Thursday, October 2, 2014

Congratulations to the 2014 Golden Goose Awardees

In 2012 I happened to sit on a plane next to Congressman Jim Cooper from Nashville, TN, where I learned of his brainchild, the Golden Goose Awards, to honor the serendipity of how basic federally funded research significantly impacts our daily lives (blog link).

The award program is first rate and has honored some notable scientists. Congrats to the 2014 awardees! Here is a well-done video of their stories.

A small investment in science brigs us the vastness of tomorrow.


What: The purpose of the “Golden Goose” award is to demonstrate the human and economic benefits of federally funded research by highlighting examples of seemingly obscure studies that have led to major breakthroughs and resulted in significant societal impact.  Such breakthroughs include development of life-saving medicines and treatments; game-changing social and behavioral insights; and major technological advances related to national security, energy, the environment, communications, and public health. Such breakthroughs may also have resulted in economic growth through the creation of new industries or companies.
Congressman Jim Cooper (D-TN) originally conceived of the Golden Goose award as a means of educating Members of Congress and the general public about the value of federal funding of basic scientific research. The name of the award is a play on the “Golden Fleece” awards issued between 1975 and 1988 by Senator William Proxmire (D-WI), which targeted specific federally funded research grants as examples of government waste. The name also alludes to the fable of the goose that laid the golden eggs. Researchers who have used federal funding to make their research breakthroughs constitute the “goose,” and the innovations stemming from their work are the “golden eggs.” The Golden Goose Award explicitly links the two.

Saturday, September 20, 2014

The Microbiome Fear-Mongering Machine

Wow, this movie trailer and Indiegogo campaign for MicroBirth seems to raise the level of fear mongering around the microbiome in a shocking way. From economic calamity to immediate worldwide health concerns, the movie interweaves the nascent science of the microbiome with all that could be bad in the developed world today. While I'm a fan of studying the microbiome and its implications, including the universality of maternal microbial transmission (related blog post), I am surprised by the significant attempt to introduce fright into the public's minds. What do you all think? Is it worthwhile or just a mashup of buzz themes today that don't rise to the level of alarm in the documentary? In the last decade, there have been many microbiome association studies and few causation studies. The field could mature a bit before substantiating the horror.

Sunday, September 14, 2014

The Microbiology of Animal Speciation: My talk at the University of Utah

The microbiome sciences are at an inflection point in which largely descriptive studies of microbial associations with phenotypes are transcending to functional studies in which microbes are shown to play a causal role in those phenotypes. Kevin Kohl and Denise Dearing at the University of Utah's Department of Biology are doing innovative work on the function of gut microbes in mammals, namely how gut bacteria allow woodrats to eat poisonous plants. I'm fortunate to say that Kevin is also considering spending time in our lab with his NSF postdoc fellowship. The visit made a big impression on me. The Department is top notch in evolutionary biology/ecology and the city has great views and very happy people! My meetings with  Mike Shapiro (evolutionary development), Colin Dale (symbiosis), and Dale Clayton (coevolution), and Nitin Phadnis (speciation geneticist) were also memorable.

Kevin and Denise invited me out to Salt Lake for a Super Seminar Bash (delicious food and beverages to accompany the seminar) on September 4, 2014. The biology group showed up in droves, and we had a sensational time discussing the Origin of Species, Wolbachia, and the Hologenome concept of evolution. Here's the talk:

Related Blog Posts:
1. The Ten Principle of the Hologenome (July 20, 2014)
2. The Hologenome Facebook Page - Discover Your Symbiotic Complexity (January 22, 2014)
3. Do Hosts Handpick Their Microbiome? (December 4, 2013)
4. The Gravity of Symbiosis (November 3, 2013)

Friday, July 25, 2014


AAM Link
This new report on the charted and uncharted viral world (what it was tentatively called last year) is now out from the American Academy of Microbiology and a group of virologists (including me). We met last summer in Washington, DC, stuck ourselves in a room for a few days, and had a fun mind jam. Here's what we and the excellent team at AAM came up with. The steering committee for the meeting included Curtis Suttle, Marilyn Roossinck, and Willie Wilson. 

Link to page:

Abstract: In contrast to their negative reputation as disease causing agents, some viruses can perform crucial biological and evolutionary functions that help to shape the world we live in today, according to Viruses Throughout Life & Time: Friends, Foes, Change AgentsViruses Throughout Life & Time: Friends, Foes, Change Agents is based on the deliberation of a group of scientific experts who gathered for two days in San Francisco, CA in July 2013 to answer a series of questions regarding the variety of roles that viruses play in the natural world.

Executive Summary: In contrast to their negative reputation as disease causing agents, some viruses can perform crucial biological and evolutionary functions that help to shape the world we live in today, according to a new report by the American Academy of Microbiology.

“Viruses participate in essential Earth processes and influence all life forms on the planet, from contributing to biogeochemical cycles, shaping the atmospheric composition, and driving major speciation events,” states Marilyn Roossinck of Pennsylvania State University, a member of the steering committee that helped to organize the colloquium.

The report, Viruses Throughout Life & Time: Friends, Foes, Change Agents, is based on the deliberation of a group of scientific experts who gathered for two days in San Francisco, CA in July 2013 to answer a series of questions regarding the variety of roles that viruses play in the natural world.

“The inspiration for holding the colloquium was that recent metagenomics studies of viruses have indicated we know very little about the real world of viruses. Almost all published research is about the viruses that cause disease in humans and their domesticated plants and animals. This certainly represents only a very small fraction of the viruses that really exist,” says Roossinck. “It is very important to understand the real world of viruses, as this can inform our basic understanding of life and its origins, as well as major earth phenomena like carbon cycling.” 

Beyond their pathogenic impact, the report examines in depth the size of the virosphere, the origin of viruses, the overlooked biological and microbial ecological role of viruses, and how these live forms have contributed to evolution. Additional highlights from the report explain how some viruses are commensal organisms or symbionts, their functioning in microbial communities, and their role in maintaining the biosphere. The array of responsibilities taken on by viruses is due to their incredible sequence diversity and genomic plasticity, referred to as “viral dark matter”.

The report concludes by stimulating the readers to think about key questions: “What if viruses had never existed on Earth? Would life have evolved quite differently”? Continued viral research will help to answer these enticing questions.

Links to papers and talks on endosymbiont phage from our lab:
3. Seminar at University of Illinois | Phage section starts at ~31 minute mark

Sunday, July 20, 2014

The Ten Principles of the Hologenome

Source: Charis Tsevis, Science News
So recently I've been thinking a lot about the principles of the hologenome. From a summer workshop at the Munster Graduate School of Evolution in Germany to various dialogues with luminaries, there is a palpable interest in what is and what is not the hologenome. From reading The Hologenome Concept by the Rosenbergs and their conceptual papers to a coming NESCENT workshop on the ecology and evolution of the host-associated microbiota, I am now taking stock of what I've stored in the attic thus far and trimming it down to make it useful for everyone. I have also set up a FaceBook community page on the Hologenome for anyone who would like to join the discussion. I anticipate that Ill publish this list in a journal at some point, but for now it is most valuable here and at once.

These are my Ten Principles of the Hologenome.

1. The hologenome is a unit of selection that incorporates the genomes of the holobiont - host genome, cytoplasmic organelles, and host-associated microbiome. These three compartments of variation can cooperate or clash to forge a unit of selection whose importance grows as we probe the functions and specificity of the host-associated microbiome. 

2. The hologenome is comprised of microbial parasites, mutualists, and commensals - all sources of variation that selection can act against or with.

3. The hologenome is best understood in terms of equating a microbe in the microbiome to a gene in the genome - if a gene can be selected for in the genome, a host-associated microbe can too. If a gene is neutral, a microbe can be too. If a gene comes and goes in the genome (i.e., recombination), a microbe can too.

4. The hologenome is not a superorganism, metagenome, organ, or the only unit of selection. It is an assembly of genomes of diverse organisms, some of which is essential to holobiont fitness.

5. The hologenome is a body of scholarship that fits squarely into genetics and multi-level selection theory.

6. The hologenome does not change evolutionary biology, but upgrades it to incorporate the microbiome as part of the genetic variation subject to selection.

7. The hologenome fits seamlessly into all canonical mechanisms of evolutionary change, namely genetic variation, intergenomic disequilibria (i.e., mitochondria and host genome), maternal transmission to some extent, and selection.

8. The hologenome reboots Lamarckian evolution (microbial acquisition) into neo-Darwinian evolution.

9. The hologenome variation arises not only from genetic variation, recombination, mutation, but also new microbial acquisition, microbe amplification, and extensive horizontal gene transfer.

10. The hologenome exemplifies the postmodern synthesis of various disciplines, including the unification of evolutionary biology, genetics, and microbiology. 


Wednesday, July 16, 2014

Out with the mosquitoes. In with the Wolbachia!

A University of Kentucky professor (disclaimer: good friend), Dr. Stephen Dobson, and his former student have teamed up to form MosquitoMate - a company aimed at using a unique approach to getting rid of mosquitoes and their transmitted viruses. Many of the readers of this blog will be familiar with the Eliminate Dengue project in which mosquitoes infected with bacterium Wolbachia are released with the aim of replacing uninfected populations that can transmit human disease agents with Wolbachia-infected ones that can not transmit the disease. 

This new approach aims to release just Wolbachia-infected males to sterilize female mosquitoes in nature. By doing so, the mosquito population size can be crashed, if not eliminated wholesale. A great video and some selected quotes below:

"Most mosquito control companies use chemical pesticides which are sprayed out of trucks and planes, or maybe out of a backpack sprayer," Dobson said. "Ours is a very different approach. By using a natural bacterium called Wolbachia and the mosquitoes' innate ability to find mates, we are applying an approach which does not require chemicals."

"A big advantage to our method is that the male mosquitoes are 'self-delivering.' We don't need to devote hours in finding and treating all the mosquitoes in your yard. The male mosquitoes find the females for us," Mains said.

I really like this work! Good luck to the team. 

Monday, July 7, 2014

Scientists: How can you afford to not be on social media?

It's no secret anymore. Science has embraced social media in a way that will have many early adopters saying "I knew this was going to happen" and those yet to adopt it saying "What's all the fuss about? How can I get involved?

Using social media for science is like any other aspect of life that needs diligence and training. If you don't care about it or don't know what to care about, you'll be missing all the fun and rewards. I had the same journey. I questioned the value of spending bits of time on twitter or why people would blog - that seemed like a major time sink. But when scientists that i respected were so involved with social media, i felt compelled to figure out what they got out of it. There are far more virtues of social media that one could list in a short blurb about it. So I will boil some of my favorite aspects of social media down to three key points.

1. Staying in touch with the current literature - If you don't use twitter, then you likely stay on top of new articles by pubmed searches, table of content emails, and word of mouth. Twitter makes these methods seem archaic as following experts and their tweets brings the literature directly to you rather than you searching for it. It also comes filtered directly from the experts rather than through luck of finding the articles in a random search. Many tweets are just links to really cool articles that you would have seen six months later in a pubmed search; but because luminary X on twitter caught it first, you get to see it and integrate it into your science far faster. Also, sometimes the tweets to publications come with a fatal criticism or major complement - helping you to see where the community places the work. 

2. Staying in touch with conferences - It seems like there are more and more conferences that we all want to go to every year, but we don't have the budget to attend all of them. Twitter users will use hashtags (i.e., #ASM2014 for this year's American Society of Microbiology meeting) that you can click on and follow the conference in a virtual way that brings you the most exciting talks and key points right to your desktop or phone. Following conference hashtags has been of such tremendous value to me that I have at times questioned the need to go to conferences all that often. Moreover, if you're not at a conference, you can interject into conference happenings by tweeting to conference goers or using the hashtag to virtually place your ideas and "self" in the conference.

3. Giving your research wings - Both twitter and blogs are venues to disseminate research and the stories behind that research to those that care. You can hope that someone reads a table of contents and finds your most recent publication or they search for your work in pubmed, but why not cast your paper into their world directly through social media. In this fast-moving and competitive world of science, getting your student's work out there is important. Or for the assistant professor, how about expediting the growth of your international reputation by connecting with tweeters from across the world? It is lab policy that all students join twitter. Some use it more than others, but at least it is something they can test out and come back to if they don't like it at first. 

I like to think that twitter is my Department of the World in which collegiality by proximity is replaced by collegiality without borders. I can tweet research questions, follow my peer's work, go to conference seminars, talk about latest results, promote students all in the social media world. It takes far less time that non-users think, it is far more valuable too, and the only question left to ask is "How can you afford to not be on social media?"

Seth Bordenstein

Twitter: @Symbionticism

Thursday, July 3, 2014

Homo evolutis: Faster than Moore's Law?

Stop what you're doing and take a moment to be inspired. We all need a little bit of it every now and then - no matter how fleeting the inspiration is. It is a bit out there but within the realm of speculation.

Let's talk about a mind-expanding idea on the future of us. Its about what Homo sapiens is about to become through the exponential growth of nanotechnology, artificial intelligence, and genomics.

With this long view of so-called "Homo evolutis" by Juan Enqriquez (TEDx talk here) in mind, the philosophical futurist Jason Silva, aka The Timothy Leary of the Viral Video Age, reminds us below of E.O. Wilson's quote:

"Homo sapiens, the first truly free species, is about to decommission natural selection, the force that made us…Soon, we must look deep within ourselves and decide what we wish to become". Here is Silva's cinematic trailer-like video "To Be Human is To Be Transhuman".

Ok. Back to reality and go have a great July 4th! But if you'd rather stay in the moment, watch this next one on "Awe".

Tuesday, July 1, 2014

What do evolutionary biologists talk about at their annual conference?

If you're like me and did not make it to Raleigh, NC this past month for the annual Evolution 2014 Conference, well there's good news. I'm jazzed to see there are a plethora of lectures online at their Evolution 2014 YouTube Channel. This meeting is one of the premier venues to share scientific research related to evolutionary biology.

Most talks are short (15 minutes) and you can get a sense of the topic and the speaker in the title of each presentation. Be sure to click the "Load More" button as you scroll to the bottom to load all the seminars. I haven't watched all the ones that I wanted to yet, but Ive saved them to my "Watch Later" bin. Anyone can do this if they have a YouTube Channel (mine is here). I highly recommend starting a professional channel as a venue to store your talks online and disseminate them to the community. Like all forms of social media in science, these tools are taking off and good ways to advance the open access nature of your science across the world, to the few people who may actually care to watch.

As an example, here's a recent talk by senior graduate student in our lab, Lisa Funkhouser-Jones. In her research, the key question is how many animal genes does it take to tame maternally transmitted bacteria (Wolbachia)?

Wednesday, June 4, 2014

Jerry Coyne Doubts That Symbionts Cause Speciation. Let's Discuss.

Any new or unexpected concept/data will be confronted with criticisms and doubts. But over roughly the 20 years that I have been studying speciation by symbiosis (TREE 2012 review), I found that the most common criticism is the least formidable. It concerns the fact that symbionts have not been shown to be a "cause of speciation", and it has just been used again by evolutionary biologist Jerry Coyne. It is time to clear this up once and for all to generate some unity around speciation by genetics and symbiosis. I have been deeply influenced by Coyne's seminal work on speciation genetics. I admire his research, yet he has not engaged me in discussions on speciation by symbiosis despite my attempts to share/discuss our work with him. I welcome the opportunity to debate him on this issue.

From Quanta Magazine, "There are no studies as of yet that prove definitively that the microbiome causes speciation," Coyne states.

Note: I previously addressed this concern in a 2003 book chapter on Symbiosis And The Origin of Species.

The criticism, while true, fails to distinguish speciation by symbiosis from speciation by nuclear genes. Rarely do speciation workers know whether the particular isolating barrier that they are investigating is or was a cause of speciation. Speciation genes found in the nucleus make a big splash in evolutionary biology, and rightfully so, but often they are found in such old species pairs (i.e., Drosophila melanogaster and D. simulans diverged millions of years ago) that researchers can not claim they are a cause of speciation as well. Read that twice.

The concern by Coyne and others is a more general and practical problem to the study of speciation, as the formation of species takes a long time. Whether or not microbial symbionts prove to be a causative agent now is not necessarily an indicator of whether symbionts have played a role in speciation in the past or will play a role in the future. The same holds true for speciation genes in the nucleus. Most of the time, the best that biologists can do is discover the factors that cause reproductive isolation and thus the entities (genes or microbes) that can cause speciation, rather than cause speciation. 

Most reproductive isolation likely evolves in allopatry as an incidental byproduct of divergence. Simply demonstrating the genetic or microbial basis of speciation may be the closest we get to this issue. In the Quanta Magazine, I think Bradford Harris gets it right when it comes to why we see the inequality in judging speciation studies.

Sunday, May 25, 2014

Do It Yourself Fecal Transplant?

YouTube is chalk full of videos like this one of fecal microbiota transplantations at home. Shocking at first, you quickly understand that the desperate nature of C. difficile infections and the patchy, but growing, distribution of clinics that offer fecal transplants has compelled a DIY treatment. I am in no way advocating for this method, just passing on the information since my post in 2012, Can a Fecal Transplant Cure…,  has attracted over 12,000 views as of May 25 this year. There are many resources listed in that post including web sites for locations that perform fecal transplants.

Here is another video of author Michael Hurst describing and acting out a DIY treatment. He used fecal transplants to treat his Ulcerative Colitis in 2011 and has been symptom free since.

Tuesday, April 29, 2014

Video: Bill Gates narrates "Defeating Dengue" with Wolbachia

This week Bill Gates appropriately labelled mosquitoes the most dangerous animals in the world in this blog post. The nearly two-minute long video below is narrated by Gates, who explains how Wolbachia researchers in the Eliminate Dengue project have been aggressively infecting mosquitoes with Wolbachia bacteria and releasing the mosquitoes into areas where dengue virus is a significant problem. "Wolbachia blocks the disease…It has a very good chance of success", Gates says.

Saturday, April 26, 2014

I F***ing Love Science. I f***ing love Charles Darwin.

The viral video age demands that science have a video anthem. And here it is (uncensored). Lyrical shots go out to Charles Darwin, Carl Sagan, and Rosalind Franklin. Rumor has it that the epic Facebook page I F***ing Love Science (13 million people follow it) will officially have this song as its official theme song. I would be remiss not to share it here. Science needs so much more entertainment like it.

Wednesday, April 23, 2014

Flipping Discovery Based Research: An Interview With High School Students

For the past decade, the international outreach program Discover the Microbes Within! The Wolbachia Project has embraced a learning revolution in discovery-based research, inquiry, and collaborative bidirectional learning. I had the pleasure to capture some of these elements with this video below. Here is the YouTube link if you can't see it.

Recorded on April 22, 2014, three talented high school students from the School for Science and Math at Vanderbilt talk about their learning experiences in peer-to-peer learning. In the last five months, their goals were (i) to become experts in the international outreach program Discover the Microbes Within! The Wolbachia Project (ii) synthesize and retool the content to transmit it back to a metro Nashville high school classroom and (iii) find out what they learned about themselves and scientific literacy during the process. The latter is what this portion of the interview captures and is the "secret sauce" of peer-to-peer learning. Find out what they had to say.

Website for the Discover the Microbes Within discovery-based research program:

Saturday, March 29, 2014

We're hiring


Seth Bordenstein ( is seeking a postdoctoral fellow in metagenomics, microbial ecology, or systems biology.  The ideal candidate will pursue innovative research that compliments ongoing work in the lab on evolution, genome-microbiome interactions, and phylosymbiosis. We particularly encourage applications in the following areas:

·      Host-associated microbiomes (including but not limited to 16S rRNA gene sequencing, metagenomics, metatranscriptomics, metabolomics, and bioinformatic analyses using animal, plant or microbial systems)
·      Systems Biology (including but not limited to novel approaches in the genesis and processing of multi-omic data and models to integrate these data)
·      Quantitative and Computational Biology (including but not limited to bioinformatics, comparative functional genomics, and population genetics of large data sets)

We welcome cross-disciplinary approaches to understand how animals develop, function, interact and evolve. All candidates must have demonstrated excellence and creativity in applying next-generation sequence data to quantitative community, evolutionary, or ecological themes.

To apply or ask questions, please send information to Seth Bordenstein ( Please submit a CV and 1-2 page research statement describing your research interests, background and your goals for your career and postdoc. Please also include the names and contact information for at least 3 references. Applications will be reviewed immediately until a suitable candidate is identified.

Monday, March 17, 2014

Is Natural Selection Not the Right Brand for Evolution?

Mutation, Not Natural Selection, Drives Evolution


I just read the above article in Discover (link: March 16, 2014) that captured my curiosity. Famed population geneticist Masatoshi Nei claims that evolutionary biology has overly relied on "natural selection" as the brand name for evolution, and he makes a fair argument. He suggests an alternative - mutation driven evolution - that can seem subtle in comparison to natural selection at first glance, but it is not subtle. Why would biologists revise their heavy use of natural selection in favor of evolution by mutation?
  • First, mutations come before natural selection. Without genetic variation, there can be no change in an organism that is directed by natural selection. Nei states:
Mutation means a change in DNA through, for example, substitution or insertion [of nucleotides]. First you have to have change, and then natural selection may operate or may not operate. I say mutation is the most important, driving force of evolution. Natural selection occurs sometimes, of course, because some types of variations are better than others, but mutation created the different types. Natural selection is secondary.
  • Second, evolution by natural selection ignores that some variation arises by neutral mutations (that have no effect on the organisms' function) and population size crashes can cause those mutations to spread. So why would biology want a universal brand name like Natural Selection that misses the "neutral" side of evolution?
  • Third, it is Nei's opinion that natural selection is a deterministic force that simply replaces the hand of God as that deterministic force. Herein lies something important to consider.
If you say evolution occurs by natural selection, it looks scientific compared with saying God created everything. Now they say natural selection created everything, but they don’t explain how. If it’s science, you have to explain every step. That’s why I was unhappy. Just a replacement of God with natural selection doesn’t change very much. You have to explain how.
Part of the crux of the theory of evolution is that random mutations arise in a manner that is inconsistent with a deterministic hand. Changes are not orchestrated by want of a higher power but by random genetic processes that cause errors in the DNA code. It's equivalent to the randomness of the universe. 

My favorite Nei quote is at the end. It is a message for all students of science:
But any time a scientific theory is treated like dogma, you have to question it. The dogma of natural selection has existed a long time. Most people have not questioned it. Most textbooks still state this is so. Most students are educated with these books. 
You have to question dogma. Use common sense. You have to think for yourself, without preconceptions. That is what’s important in science.

Monday, March 10, 2014

Al Gore on the Microbiome and Darwin

When former Vice President Al Gore preaches the MICROBIOME, it may be time to switch fields as the bubble of exponential growth has officially burst. Sorry folks, but tis true. He does give a shocking and swift shout out to Darwin though. In all seriousness, I applaud the former VP for preaching fairly accurate science. Every drop of science education counts in the U.S.A. 

Saturday, March 8, 2014

President Obama to introduce Fox's 'Cosmos' series on March 9

"We are made of star (microbe) stuff. We are the way for the (micro)COSMOS to know itself." - Carl Sagan (modified)

Tomorrow night, Science comes back to mainstream TV to reclaim its rightful entertainment and knowledge value. Join the journey and share the excitement about the new COSMOS show hosted by Neil Degrasse Tyson - the heir apparent to  Carl Sagan - who is serving the public's appetite for science and wonder. The mission of this TV show and what we all do as scientists are aligned in advancing science education and the beauty of discovery. 

Here is Neil Degrasse Tyson speaking at his usual best on scientific literacy.

Friday, February 7, 2014

Guest Blog Post on Helicobacter pylori: Friend or Foe?

We're not too far into 2014 and we already have a contender for "favorite paper of the year". This treat is the story behind that paper - one that remarkably interconnects phylosymbiosis with human health. 

Kodaman et al, PNAS 2014 

Contributed by Carrie L. Shaffer, PhD
Twitter @CLShafferPhD

Electron micrograph of H. pylori (Source)

Global dissemination of Helicobacter by modern humans

One of the most successful human pathogens in recorded history is Helicobacter pylori, a Gram-negative bacterium that has colonized the gastric niche of modern humans since our migration out of Africa approximately 60,000 years ago.  Since leaving Africa, H. pylori has diversified in parallel with its human host.  Because of the predominantly vertical transmission of H. pylori within family units and the chronic carriage of H. pylori for nearly the entire lifetime of an individual, we have the remarkable ability to trace human migrations by analyzing H. pylori genetic signatures.  Recent evidence suggests that H. pylori has colonized humans for at least 100,000 years, and points to a second exodus out of Africa 52,000 years ago that resulted in generation of a hybrid European lineage of H. pylori strains (Moodley et al.).

Today, H. pylori colonizes the gastric mucosa of at least 3 billion people worldwide. Gastric colonization by H. pylori results in the development of asymptomatic chronic non-atrophic gastritis in all cases.  However, in a small percentage of cases, severe gastric disease can manifest, including emergence of peptic ulcers and gastric adenocarcinoma, which is currently the second leading cause of all cancer-related deaths worldwide. In contrast to the United States, where the prevalence of gastric cancer is low, the incidence of gastric adenocarcinoma varies globally with the highest rates occurring in Japan, China, South America, and Eastern European nations.

Because of its diverse and segregated geographic and ethnic landscape, the South American country of Colombia serves as an ideal natural laboratory for the study of H. pylori-related disease and its association with gastric adenocarcinoma. Separated by only 200 kilometers, the Colombian towns of Tuquerres and Tumaco have sharply contrasting rates of gastric cancer.  Tuquerres, located in the altitude of the Andes Mountains, has one of the highest rates of gastric cancer in the world (approximately 150 cases/100,000 people), whereas the coastal town of Tumaco has a gastric cancer rate of just 6 cases per 100,000 people, despite a nearly universal rate of H. pylori colonization throughout Colombia.  

Health outcomes echoing a continued legacy of European colonization

A rich history of settlement by native Amerindians coupled with both colonization and conquest by Spanish invaders and the introduction of African slave trades led to racial and ethnic segregation within Colombia.  People residing in modern day Tuquerres are mainly of mestizo (Spanish and Amerindian) descent, while the residents of Tumaco are primarily of mulatto (African and Spanish) descent.  These observations led us to the central question of our recently published paper in PNAS (Kodaman et al.): Are the rates of gastric cancer in Colombia governed by human or Helicobacter ancestry? We reasoned that a 25-fold difference in the rate of stomach cancer between the two populations could be attributed to differences in the host genetic composition; differences in host immune responses to chronic infection; phylogeographic origin and/or virulence factors harbored by H. pylori; environmental factors such as diet and smoking status; or a combination thereof. 

Our previous work (de Sablet et al.) demonstrated that European H. pylori ancestry is strongly predictive of increased premalignant lesions and epithelial DNA damage in both Colombian populations, while African H. pylori phylogeographic origin is associated with reduced severity in histologic disease parameters.  These findings are significant because we were able to show that in this region, the genetic ancestry of H. pylori is both a risk factor for development of gastric disease and a determinant of gastric disease severity, irrespective of the presence of the major virulence factors CagA (an oncoprotein present in some strains of H. pylori) and VacA (a secreted toxin present in all strains of H. pylori).  However, this study was constrained to a small subset of our larger cohort, and thus, we wanted to further investigate how Helicobacter phylogeographic origin contributes to development of gastric cancer.

In our follow-up study, we expanded the number of patients analyzed to 242 (122 from Tumaco and 120 from Tuquerres), and focused our efforts on analyzing human ancestry in parallel with the phylogeographic origin of the H. pylori cultured from patient-matched gastric biopsies.  Using Immunochip analysis to genotype nearly 200,000 SNPs in each patient’s blood sample, we determined that human ancestry closely followed expected patterns based on historical events: the people of coastal Tumaco trace the majority of their ancestry to Africa (58%), while the mountain population of Tuquerres are largely of Amerindian (67%) and European (31%) descent. We used multilocus sequence typing (MLST) to determine the matched H. pylori phylogeographic origin from each patient, and classified each isolate into an ancestral haplotype based on analysis of housekeeping gene sequences using STRUCTURE.  Helicobacter phylogeography recapitulated our previous report indicating that the bacteria derived from ancestral European, African, and East Asian (Amerindian) lineages.  The matched human and Helicobacter ancestries were then correlated to histopathology scores from gastric biopsies taken from each patient in order to determine if either human or H. pylori genetic ancestry was associated with disease severity.

The answer surprised us: we found that perturbation of human-Helicobacter phylosymbiosis can shift a benign infection to a potentially catastrophic relationship that results in disease progression to gastric cancer.  Rather than either the human or the bacterial ancestry acting alone, the contribution of bacterial-host genetic interplay was found to be the most significant factor for predicting disease outcome.  This result was even more captivating when we analyzed the influence of the major carcinogenic virulence factor CagA on the progression of advanced gastric disease within this cohort – human-microbe incompatibility had a greater effect on the risk for developing severe disease than the bona fide Helicobacter oncoprotein.  We went on to show that disruption of human-Helicobacter phylosymbiosis accounts almost entirely for the differences we observe in stomach cancer risk between Tumaco and Tuquerres.  To our knowledge, this study was the first report of matched genetic analysis of the host and pathogen with subsequent correlation of human-microbe phylosymbiosis to clinical outcome.

Reflections of a distant past

So what do our results mean? One theory is that invasion of Colombia by the Spanish conquistadors introduced ancestral European H. pylori to the Amerindian populations, and these bacteria replaced the East Asian H. pylori strains naturally harbored by the Tuquerres population.  It is thought that H. pylori of European ancestral origin may be more virulent than some other lineages, including H. pylori of ancestral African and Amerindian haplogroups. Since many people are often co-infected by multiple H. pylori strains, it is reasonable to hypothesize that H. pylori of European lineage could have outcompeted strains of Amerindian lineage in native Colombians. Alternatively, co-infection with multiple H. pylori strains and the natural competence of the bacterium leads to a propensity of H. pylori to uptake DNA for recombination, resulting in generation of new strains that are entirely unique at the DNA level. Another possibility is that differences in virulence factors between H. pylori phylogenetic lineages could provide a competitive advantage during co-infection. In fact, analysis of the cag pathogenicity island (which encodes components of a molecular machine used by H. pylori to inject CagA into gastric epithelial cells) in several Amerindian H. pylori isolates revealed numerous changes, including gene rearrangements, indels of approximately 11.2 kb (one quarter the size of the entire pathogenicity island), and gene inversions (Olbermann et al.).  Despite these dramatic variations in macrodiversity, the Amerindian isolates retained functional secretion system machinery, suggesting that the changes are non-deleterious to pathogenicity island function, and are likely under neutral or positive selection.  Strikingly, our study reveled that patients with a high proportion of Amerindian ancestry who are infected with H. pylori strains that have a substantial percentage of African lineage (>20%) develop the most severe gastric lesions. Perhaps the frequent differences in macrodiversity found in Amerindian H. pylori isolates are essential for maintenance of host-microbe phylosymbiosis in the native Colombian population.

The results of our study provide insight into an ongoing debate in the field regarding classification of H. pylori as a pathogen rather than a commensal.  While it is true that H. pylori colonization is associated with a significantly increased risk for development of gastric disease, H. pylori may provide some benefits to its host.  For example, it has been suggested that H. pylori colonization is protective against development of esophageal reflux, cancer of the upper stomach, and cancer of the esophagus.  H. pylori may help to prevent Mycobacterium tuberculosis infection from progressing to active tuberculosis, and may play a role in providing protection from development of asthma and other allergic diseases.  The protective advantages of this fascinating microbe are intriguing, but nonetheless, additional investigation will be required to determine the mechanisms by which H. pylori provides such advantages to its host.  Our study points towards co-analysis of host and microbe genomic variation to identify those at highest gastric cancer risk so that we can selectively target H. pylori eradication.

Finally, our study brings new perspective to the so-called ‘African Enigma,’ a theory that describes the discordant prevalence of H. pylori infection and H. pylori-related disease in continental Africa.  Our findings suggest that maintenance of a harmonious host-microbe phylosymbiotic relationship can account for the low incidence of gastric disease throughout Africa in spite of H. pylori colonization rates estimated at greater than 90%.  In future investigations, it will be important to recapitulate our findings in cohorts from diverse sites including Africa, East Asia, and additional locations within Central and South America in order to determine the extent to which human-Helicobacter phylosymbiosis dictates disease outcome in global populations.