MiSciWriters is proud to partner with the UM Center for Microbial Systems to provide live coverage of the 2016 Michigan Meeting “Unseen Partners: Manipulating Microbial Communities that Support Life on Earth.” We will live-blog Monday’s events here, and live-tweet from @MiSciWriters 9:00am-3:30pm, 7:00-8:30pm.
We hope you’ll join in the conversation by commenting below or tweeting with the hashtag #MiMicrobe. Enjoy!
“Invisible Influence: Microbiomes in the World”
Ed Yong, Atlantic science writer, and Jack Gilbert, B.Sc., Ph.D, University of Chicago
Moderator: Nick Wigginton, Ph.D., Science Magazine
Editor: Ada Hagan
Bloggers: Liz Wason and Alex Taylor
8:45pm – Liz
A question from an ecologist in the audience: This Ph.D. student in the audience has learned that we can use our knowledge of connections among organisms in a community to push the community toward a desired outcome, according to human specifications. Such manipulation already is extremely complicated, and a microbial community has orders of magnitude more species than some of the most complex communities. Is the manipulation of the microbiome less tractable? Could it possibly be more tractable to manipulate the microbiome, given the studies that the speakers have cited at tonight’s panel?
Gilbert answers: More tractable. He has great confidence in new computational algorithms that researchers are developing as we speak. Those algorithms, plus the efficient collection of ever larger datasets, makes him optimistic that we can get a handle on how to constructively manipulate the microbiome.
8:40pm – Alex:
The first question came from the moderator, Nick Wigginton, who wondered about the hype and misunderstanding evident in flashy, pseudoscientific news articles and the dubious efforts of the DIY-fecal transplant community.
Yong responded first, from a science journalist’s perspective: of course he’s excited by the possibilities of microbiome research, but feels it’s his professional duty to keep it in check and be realistic. He also invoked a journalistic karma: if you do overstate claims, it’ll come back to bite you in the a**.
Gilbert approached it from the angle of the scientist interviewee: he tries to talk to and trust quality science journalists, reign in hyperbole, and keep his claims grounded in reality. He thinks it’s important for honest scientists to call out the snake-oil salesmen, and steer science journalists away from them.
Yong then advised science journalists to send their work to other trusted scientists for comment. Gilbert added that when scientists publish big, flashy, flawed studies, he leans on honest science journalists to help tamp down the hype and point out the problems, in a post-peer-review, peer-review.
It was clear from the exchange that, despite the constant ribbing, the two trust each other immensely and rely on that trust to keep the facts straight.
8:33pm – Liz:
Gilbert flashes a slide with the heading, “Some bacteria can make you fat.” He describes some experimental results: Transplant the microbiome of an obese person into an average mouse. The mouse becomes obese. Transplant the microbiome of an obese person plus a certain other bacterial species into an average mouse. The addition of that bacterial species “protects” the mouse from becoming obese. See? An understanding of the microbial community can, in turn, help us understand how to manipulate the microbiome to achieve our own ends.</span>
Gilbert would be remiss if he didn’t use an example that surgeons could get behind. Let’s take an example from the operating table. We’ve just finished a surgery in the intestine and have patched up the surgical site by stitching a piece of the intestine back together. Unfortunately, Gilbert says, “Some of the bacteria that were already present in the gut GO ROGUE.” Those gut bacteria create a biofilm that dissolves and ruptures the gut at the point of suture. WHYYY?
It turns out that, post-surgery, the gut bacteria suddenly find themselves without the phosphates they feed on. To get the phosphate they need so direly, the bacteria break down the exact spot of the intestine where the body has begun trying to repair itself.
The solution? Gilbert figured that oral ingestion of new phosphates to replace the phosphates lost during surgery can feed the rogue bacteria–this tactic prevents the bacteria from getting phosphate-limited and phosphate-stressed enough that they destroy the surgeon’s careful work. And so: careful manipulation of the gut microbiome can make everyone happy. Humans and microbes alike.
Gilbert ended by sharing an example of how studying the microbiome can help a burgled family identify their thieves…but you can read about that elsewhere.
8:13pm – Liz:
Early in his talk, Yong had everyone laughing by claiming authorship over his own poop jokes. For instance, suggesting that an article titled “Some beards are so full of poo they are dirty as toilets” referred to our second speaker on the panel, University of Chicago professor Jack Gilbert.
The joke’s on Yong: Gilbert doesn’t have a beard. Gilbert starts by soliciting laughs with his own claim–that now the audience will get an actually scientific presentation. In any case, speaking of science…
Gilbert begins with a bit of his personal background. Why is a professor of surgery, like him, preoccupied with the microbiome? At U of C, he teaches students to incorporate an ecological understanding as they use their scalpels on the operating table. Gilbert mentioned that he has a few genetic markers that make him more susceptible to Alzheimer’s disease. But he wonders, given a certain probability of getting Alzheimer’s disease, what would tip him toward or away from the illness? Do maternally-inherited microbes play any role? How about microbes acquired from the environment?
And here’s another example of the power of microbiomes that may strike a chord with more of us: Gilbert cites a study in which scraping the microbes from the tongue of Fruit Fly A who’s smitten by Fly Z, are then transplanted onto the tongue of Fly B. As a result, Fly B becomes smitten with Fly Z. Gilbert asks: Wow. To what extent do our microbes determine our soulmates and life partners?
Maybe we can manipulate the microbiome to get our crush to fall in love with us. Or maybe we could apply our knowledge of the microbiome to reduce food allergies in school kids. Maybe the microbiome prevalent at a small farm explains lower rates of asthma in those Amish farmers, compared to the higher rates of asthma that Hutterite farmers suffer on industrial–read: more sterile or more microbially homogeneous–farms. So beyond those pipe dreams involving the microbiology of love and desire, the potential exists to improve human health by manipulating the human microbiome.
7:52pm – Alex:
Yong then pivoted to the relationship between Wolbachia and invertebrates like insects and nematodes. Wolbachia infects many different species of invertebrates, with quite different effects. Targeting Wolbachia in nematodes can reduce the horrific effects of the Elephantiasis disease.
Infecting mosquitoes with Wolbachia seems to prevent them from carrying the virus that causes Dengue fever, offering a potential avenue for combating this disease. Early studies involving releasing Wolbachia-infected mosquitoes into wild mosquito populations in northern Australia has had promising results, and these studies are being extended to other mosquito-borne viruses like Zika and Chikungunya.
Yong closed by noting President Obama’s National Microbiome Initiative, and reinforced the same cautiously optimistic note that had infused his talk. If we can understand the nuanced way that microbiomes interact with their hosts, the potential for human health is immense. The early findings are promising, but our ignorance still runs deep.
7:47pm – Alex
To further drive home the importance of nuance in manipulating microbiomes, Yong turned to the humble, dopey cow. Certain cows, with specific bacterial partners living in their guts, are able to digest the otherwise-poisonous plant Leucaena. Introducing a particular bacterial species from a cow doesn’t work, but introducing goop from the gut of a properly-inoculated cow – the whole bacterial community – does.
Which takes us, inevitably, to human fecal transplants. The evidence of their effectiveness is startling: as Yong put it, “this s–t really works.” However, transplanting human feces can also be very dangerous, potentially infecting the recipient with a damaging bacterial parasite. This is readily apparent in the travails of the “DIY-fecal transplant” community (yes, of course it exists). Yong proposed that in the future, we would make pills that isolate specific bacteria from the poo, instead of transplanting the stuff wholesale: a “sham-poo,” he ventured, to widespread groans and laughs from the dad-joke community.
Devising the ingredients list to this sham-poo is going to require a much more thorough understanding of the microbial communities dwelling in human guts, and the way they behave. Large microbiome studies are beginning to build and refine this understanding, but we must be humble about the current limits of our knowledge. As a recent study demonstrated, we don’t even know many of the players in the microbial world.
7:31pm – Alex:
Nick Wigginton, a senior editor at Science magazine, opened the public panel discussion by seeing who in the audience was actually from the public (about two-thirds had been at the conference all day). Without much further ado, outside of a nod to his children’s excellent poop jokes, Wigginton welcomed Yong on stage.
Ed Yong opened by discussing the prevalence of microbes all around and within us, and their presence for the vast majority of Earth’s history. Yong dispelled the common notion of bacteria as simply disease-causing scourges, or disgusting films over our cell phones. He talked about the ability of microbes to open evolutionary and ecological opportunities for their macroscopic kin, for example by allowing them to digest tough and otherwise toxic foodstuffs.
Yong discussed the increasing awareness of the importance of a functioning microbiome for human health, and poked fun at the inevitable overstatement of that effect. This effect isn’t limited to humans: for example, particular bacteria may help ward off the “Bd” fungal epidemic in frogs. However, attempts to inoculate susceptible frog species with these beneficial “probiotic” bacteria have been unsuccessful. Perhaps this is due to the differences between frog species, or the stage of development of the frogs’ immune systems. This example highlights the need for a nuanced understanding of the way beneficial, probiotic bacteria interact with their hosts. He expressed doubt about the advertised beneficial effects of probiotic yogurts.
Big news: The White House just announced a partnership with the Michigan Microbiome Project, based at the University of Michigan. This National Microbiome Initiative has brought together U-M and other partners (including the Bill and Melinda Gates Foundation and UC San Diego) to gain a better understanding of the microbiomes associated with human health, food, and the environment.
The goal of the Michigan Microbiome Project involves learning how to use dietary interventions to manipulate the microbes that live in the human gut—in this way, people can have some control over creating settled stomachs and healthier humans. The goal of the National Microbiome Initiative is to find ways of applying new knowledge for the benefit of individuals, communities, and societies.
The big news has big relevance to tonight’s speakers: science writer Ed Yong and Professor Jack Gilbert. Gilbert is the director of the Microbiome Center at the University of Chicago (another partner in the White House’s brand new microbiome initiative), and Yong’s new book on the microbiome, I Contain Multitudes, comes out this summer.
In a discussion that’s open to the public, Yong and Gilbert will share their thoughts about the prevalence of microbes across the planet and in our bodies, the impact of microbes on other organisms, and how humans can manipulate microbial communities to improve human and environmental health.
“Ramifications for Managing Microbiomes” – A Panel Discussion
Editor: Irene Park
Blogger: Bryan Moyers
Dr. Mueller, a professor of integrative biology at the University of Texas at Austin, spoke on artificial selection on beneficial microbiomes to improve plant and animal health. Because microbiomes can have positive effects on animal traits, animal traits may be improved by changing their microbiomes. For instance, if we could select for microbes that greatly improve grain production in wheat, we could improve agricultural efficiency. There are many exciting possibilities in this realm, and Dr. Mueller gave his perspectives on the issue.
Dr. Mueller’s work focuses on the methods for artificially selecting microbiota in hosts. Dr. Muller focused on what’s called “indirect selection”, where we don’t explicitly select for microbes that give the results we want but instead we take the hosts that have the best traits and breed those. The traits could be a result of the host’s genome or of the microbe’s genome.
In Dr. Mueller’s experiment, all of the plants were genetically identical. This means that most of the selection was probably happening on the microbiome because the plants’ genetics were all the same. (see here for a schematic of the “indirect selection” experiment)
Throughout this process, we can help the microbes to optimize for a controlled environment that we set, and the microbes also become better at supporting the traits of interest. After three years of work, Dr. Muller found that it was incredibly easy to change a plant’s phenotypes by just selecting for microbiomes. What’s more, no matter what phenotype he tried to select for, he found that the microbes could have a strong effect. He wasn’t able to find any phenotype that the microbes didn’t influence.
As one example, Dr. Mueller showed us how he was able to develop salt tolerance in plants using these microbiota. Salt is normally so good at killing plants that it’s a common method for killing unwanted weeds. In only nine generations, Dr. Muller was able to significantly improve a plant’s salt tolerance. He also performed the same experiment for aluminum tolerance, another soil nutrient that can kill plants, and he was able to significantly improve aluminum tolerance too.
Dr. Mueller found that the microbes that weren’t helping plants to survive all types of stress, but rather the microbes were specifically helping plants with one kind of stress. This was a level of specialization that Dr. Mueller didn’t expect.
Dr. Mueller set the stage for designing plants for surviving in specific, difficult environments, which can be useful for farming in space in the future or farming in extreme environments on Earth. This also could be a generalizable phenomenon that could be used in animals, like livestock. And this method may have implications for managing the human microbiome. It’s an exciting new realm of health and agriculture.
After the talk, Dr. Mueller handled a number of questions from the audience. In response to one question, Dr. Mueller emphasized that this system required that the plants likely couldn’t survive in the absence of the microbiome. For this system to work, there must be an unbreakable interaction between the plant and its microbiome.
Another audience member touched on a philosophical point, calling this method “indirect selection” is somewhat semantic. The audience member said that we’re selecting on a plant feature that we can see, but fundamentally, we’re selecting the microbiome’s phenotype, specifically the microbe’s ability to promote a certain plant phenotype. Dr. Mueller, without any exasperation, commented that this is a historical definition that evolutionary biologists have created.
Dr. Theis talked about how we can view medicine through a hologenomic lens. The hologenome is a concept similar to the holobiome. The hologenome refers to the host’s and its symbiotes’ collected genetic information.
At a given time, about one-third of the metabolites in our blood have come from microbes. Even though our relationship with the microbes can be beneficial, microbes can sometimes be harmful! Dr. Theis investigates this interaction between our microbiome and our behavior, referred as a behavioral holobiome perspective.
An example of microbe-host behavior relationship is ants who are turned zombies by fungal infection, but there have been other suggestions that in humans gut microbes can affect our behavior. The fact that these microbes can play a role in abnormal behavior suggests that they also contribute to normal human behavior.
There are several tenants of the hologenome concept. Using these tenants, we can test the hypothesis by determining if the tenants are true. Dr. Theis noted that this whole concept of hologenome is a hypothesis currently in debate. Critics of the concept say that the focus should be on species-level interactions (a reductionist view), not the emergent properties of several species taken together. Perhaps we can get more important insights by considering the individual parts, but Dr. Theis commented that both perspectives have value, and that the systems-level approach can offer information that a reductionist view can’t.
Dr. Theis suggested that evolutionary medicine is a great way to test the hologenome idea, as it specifically looks at evolution’s applications to medicine. Because the hologenome can evolve quickly, this is an opportunity to apply a hologenome perspective. Another area is in precision medicine. Microbial biomarkers in a person’s medical records can help to guide treatments, and a person’s microbiome can be managed individually to help make a person healthier.
Dr. Theis concluded by giving a case study in perinatal medicine as another opportunity for using the hologenome concept for medicine. The vaginal microbiome is a large group of microbes dominated by Lactobacillus. Lactobacillus provides a barrier against infections by creating an acidic environment that kills the harmful bacteria. Vaginal and uterine infections could result in premature delivery of a fetus. In the big evolutionary picture, this might be a positive response, as it improves the overall survivability of the mother or the fetus. However, from a medical perspective, premature delivery can be dangerous for the baby. We can use the hologenome concept by fighting infections with probiotics that support the natural microbiota in the vagina.
The story becomes more complex when we consider the microbiome of the placenta surrounding the fetus. There are various microbes are transmitted from mothers to offspring. These bacteria are thought to be critical for the fetus surviving in the mother, fetus’ developing a strong immune system, or fetus’ surviving after birth. Which of these are true is still under investigation. Dr. Theis emphasized that figuring out which of these is true requires us to be very careful as it’s really easy to over-interpret the data.
One audience member suggested that the selection did not act at the species-level, but on the interaction among the species. Dr. Theis agreed and gave an example of the squid’s camouflage phenotype, which relies on a host-microbe interaction.
Another audience member suggested that Dr. Theis’ plan to confirm or reject the hologenome concept was too simple. The gut microbiota change so much throughout a person’s life, that it’s difficult or impossible to really detect the evolution of this community. Dr. Theis responded that the consistency of human responses across generations suggested that these host-microbe associations can be selected by evolution.
Unfortunately, Dr. Jan Sapp, wasn’t able to attend. As a historian of science, Dr. Sapp intended on discussing and resolving “the central enigma of ecology”. Unfortunately, we won’t know what that enigma is until he arrives at the conference. Fortunately, he has a book coming out in a few months about this topic, so watch his Amazon page for its publication if you’re interested!
Dr. Lloyd, a historian and philosopher of biology, is an expert at defining units of evolution and selection–which is a major question in the philosophy of biology. She talked about the usefulness of a holobiome, which refers to the collection of organisms that make up the host and all its symbiotes. This is a useful definition because we rely on the health of the microbes living inside us for our own health (and they rely on ours).
Dr. Lloyd emphasized whether or not it’s useful as a “unit of selection”– that is, what evolution acts on (as opposed to a gene, an individual, or a full species). This is a subject of an ongoing debate in evolution and microbiology, influenced by a number of thinkers, including Richard Dawkin’s book, “The Extended Phenotype” that discussed how an organism’s phenotype wasn’t just limited to its own proteins. It turns out that there’s a complicated interaction between an organism, the environment, and other organisms, meaning that we have to take a large, holistic view when considering questions of evolution.
Organisms interact with their environment as a whole, but there’s a whole different level of interaction going on within the organism, in its microbiome. The microbiome interacts with the host, with itself, and with the environment. This complicates our view of evolution and ecology. A key problem in promoting human health is understanding how the microbiome interacts with the host and environment. We have to not only think about the microbiome and the host individually but also together.
As an example, when we apply antibiotics to a person, it may save them from an infection, but it might damage the organism’s microbiome, causing long-term concerns for host recovery and health. If we wipe out the bacteria that help us digest our food, we have to reestablish those populations. We can’t survive without the correct microbes in our guts! Future research in antibiotics should be aware of the damage on the microbiome and the holobiome.
In particular, future antibiotic research might focus on the specificity of antibiotics–do they kill the bad microbes, but not our beneficial microbes (or at least hurts these microbes less)? Dr. Lloyd commented on the nature of several antibiotics, including Xifaxan and Biaxin. She commented that long-term treatment regimens involves switching between these two antibiotics, and that our understanding of antibiotic resistance (and evolution) can help us design drug regimens that are least harmful to our microbiome while still eradicating invasive bacteria.
A question from the audience asked about how the microbiome responds to various environmental stimuli independently of the host. For instance, because the microbiome generates offspring much more quickly than the host species does, it can respond in evolutionary terms to dangerous environments in a way that the host can’t. Dr. Lloyd assented that the microbiome can generate genetic variation on a timeline that the host simply can’t, and this can inform our understanding of the evolution of a host’s phenotype because it’s not only dependent on the host genotype, but also on the microbiome genotype.
What are the consequences for managing the microbes that live inside each of us? Could there be health benefits? What are the dangers? Microbial communities are complex entities that interact in dizzying ways, and because of these interactions we have to sometimes wonder: when we’re managing the microbes inside us or in our food, how much are we actually managing ourselves?
These are the kinds of questions that Dr. Elizabeth Lloyd (Professor of Biology, History, and Philosophy of Science, Indiana University), Dr. Kevin Theis (Professor of Microbiology and Immunology, Wayne State), and Dr. Ulrich Mueller (Professor of Integrative Biology, University of Texas at Austin) are investigating during this panel. Through a combination of short presentations and panel-audience discussions, we’re getting the views from a diverse group of experts in this sphere.
“What Can We Expect from the Human Microbiome?”
Editor: Irene Park
Blogger: Alex Taylor
Though Dr. Schloss’ talk was largely about the interaction between microbiome research and the wider society, and his questions were mostly about the technical questions regarding methodology and quantification, which is unsurprising in a crowd of microbiologists.
Byron Smith, a PhD student in EEB, asked about how best to break down microbiome data. For example, if we could categorize the microbial communities into broad categories or whether we need to rely on “Random Forest” models that retain a massive number of variables. Dr. Schloss replied that different models may be useful for different questions.
Ed Yong, a science journalist at The Atlantic, asked whether a keystone species (a species that plays a key role in an ecosystem’s function) in these microbial communities could be driving the relationship between different microbial communities and diseases. Dr. Schloss emphasized the “chicken and egg” nature of these systems, in which a particular keystone species like Fusobacterium might be driving the health impact, but other bacterial species in the community could be creating the niche that allows Fusobacterium to proliferate.
Another way that microbiome research could deliver practical results is by guiding therapies, highlighting the work of Dr. Joe Zackular, a postdoctoral scholar at Vanderbilt University, in looking at whether tumor formation could be arrested by changing microbial communities. He showed work by Dr. Zackular showing that antibiotic treatments that manipulate bacterial communities had a significant effect on tumor growth. Dr. Schloss also noted the possibility that we could use information about microbiomes to identify if certain people are at increased risk for particular disease.
So if manipulating the microbiome could possibly reduce the risk of developing a disease or slow the progression of tumor formation, then two questions follow. The first is how we can best manipulate these communities, and the second is what negative consequences that could hold. Dr. Schloss warned against taking this second question lightly, as our knowledge is limited and we can see that microbial communities can have drastic effects on health.
Dr. Schloss closed by thanking his research team, and emphasized the importance of keeping basic research relevant by noting that each dot on his graphs was a “real human person.”
After this overview of the field and its reception in the culture at large, he moved onto the main thrust of the talk: what we can do with the current discoveries of microbiome research. He used the example of colorectal cancer, one of the main research topics of his lab. Colorectal cancer is relatively treatable if diagnosed early on, but that requires invasive and expensive testing like colonoscopies. Dr. Schloss’ lab asked whether we could use microbiome information to predict colorectal cancer in individuals, and whether this testing step bypasses the need for colonoscopies.
This is the kind of work that could transform microbiome research into a relevant research field with real, direct impact in people’s lives rather than just an abstract and academic demonstration of the world’s complexity and our ability to interrogate it.
Dr. Schloss and colleagues developed a statistical model that incorporates information from Fecal Immunochemical Testing (FIT) as well as data about the presence of particular bacterial species to predict whether or not a patient has colorectal cancer (or adenomas, which are benign tumors). He discussed some of technical difficulties in building these models, such as the trade off between specificity and sensitivity, and the large amount of overlap between healthy and unhealthy microbiomes.
While it’s exciting to see that the microbiome research is gaining attention, Dr. Schloss warned against several myths that are emerging as the microbiome enters the public consciousness. He surveyed the bizarre cultural landscape as society at large begins to digest the microbiome, highlighting everything from the parody twitter account “#2 and me” joking about deluxe fecal transplants to a rogue NASA scientist offering microbiome services.
The chief myth he warned against, though, was the idea that there is an “average human microbiome,” and the associated ideas that there is a “healthy” and “unhealthy” microbiome. A slide titled “There is no one human microbiome” showed the variation in microbial communities across humans.
In addition to the myths bubbling up from microbiome research, Dr. Schloss also discussed other myths in the field that microbiome research is disproving, including the idea that diseases arise from a single causative organism. As we delve further into microbiomes, it’s becoming increasingly clear that some diseases arise not from a single pathogen species, but rather from entire communities of microbes.
Microbiology and immunology assistant professor Evan Snitkin expressed gratitude for Dr. Schloss’ mentoring and commitment to rigorous analysis and moving the field forward. When Dr. Schloss took the stage, he emphasized the importance of the microbiome by showing pictures of the very different guts of mice raised with and without a normal microbiome.
While we’ve made great strides in understanding the bacterial communities living in humans, Dr. Schloss warned that we are still in early days, and plenty of today’s microbiome studies show spurious associations between particular diseases and microbial communities. He talked about how we are still fundamentally struggling with the same question as Dr. Escherisch all the way back in 1888: a patient comes in with diarrhea, and we need to figure out how the bacteria in their gut relate to their suffering.
But microbiome research is starting to gain steam, with the White House having just announced a major National Microbiome Initiative. This initiative aims to bring together many different private and public stakeholders including federal agencies, universities, and non-profits, to collaborate across disciplines and address a hodgepodge of questions raised by microbiome research.
The University of Michigan has offered to pitch in $3.5 million to this $520 million effort, focusing on training students in the microbiology and bioinformatics techniques necessary to address these questions. Dr. Schloss highlighted this initiative, as well as other efforts such as citizen-science projects and private companies like uBiome that offers microbiome sequencing services.
At first glance, Dr. Patrick Schloss is a scientist looking towards the future. His laboratory uses supercomputers and new sequencing technology to analyze the DNA of bacteria directly from environmental samples, a cutting edge field called “metagenomics.” When he entered the field, the computational tools to make sense of the kind of data he was collecting didn’t yet exist, so he and his colleagues had to develop them.
But while the techniques employed by Dr. Schloss’ lab are shiny and new, the questions they aim to answer are well over a hundred years old: how do the microbes living inside of us affect our health? Or, as Thomas Escherich, the microbiologist with the dubious honor of being the namesake for Escherichia coli (E. coli), put it in 1888:
“…It would appear to be a pointless and doubtful exercise to examine and disentangle the apparently random appearing bacteria in normal feces and the intestinal tract, a situation that seems controlled by a thousand coincidences… Yet I have nevertheless devoted myself now for a year virtually exclusively to this special study, it was with the conviction that the accurate knowledge of these conditions is essential, for the understanding of not only the physiology of digestion…, but also the pathology and therapy of microbial intestinal diseases.”
This quote is on the homepage of the Schloss lab website and appeared early in Dr. Schloss’ talk. This quote not only immediately forms an explicit bridge between the microbiology from the 19th and 21st century, but it also grounds these fancy new techniques in the deadly serious relevance to lethal diseases of the microbiome such as colorectal cancer and Clostridium difficile infection.
This focus on the real-world implications of microbiome research is important in a field where it’s easy to get lost in the exploding datasets and whiz-bang methods. So it’s fitting that Dr. Schloss’ talk focused on what we can expect from microbiome research, on the real-world “deliverables” that this research could yield to remain valuable and relevant to society at large.
“Diving Deep into Freshwater Lake Community Genomes to Infer Traits and Track Populations”
Katherine McMahon, Ph.D., University of Wisconsin
Editor: Ada Hagan
Blogger: Bryan Moyers
Dr. McMahon’s talk covered a wide range of studies and types, which allowed for many questions.
One audience member studied these same bacteria in Lake Erie. They found that certain types of bacteria were present before, during, and after bacterial blooms– events that can have large effects on lake ecology and human health. The audience member noted that these species were present in Dr. McMahon’s research, and asked if her lab had noticed the same patterns. Dr. McMahon *had* noticed this. She had a few comments on the timeline for these patterns.
I was able to squeeze a question in about how much the lake’s microenvironment influences her studies. Different species might live on the upper parts of a lake compared the the lower parts of a lake. These different species may or may not interact. Dr. McMahon gave a quick explanation of how water circulates in the lake, but commented on the difficulties of knowing how quickly this happens. Is it on the scale of hours? Days? She mentioned that all of her study focused on a particular area of the upper lake. But these questions of interaction between lake layers is an area to be studied.
Other questions were asked, but quickly became highly technical, as they often do in a room full of experts! It was difficult for me to keep up. What I can say is that the questions were numerous and engaged. Dr. McMahon really touched upon an excited area of microbiology, ecology, and evolution.
The third vignette, Dr. McMahon says, is wildly different from the first two, as here she studies protein structures. One protein type of interest are rhodopsins, a type of protein that exists in the human eye and is important for sight in all animals. Her research is all based on the metagenomic data, not on studies of the bacteria in lab– remember, these bacteria can’t be grown in lab!
Why would bacteria have rhodopsin, and what do they use them for? Bacteria don’t see, as far as we know– at least not the same way we see. Based on the genetic data, the lab tried to figure out a coherent story to explain what this gene is being used for. Here’s what the lab came up with:
The rhodopsin proteins can work as sodium and proton pumps, by capturing energy in the form of light. The light allows bacteria to pump sodium out of the cell, which will then rush into the cell through a separate protein because of a gradient. This energy of sodium rushing into the cell can be captured to create ATP or other energy molecules. One particular species, Salinibacter ruber, contains a proton pump with a special structure called a carotenoid antenna. Instead of capturing sound waves, this antenna captures a particular wavelength of light that if the bacteria is exposed to, could be converted to energy. The lab studied all of the various proteins coming together to make this system work, and modelled their structure to confirm that this could be a method for energy capture in the bacteria.
All this work allowed biophysicists in the lab determine how the bacteria can absorb light and generate energy. To confirm that this could work in practice, they took all the necessary genes and put them into E. coli to see if the genes would work together to produce energy in this bacteria, which could be grown in lab. They found that the E. coli were able to use the rhodopsin (and associated proteins) correctly, as expected.
This is an example of reverse ecology in action– based on the genetics of a community, the lab was able to tell a story about what was going on in the bacteria, and confirm several of the steps at the bench.
Dr. McMahon next moved on to questions about what lessons we could draw from genomic information. It’s really tough to measure all of the changes that happen in a microbial community in real-time in a lake. But our understanding of genetics and protein networks might help us predict this kind of information from genetic information. By going out and sequencing all of the genes present in the bacteria from a lake sample, we might be able to understand what’s going on in the lake. These sequencing studies can be a lot faster and more linear than trying to measure all kinds of lake nutrients or other compounds found in the water. This is a matter of getting as much information as possible from as few tests as possible.
One finding from this area of study is evidence for specialization in the community. Why is this important? Well, if we can find specialization of certain bacterial types and the functions they’re specialized for, then when they show up in our metagenomic data we can say “Aha! This species is present, and it’s really good at (for example) eating nitrogen! This bacteria will probably reduce nitrogen levels in the lake.” There could be any number of examples like this. Another example would be finding out that the entire community has no method to synthesize a particular metabolite, like an amino acid, so it must be provided by the environment.
So the lab constructed a huge model of how metabolites are affected by a particular phylogeny/community of bacteria. This is what the lab calls “reverse ecology”– determining something about how the ecology of a group works based on the kinds of species found in that environment and the genetics of those species.
This method can also tell us about how much cooperation or competition is going on among the various species. How exactly this was done seemed pretty complicated, and was well over my head! But it seems like a pretty good method, as it reproduced a well-known finding in evolution and ecology — competition is more intense between species that are closely-related. So, two bacterial species in the same lake that are very similar to one another tend to fight one another over resources and locations. What *wasn’t* expected was that they found that these closely-related species were actually cooperating for some metabolites. This helps us get a more correct (if more complicated!) understanding of how ecology and evolution works.
Reverse ecology is a pioneering new method that is helping us to get an idea of how microbial freshwater species operate around the world.
Most of the bacteria under study are Actinobacteria. This group is interesting because it’s a type of bacteria with an extremely small genome that relies on the community for survival. This means that they’re difficult (currently impossible) to grow in the lab, as we do with yeast cells and E. coli. This is an important point– some of the most important species for us to understand are some of the hardest to study! It brings up a difficult question: What is a “coherent unit” when studying these populations? If a species can’t survive by itself, what context can it survive in? How many species does it need to help it? We can study this by taking a sample of the lakewater and looking at all of the DNA present in that sample. Because we have so much data on genomes compiled by the National Center for Biotechnology Information (NCBI), we can get a sense of how many species are present from metagenomic data. What Dr. McMahon discovered was that there was a lot of genetic variability compared to the reference genome, an example sequence for a particular species. This means that there were plenty of species present, each with their own unique genetics.
So, Dr. McMahon had the difficult task of determining all of the different kinds of species in the sample just from the metagenomic data, and she was able to identify several individual populations. The next question was: how representative is this of other lakes? By comparing the data to other lakes, including one German lake, they found that there was some amount of overlap, but the overlap between lakes was never really perfect. What seems to be the story is that each lake has its own, somewhat unique, metagenome that’s spread out over several species. But the details of how nutrients are handled in each lake are different– because the species community is slightly different. The story here is that there are different ways to make a community work together and succeed.
Over time, the population structure also changes. These communities adapt in short-term cycles to deal with the specific problems of the season and environment. What’s most interesting is that the overall structure of the community changes very quickly, more quickly than we would expect if we only studied one of the species alone. This helps us understand that these communities can respond rapidly to the environment, sometimes in predictable ways. If we can understand the ways that these communities change in response to the environment, we might understand how they will respond to human activity.
This vignette closed with some lingering questions: When do specific populations, exist, and when do they not? What are the relationships between lifestyle and population-level changes? What forces contribute to population expansion? This is an example of a story in progress, which is the usual state of science!
Dr. McMahon started by commenting on her massive respect for the audience members– she follows several on Twitter. She mentioned that any fast talking is due to her nervousness and respect for these audience members! I’ll say that my massive respect for Dr. McMahon explains any points that I don’t take down quickly enough. I’m too captivated by her talk. She largely studies cyanobacteria (marine bacteria that employ photosynthesis), appropriate for a sea-foam green room with green velvet chairs.
Dr. McMahon wants to discuss three vignettes: How can we track microbial populations through time, and what communities are there. Inferring traits from genomes using reverse ecology– this helps us know how bacteria will behave based on their genetic information. And, the hard slog: confirming genetic pathways one at a time to be sure we understand how these microbial populations are really working.
Dr. McMahon focuses her work on Lake Mendota in Wisconsin. In science, big-picture ideas can frequently be both tested and confirmed by work in one location, and this is a classic example of that. The lake is freshwater embedded in an agricultural landscape (emphasizing the importance of this research for human health). From this lake, she has a huge amount of data from over 102 different bacterial genomes found in the lake. Dr. McMahon commented on the different kinds of microbes in the lake, and the first thing to notice is that there are a lot of them! The most common bacteria makes up only around 11% of the community. Ecology is a complicated web of interactions between species, making it difficult to get the whole story. The community changes throughout the year, making it even more difficult. But something that’s helpful is that the top 8 species are always present in every sample, giving some sense of continuity to help with study of the community. The work on these bacteria has helped create the Guide to the Natural History of Freshwater Lake Bacteria— a dense text that sets the groundwork for this kind of study worldwide.
An email with the subject “Air Canada Sucks” is just one example of some last-minute changes happening with the meeting. One of the changes occurred with this session, where Dr. Katherine McMahon will be speaking in place of Peggy Chishom as originally scheduled. The fact that a new speaker was found only three days out is an indicator that this field is amazingly active, with tons of perspectives ready to be shared.
Dr. Katherine McMahon, a professor of bacteriology at Wisconsin, will talk about the kinds of bacteria that live in lakes and their traits that allow us to track their populations. Tracking microbial populations can be very important, as they have huge effects on human health. An example is an algal bloom that left half a million people without drinking water in Ohio. So our ability to monitor and quickly identify dangerous changes in microbial communities is a major public health concern. Dr. McMahon’s website also emphasizes the opportunity for capturing these traits for engineering applications– cleaning water supplies, producing energy, capturing atmospheric carbon, and others. Dr. McMahon specifically focuses on carbon, nitrogen, and other nutrient cycles in lake microbiota and their application to wastewater and freshwater treatment.
“The Electromicrobiome: Ecology, Evolution, and Application”
Derek Lovley, Ph.D.
Editor: Ada Hagan
Blogger: Bryan Moyers
In closing, Dr. Lovley commented that there are several interesting avenues for study here. There are not only deeply interesting biological questions for basic science, but amazing biotechnology applications. Dr. Lovely had ample opportunity for audience questions after his talk, and people were eager to ask.
One audience member commented that they taught anaerobic digestion to engineers, and highlighted the competition between microbe species. For the longest time, these species were thought to be competitors, but this research suggests that there’s some amount of cooperation. An audience member wondered how these findings would affect future explanations of how models of microbial communities interact. Dr. Lovley commented that “the data is the data”, and the narrative we put on these has to change to match the data. Where exactly the future models will land can’t be clear, but he offered some potential explanations.
Another member commented that he knew nothing about the field (a common problem in extensively multi-disciplinary areas). He asked about the different strategies for electron transfer, and the fact that some systems might allow for “cheaters”– organisms that steal electrons from hard-working energy producers with no benefit to the producers. Dr. Lovley commented that this might be okay– producing “stealable” energy is way easier than producing energy through biowires and DIET systems, where a species can protect its investment. There’s a tradeoff between accepting the existence of cheaters or building an entirely new energy infrastructure. Understanding the conditions that favor one strategy over the other might be important for designing microbial communities for microbial fuel cells in the future.
Other questions were asked too quickly to record! But what’s clear is that the talk generated some interesting questions among many audience members. The field, while difficult to understand, has exciting implications for the future.
How did a species evolve a system like this for electron transfer? What would make a biological organism develop wire-like properties that we can then use like modern machines? Because this species evolved in an oxygen-poor environment, it needed a way to transfer energy. We aerobic organisms use oxygen molecules to generate energy by combining the oxygen with carbon to make CO2, and storing the excess energy in the form of ATP. These organisms don’t have that option, since they don’t have oxygen available. This organism “discovered” that by using iron oxides, it could get the same benefit, but it needed a way to transfer the energy taken from the iron oxides to Geobacter cells that weren’t nearby. I would consider this an example of kin cooperation, as helping the community helps yourself. The tools that this bacteria developed were very efficient thanks to millions of years of trial and error, which is why the conductive pili are useful to us today.
How did we track this genus down in the first place? Dr. Lovley’s lab found that electrically conductive microbial communities were largely made up of Geobacter species through the use of metagenomics– taking DNA from a collection of microbes and sorting out which species are present. He then showed that in many settings, the more conductive a microbial community is, the more Geobacter was present. A pretty strong indicator that it was the Geobacter is the source of conductivity. Based on this, Dr. Lovley looked at what genes were active in Geobacter, and found that all of the usual genes involved in transfer of electrons through molecules weren’t expressed. From this, he knew that something else must be going on. Looking closer, he found that only the Geobacter with these interesting pili structures could produce conductivity. It turns out that it these pili were facilitating DIET.
So why do we care about all of this? This process, DIET, is produces a lot of methane, a greenhouse gase and potential source of bioenergy. Understanding this process is not only important for energy production, but also for understanding the nature and future of global warming. Dr. Lovley commented that there are studies that have suggested connections between these anaerobic organisms using DIET, and methane production throughout the world both on land and in oceans. Several studies have established the presence of DIET and its scope in several species at many levels– single-cell studies all the way to large communities.
Given how widespread DIET seems to be, there are many poorly-characterized microorganisms that might be using this mechanism. Dr. Lovley has screened these organisms for DIET and conductivity, finding that several species can produce as much as 14 milliamps, while others produce virtually none. The wide range of microrganisms that have DIET and are conductive (and their relatives that can’t) suggest that some kind of convergent evolution is going on– that is, this is an effective strategy. It’s so effective that different species keep on developing it independently.
So, there’s all this research on where DIET happens and why it occurs… but how can we harness it? It turns out that using granular activated carbon and other inexpensive non-biological materials, we can increase the conductivity of these organisms even further. This increase in efficiency is a major barrier to large-scale implementation of bioenergy strategies. We can also increase efficiency by taking tips from evolution– we can artificially select these communities, specifically culturing communities that are more conductive to select for efficiency. This optimization of conductivity is important for creating microbial fuel cells, which are essentially batteries that take advantage of the bacteria’s ability to generate electrons from the degradation of sewage or other biological materials.
Aide from producing energy, what can we use this knowledge and mechanism for? Well, it turns out that we can combine energy production with water treatment plants. These bacteria don’t *just* use iron oxides to produce energy, but they eat up a lot of other metals, like uranium, and organic substances. This system could be used for groundwater cleansing for human and agricultural use. Dr. Lovley mentioned some interesting Nature reviews discussing these various uses.
Finally, another exciting application is the creation of biowires. Dr. Lovley suggested that synthetic biowires, with proper genetic manipulation, might have 5000 times higher conductivity than the natural pili biowires. They would be highly durable and even potentially self-repairing wires.
Dr. Lovley started by ensuring that all of the equipment was working correctly, setting the stage for his experience and expertise with technology. Unfortunately, shortly after Powerpoint crashed, emphasizing that there are always unforeseen difficulties in these realms.
His talk began with an image of red and green dots, explaining that the colors referred to different species. He explained that these species worked together to move electrons, an important process for us to harness these organisms for energy. But these efforts require many efforts and steps. Metagenomics, synthetic communities of organisms, proteomics and protein structure studies. The list went on! This area requires a large range of expertise, and presents special difficulties for the future.
Dr. Lovley then moved on, commenting on the many ways that microbes can share electrons and the studies that established this knowledge. Sharing and moving of electrons is a key part of using microbes for energy productions. The first way is by sharing electron-carrying molecules, such as H2, between species. But the second, perhaps more exciting, is DIET– Direct Interspecies Electron Transfer, which relates to microbial nanowires.
Microbial nanowires– now called electrically conductive pili— are small extensions from bacteria that have special molecules for quickly transporting electrons up and down the pili, and even to the pili of another organism. These pili, and the connections between pili, make a very conductive material. Just like a metal wire that we might use. In fact, these structures have been compared to carbon nanotubes. Dr. Lovley even showed a visualization of charge moving along one of these pili. In the case of Geobacter species (one of the most common anaerobic bacteria being studied in this area), PilA is a protein that has special properties which is important for the conductivity of these pili. Geobacter has a special mutation in this protein that is not found in other species, giving it these special properties.
We’ve known since 1911 that microbes could be used to produce energy. A major advantage of this approach is that bacterial cells could be used to perform multiple jobs, such as cleaning water while providing energy. But the technology hasn’t taken off because it’s difficult to get a system efficient enough to match modern fuel needs: the microbes present in a water treatment plant serving 100,000 people could only provide enough energy for 500 homes. Is there a future for microbial fuel cells?
Derek Lovley, a Distinguished Professor of Microbiology and the Associate Dean of the College of Natural Resources at the University of Massachusetts, researches anaerobic microorganisms, those that live in low (or no)-oxygen environments and are the major microbes being researched to create energy. Dr. Lovley’s talk is on the electromicrobiome, how microbes in this realm interact and evolve, and how we can take advantage of this knowledge.
Opening Remarks by Mark Schlissel, Ph.D.
Editor: Ada Hagan
Blogger: Bryan Moyers
Mark Schlissel, President of the University of Michigan, offers some opening remarks. As a university president, Dr. Schlissel is familiar with big-picture questions. But as a medical doctor with a research background in microbiology, he offers a unique view for this conference.
Dr. Schlissel commented on the interesting topics that have been selected for past Michigan meetings– such as science communication– and that the wide-reaching, multidisciplinary nature of this conference is very in line with that theme. The fields of medicine, geology, oceanography, and evolution, among many others, are all related to this realm.
This multidisciplinary nature makes engagement with the community key. Dr. Schlissel commented on his excitement that this conference would be live-blogged and -tweeted. He further noted that it’s extremely important for experts to be vocal in this realm to avoid being “trumped” by political voices with more agenda than knowledge.
With the current political climate, Dr. Schlissel worries that the importance and benefits of public universities is being overlooked. He spoke about views from a politician friend that many think universities should only be teaching institutions, not generators of knowledge and sources of politically-relevant information and discussions.
Finally, Dr. Schlissel gave us some perspectives on the history of microbiology and its relationship to our situation today. Avery, McCarty, and MacLeod were microbiologists who, along with Hershey and Chase, conclusively showed that DNA was the hereditary material. Microbiologists were pivotal in showing the role of DNA in inheritance, the impetus for the field of genetics.
Jacob and Manod were microbiologists who worked with the lac operon, a well-known system in gene regulation. The work on lambda phage was performed by a microbiologist, and was key to understanding virology. Dr. Schlissel comments that this work on lambda phage were what made him focus more on research than applied medicine– it’s that exciting and interesting. The central dogma of molecular biology: that DNA is transcribed to RNA, which is translated to protein, was all made clear by microbiologists. A fundamental tool in biotechnology, restriction enzymes for cutting DNA in specific locations and stitching particular sections of DNA together, were discovered and harnessed first by microbiologists. This was valuable information learned from research studying “bacterial sex”, yes, grants for studying bacterial sex… Something to consider the next time you think a research grant sounds silly! The first work done on sequencing DNA used E. coli, perhaps the canonical model organism in microbiology, and even the enzyme we use in sequencing work called Taq polymerase was discovered in microbiology. The person who discovered this, Kary Mullis, won the nobel prize. Finally, one of the most recent biotechnology tools, the CRISPR/Cas9 system, was discovered when researching microbial immunity to viruses. It’s difficult to find an area of biology that isn’t touched on by microbiology.
Of course, when we think of microbiology, we typically think of medicine. This goes back to the Germ Theory of Disease and Robert Koch’s Postulates. Antibiotics were discovered through microbiology, and have revolutionized all of modern life. Vaccination was first developed in the 1700s by Edward Jenner. Vaccination has completely wiped out smallpox for some time, and has reduced the incidence of several other diseases profoundly.
The talks in the next few days will build on all of these findings. But it’s important to see that some of the most profound discoveries and advances in technology have been spawned from studies that only wanted to understand basic biology. It was curiosity, not only drive for improving life, that caused these wonderful discoveries.
“Should We Accelerate Efforts to Manage Naturally Occurring Microbiomes”
Thomas Schmidt, Ph.D.
Editor: Ada Hagan
Blogger: Bryan Moyers
The conference opened with several examples of major new findings in microbiology. The number of necessary genes for a microbe is now known to be fewer than 500. Advances in the understanding of the mosquito Aedes aegypti, the bacterium Wolbochia, and its relationship to Zika are clearer. Microbial fuel cell development is expanding. With everything going on, this meeting is quite timely!
Dr. Schmidt notes that the National Microbiome Initiative has noted that “Scientists still lack the knowledge and tools to manage microbiomes in a manner that prevents dysfunction or restores healthy function.” Despite the major advances, there is a national push to improve our understanding. In 2016 and 2017, currently over $121 million are committed to research to improve the state of the field.
Dr. Schmidt noted that the history of the University of Michigan is tied to microbiology. Dr. Salk announced the Polio vaccine at the University of Michigan, and Michigan has been pioneering in the use of fecal transplants for Clostridium difficile treatment. Such transplants might eventually be used to help with weight loss. But these major issues underscore the importance of the question: What should the limitations and regulation of manipulating microbiomes be? What are the benefits, barriers, and trade-offs in this realm?
These remarks set the stage for the coming three days of presentations and conversations. The conversational nature of this conference is meant to spark fruitful discussion and lasting collaboration. As exciting as this new field is, there are plenty of opportunities for learning and growth from many areas of biology.
Should we be messing around with the microbes in our bodies? There are as many of them inside us as there are our own cells. Messing with them could be dangerous. But it might also produce some powerful results. Fecal Transplants are being used in attempts to help treat difficult infections in humans by introducing different microbes and they might also be used for weight loss. Microbes can have huge effects outside the human body, such as on the presence of important greenhouse gases, and managing these microbes might help us mitigate the damage of climate change. There seem to be great rewards to manipulating microbial ecosystems, but what are the risks?. Dr. Thomas Schmidt is opening the conference by approaching this question: should we accelerate efforts to manage naturally-occurring microbiomes?
Thomas Schmidt, a professor in Microbiology and Internal Medicine at the University of Michigan, is in a unique place to answer this question. Dr. Schmidt studies interactions in the metabolism of microbes in soil and in the human gut, and how small changes, such as the amount of oxygen present, can cause population explosions in microbes. Dr. Schmidt uses his understanding of ecology, biochemistry, and microbiology to study how these small metabolic changes work.
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