enterica strains and the outgroup S. enterica subsp. arizonae.

doi:10.1371/journal.pgen.1001050.g001

2. Carry out a variety of analyses of the pseudogenes such as

looking at ratios of Ka/Ks (this is in essence a ratio of amino acid changes – aka non synonymous substitutions to “silent” synonymous changes which occur when the DNA sequence changes but the same amino acid is encoded).
examining the types and frequencies of gene inactivating mutations

3. Then they looked at the “ages” of pseudogenes – with age being estimated by the position in the tree in which the pseudogenes appear to have arise.

4. Finally the examined the age class distribution of pseudogenes as well as whether there were other differences between pseudogenes of different ages. And what they found was inconsistent with a neutral model. Instead, what they conclude is that something is making it advantageous to delete pseudogenes more rapidly than one might expect.

What explains this? After testing multiple possibilities the authors conclude that their is some negative selection against pseudogenes (or I guess positive selection for deletion of pseudogenes).

They conclude by suggesting this is likely to be pervasive across all bacteria and even in archaea. And furthermore make a connection to possible selection on intron size in eukaryotes. Anyway – the paper seems quite interesting and worth a read. Still pondering what it all means, so I would welcome comments.

Kuo, C., & Ochman, H. (2010). The Extinction Dynamics of Bacterial Pseudogenes PLoS Genetics, 6 (8) DOI: 10.1371/journal.pgen.1001050

Starting to like Academia.Edu, except for annoying emails re: who is searching for me

Well, I am continuing to play around with Academia.Edu. I created a profile there for myself and am also building one for my father Howard Eisen as part of my campaign to “Free my father’s publications.” Academia.Edu has some nice features. I think I still like Mendeley more, but am reserving judgement.

That being said, the default setting at Academia.Edu for email updates is really annoying — I keep getting messages like

Hi Jonathan,

Someone just searched for you on Google, and found your page on Academia.edu.

To see the search query they used, what rank you are on Google for this query, and what country the search came from, follow the link below

Link removed by me

Thanks,

The Academia.edu team

Tip:

To ensure that your Academia.edu page appears high up on Google, link to it from the website of your department, college, university or blog. 88% of people on Academia.edu who link to their page like this appear #1 on Google for searches for their name + university, e.g. ‘Richard Price Oxford’.

First of all, getting emails like this should be Opt In not Opt Out. Second, I find this to be a bit too earnest an attempt to manipulate google rankings to help out Academia.Edu. (I note, while creating this post, I did a search for myself and Academia.Edu and got the links above and then I got an email again, telling me someone searched for me. I know. It was me. I mean, I guess link trading is a real thing, but telling me to add a link do that my Academia.Edu profile might move up in searches is I guess annoying to me.

Anyway – still playing with Academia.Edu. Still liking much of it. But if you search for me on the web and go to Academia.Edu I am sorry but I will not know as I will be disabling email messages from them.

Ooh – Science Quiz Show for the Explorit Museum in #DavisCA #ScienceIsFun

Quick link here — for those in the Davis area interested in science in any way you might want to check out the upcoming Explorit quiz / game show/ challenge. October 7 2010 at Freeborn Hall.

2010 Science Challenge — Explorit Science Center

Human genome project oversold? sure but lets not undersell basic science

Well, the piling on the human genome project continues, it seems at an accelerating pace. I think most of this comes from the fact that we are in the range of the 10 year anniversary right now. Here are some examples of recent stories suggesting the human genome project (or projects, if you count the public effort and Craig Venter’s effort as separate) have had little benefit:

7/31/10: The Human Genome Project: 10 Years Later, Progress but Still a Puzzle – WNYC. Interesting piece by Sarah Kate Kramer discussing the limited clinical value of the HGP. Includes some criticisms of personalized genomic medicine.
7/29/10: Spiegel interview with Craig Venter with the headline “We have learned nothing from the genome”. Has lots of interesting tidbits. Love the Venter line “Well, nobody likes to be beaten — by superior intelligence, planning and technology. That gets people upset.” But I note Craig emphasizes the basic science value of human genome data.
7/6/10: Public Radio mini story about Mike Mandel’s article on the failure of the human genome project.
6/12/10: Nick Wade’s NY Times article on “A decade later, genetic map yields few new cures“. In this Wade discusses many of the issues with both the sequencing of the human genome and some of the spinoff projects (and also butchers some evolutionary biology for which I gave him a twisted tree of life award).

These are but a small sampling of the many many blogs, articles, and other reports that either directly state or suggest that much of the money spent on the human genome project was a waste.

Certainly, contrary to the suggestion of some of these articles, there have been some practical benefits that have come directly or indirectly from human genome sequencing. But equally certainly, these critiques have a segment of truth to them in that the practical benefits have been few and far between.

Normally, one would not expect too many direct practical benefit to come from this kind of science project. But alas, the problem here is that many of the key players (e.g., Eric Lander, Francis Collins, Craig Venter) in the sequencing of the human genome(s) oversold the potential benefits that could come from the sequencing. In a way, it was their job to oversell the sequencing, since each was a cheerleader in ways for getting others to do a lot of work.

Many people knew at the time that this overselling was going on. It was talked about extensively at various genome conferences and even occasionally in the press and scientific literature (boy do I wish I had had a blog then, because I was one of those people at conferences practically begging people to not oversell the benefits of the project – I now even give out an “overselling genomics award” on my blog ). The cautionary voices were mainly saying that there was no need to oversell the project and that we should stick to the benefits of “knowing” ourselves and not guess about how it will lead to immediate cures for diseases. And many said “If you oversell this now, it will come back to bite you“

And thus it is not surprising to me that there is somewhat of a backlash now. But there is a very dark side to the backlash that has potential to hurt science for many years to come. If there is a need in the future for large scale science / medical projects, I can guarantee that some critics will step up and say things like “Well the war on cancer failed. And the human genome project failed. Why should we trust you now?”

The problem here is that the human genome project should never have been sold as a means to a series of practical ends. It should have been sold as a massive basic science project, much like going to the moon or building a giant linear accelerator. That is, the human genome project was, and still really is, about knowledge. It is about knowing ourselves. It has enormous potential benefits in all sorts of areas, like human medicine. It should greatly aid and abet studies of human biology and genetics and disease. But given that benefits that come from such studies are impossible to predict, the human genome project should have been presented in a different way. We need to discuss more in public why basic science is important even if one cannot predict what the benefits are.

In many ways, this is very much like the “war on cancer” which some have argued failed because we still have cancer killing a lot of people. But this is off base because in fact the war on cancer has provided us with an incredible baseline of information about the biology of cancer. We need to do a better job in all of these cases of defending the need for knowledge, and discussing how fighting cancer and curing diseases is not the same as building a big bridge or road.

The best person discussing this issue for the last ten or so years in my opinion has been Harold Varmus, who was once the head of NIH and is now the new director of the National Cancer Institute. I have heard him repeatedly defending the “war on cancer” in terms of its basic science benefits. For example see his comments on Science Friday 1/30/2009 and 7/16/2010. There just have not been too many people doing a good job of this with genomics. Venter and Collins have been OK here and there. But we need more.

On a related note, we probably should have more discussion about how the money spent on the genome project and the war on cancer pales in comparison to money we spend on other things (e.g., interest on the national dept, wars, etc) but perhaps that is a side discussion.

Most importantly, we need to bring out to the public more of a discussion of the benefits from basic science. Here are some useful resources if you want to try and help:

I also encourage people to look at the National Academy of Sciences report A New Biology for the 21st Century: Ensuring the United States Leads the Coming Biology Revolution. I note, I was one of the coauthors. You can download the PDF of the whole document after giving your email address.

I am going to start a new series here on this blog called “Benefits of basic science” where I will be discussing these issues. I encourage others out there to also bring more to the forefront discussions of the need for basic science.

——————–
UPDATE

Also see

Twisted tree of life award #6: Scientific American Origins piece for dissing microbes

There is an interesting series of mini articles in the August 2010 Scientific American tracing the origins of various concepts and things: Origins: Going Back to Where the Story Really Starts: Scientific American

Not open access mind you, but if you have a subscription it is worth checking out. They track the origins of the following:

swiss cheese
paternal child care
computer viruses
animation
sexual reproduction
malaria
fireworks
barbed wire
hand washing in hospitals
human morality
electric cars
the influenza virus
wheeled vehicles
black holes
zero
biodiversity
noodles

Many of the discussions are interesting. Some are a bit trite. But that is not what I am here to report on. I am here to complain about one aspects of the article series: too much emphasis on humans and multicellular organisms as “higher” creatures. There are various subtle phrases here and there that I did not like too much but the parts that really grate on me are the two below:

In the article on biodiversity Melinda Moyer discusses the remarkable possibility that single celled creatures might have in fact had some diversity in them “Today we think of biodiversity in terms of multicellular life, but flowering plants and animals didn’t arrive until relatively recently” she writes. And ends with “It is no comfort to know that the worst catastrophe would still preserve some biodiversity — even if only for the lowly cell.“
In the mini article on sex, Brendan Borrell writes “The truth is, nobody really knows why people — and other animals, plants and fungi — prefer sex to, say, budding.” This of course leaves out all the other eukaryotes that are not plants, animals and fungi that have sex.

And though these are certainly subtle small issues, I feel that Scientific American should do better. So for directly and indirectly dissing the microbes on the planet – I am giving them my coveted Twisted Tree of Life Award #6. Previous winners are listed below:

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