Why It's Time to Map the Microbiome (Kavli Roundtable)

Alan Brown, writer & editor for The Kavli Foundation, edited this roundtable for Live Science's Expert Voices: Op-Ed & Insights.

Microbes make life on Earth possible, yet we know so little approximately them. Now, a team of scientists aim to alter that through an ambitious effort — with researchers from 50 institutions — called the Unified Microbiome Initiative. 

Their goal is to develop next-generation technologies to unlock the secrets of microbiomes, complex ecosystems of microorganisms — from bacteria & fungi to algae & viruses — that inhabit nearly every square inch of the planet & have densely colonized our bodies. 

p> Doing so, the scientists argue, could improve human health & the environment. Harnessing microbiomes could cure disease, reduce resistance to antibiotics, rejuvenate depleted farmland, moderate fertilizer & pesticide use, & convert sunlight into useful chemicals. 

But to achieve that, scientists will need a new generation of research tools to take them beyond just cataloging the members of these microbial communities, which may contain tens or even hundreds of thousands of individual species. Researchers need instruments to further study microbial genomes & the chemical signals microorganisms use to communicate, as well as new computer science tools to analyze the data these techniques produce.

On October 27, The Kavli Foundation spoke with three of the scientists who authored the Unified Microbiome Initiative proposal, which appeared the next day in the journal Science.

The participants were:

Rob Knight is the founder of the American Gut Project, an open-access project to survey the digestive system's microbiome & its effect human health & development. He holds appointments at the University of California, San Diego, School of Medicine & Department of Computer Science & Engineering, where he develops bioinformatics systems to classify & interpret large sets of biological data.

Janet Jansson is chief scientist of biology in the Earth & Biological Sciences Directorate at Pacific Northwest National Laboratory (PNNL) & sector lead for PNNL research in the U.S. Department of Energy (DOE) Biological Systems Science Division. She coordinates two of PNNL's biology programs, including the Microbiomes in Transition (MinT) initiative to study how climate & environmental changes impact natural & human microbiomes & the DOE Foundational Scientific Focus Area.

Jeff Miller is director of the California NanoSystems Institute, a multidisciplinary research organization, & the corresponding author of the consortium's Science paper. Based at University of California, Los Angeles, Miller is the chair in NanoSystems Sciences & is a professor of Microbiology, Immunology & Molecular Genetics.

The following is an edited transcript of their roundtable discussion. The participants have been provided the opportunity to amend or edit their remarks.

The Kavli Foundation: Let's start with the obvious question: Why is there so much interest in the microbiome right now?

Janet Jansson: We live in a microbial world. In fact, we are more microbial than human. We have approximately 10 times more microbial cells in & on our bodies than we have human cells, & those microbes encode approximately 100 times more genetic information than our human DNA. Microbes are moreover everywhere in the environment, where they carry out such significant processes as cycling carbon & other nutrients, promoting plant growth, & preventing disease.

Jeff Miller: Microbiomes moreover have an enormous impact on the environment. Janet's work on permafrost, the Arctic's permanently frozen subsurface soil, shows that. As the climate warms, the metabolism of microbes in the permafrost will speed up. One of the huge questions is whether they will commence converting vast amounts of carbon in the permafrost into carbon dioxide, methane & other greenhouse gases. At a time when we are talking approximately Middle Eastern cities becoming too hot to inhabit by the end of the century, understanding how those microbiomes influence climate is important. 

Also, as Janet noted, we have 100 to 150 times more microbial genes than human genes in our bodies. Changing our own genome is a daunting prospect. But we can alter our diet to alter our microbiome.

Rob Knight: That is true. For many aspects of who we are, microbial genes may be even more significant than our human genes. For example, we can tell if you're lean or obese with 90 percent accuracy based on your microbial genes, yet with only approximately 58 percent accuracy based on your human genes. So the three pounds of microbes you have inside your gut may be more significant for some of your traits than every gene in your genome.

Moreover, we're born with our human genes, yet our microbes continue to alter over the course of our life. If we're able to take control of these changes, whether within our bodies or over our entire planet, we could have a huge impact on many of the problems facing us as individuals & a society. [Friends for Life: How Good Bugs Keep You Healthy (Op-Ed)]

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When ice-rich permafrost thaws, former tundra & forest turns into a thermokarst lake as the ground …

J.M.: Some of today's health mysteries might have a link to the microbiome. Why has asthma increased so dramatically over the last 50 years? Why is obesity such a problem? What approximately metabolic syndrome, type 2 diabetes, inflammatory bowel disease, autism & other conditions? There are so many unknowns that are likely to have a tie to the microbiome & its interaction with the environment. 

TKF: Microbiomes are clearly important, yet we weren't talking approximately them 10 years ago. What's changed & why is this the right time for the Unified Microbiome Initiative?

J.J.: I was trained as a soil microbial ecologist, & we never used to call these soil communities a "microbiome." But we do now. It's a term coined by clinical microbiologists, & it originated with the advent of "high-throughput" genome sequencing technology. This is something Rob can discuss in detail.

R.K.: Right. DNA sequencing has received a million times cheaper — literally — over the last 15 years. High-speed automated equipment can speed read a genome for less than $1,000. This has really catalyzed our ability to discover patterns in microbial communities. Yet we are far less able to understand how those microbes function — what they provide or add to their community. 

What we need next is a game-changing technological advance that increases our ability to read out microbial functions at different scales. Those might range from the inside of one cell up to the size of our entire planet, using satellites & other remote sensing technologies, for example. 

We want to catalyze the next series of tools to fully realize the potential of the microbiome for healthcare, agriculture & environmental applications. We are calling for a unified initiative to bring together different fields of research, government agencies, private enterprise & private foundations to make that possible. 

TKF: Let's delve a little deeper into the impact of advances in genome sequencing. Has it changed the way we think approximately microbial communities?

J.J.: In the past, we did not fully understand the complexity & richness of microbiomes, & we were limited because we could not grow the majority of bacteria in a lab, & so they were complex to study. Now, because of the advances in sequencing, we can classify the composition of these communities based on sequence information. This has led to the discovery of hundreds of new bacterial phyla, large groups of related life forms, many times more phyla than all the phyla of multicellular animals in the world. That gives us a window, for the first time, into who is there. But as Rob was saying, in most cases we don't know what they're doing. That's what the next stage of technology would do, let us tackle their functions.

J.M.: Knowing who's there is really complicated, because microbiomes differ from person to person & even for a given person, depending on time, environment, life events & other factors. Understanding what constitutes a normal human microbiome is enormously complex, especially since communities may have similar properties yet different compositions. All this raises the question, "What is a healthy microbiome?" 

R.K.: There is no one healthy microbiome, but, rather, there are many different healthy microbiomes. The problem is figuring out how to obtain a handle on all that diversity. We can collect lots of samples & quantify the differences in one person's microbiome over time, between different people, & between people with different ethnic backgrounds, environmental exposures, & medical conditions. We're moving rapidly towards understanding which changes in the microbiome really matter, especially for health, & which changes are more or less random variations. 

With so much data, we need machine learning & other high-end statistical techniques to try to make sense of the vast flood of data that we're getting from DNA sequencing & from other techniques, such as mass spectrometry, which measures proteins & chemicals.

TKF: As our understanding increases, are researchers rethinking how we might harness the potential of microbiomes? 

J.J.: Yes. For example, we hope to take advantage of each person's unique microbiome to produce more personalized medicine. We want to understand how the way your microbiome metabolizes medications differs from your neighbor's microbiome. For example, one person's microbiome might have an adverse reaction to a specific drug, while another's does not. 

J.M.: Actually, digoxin is a perfect example of what Janet is talking about. It is a heart drug that can be metabolized & destroyed by certain microbes that live in some human gastrointestinal microbiomes yet not others. 

Also, over the past two or three years, we have seen the first medical intervention for a serious disease that is based on crude, though extremely effective, microbiome engineering: fecal transplant therapy for colitis, an inflammation of the large intestine caused by the bacterium Clostridium difficile, which is normally excluded by our gut microbiomes. 

This is how it works: We excrete part of our microbiome with our feces. So a fecal sample is taken from someone with a "healthy" gastrointestinal microbiome, processed, & infused into someone who lacks a protective microbiota in their gut & has C. difficile disease. The treatment is between 85 & 95 percent effective for recurrent disease, compared with 20 to 30 percent for the very best antibiotics that we have. This is actually the first proof of principle that we can manipulate microbiomes in a very deliberate way to treat a serious human disease.

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Photomicrograph depicting the siliceous frustules of fifty species of diatoms arranged within a circ …

TKF: The Unified Microbiome Initiative calls for bold research to develop transformative tools. Instead of talking only with microbiome experts, you put that agenda together with physicists, engineers, chemists & computer scientists. What did they contribute?

J.J.: What's significant here, at least to me, is that a community composed of many different disciplines realizes the importance of the microbiome & is calling for us to do something on a grand scale. For example, I've been advocating for improved mass spectrometry to obtain higher throughput measurements of proteins & metabolites, the molecules microbes use to interact with their environment. We moreover need better databases, so we can understand how those molecules function in a spatial context. And we need improved imaging technologies. 

I need all of these things to study soil microbiomes, which I usually pertain to as the worst-case scenario. It's one of the most diverse microbial environments. The cells live in dense communities & aggregate around soil particles & pores. We can tell what kind of microorganisms are there by sequencing their genes, yet we lose all that spatial information approximately where they live in the soil matrix. It is a really difficult habitat to study, yet an extremely absorbing & significant one.

R.K.: Physicists bring quantitative techniques they have perfected for understanding dynamical systems. Engineers want to use that knowledge to control & manipulate the microbiome to achieve particular results. And, as Janet noted, they are the ones who will develop new technologies to read out the microbiome better, faster, cheaper, more precisely & on different scales.

J.M.: Exactly. And while, as Rob mentioned, the quantitative sciences are extremely important, we are moreover going to need people to commercialize these discoveries, as well as ethicists & legal experts.

TKF: Why ethicists & legal experts?

J.M.: Whenever we manipulate something in an animal or a human being, we need to consider the ethical issues. But the idea of potentially engineering Earth's microbial ecosystems raises very legitimate questions. The prospect for doing harm is there. With something so complex & so dynamic, we need to ensure we understand it well enough to justify that manipulation. It is an thrilling prospect, & moreover a somewhat daunting one. 

R.K.: There are moreover intellectual property considerations. For example, if we isolate a microbe from your body, do you own it? Does it matter if it is unique to you, or if millions of other people share that same strain? Similarly, do you own the microbes in your home, in the soil of your garden, & on your plants? If researchers commence to extract commercial value from the microbiome, we need to pay much more attention to those issues. 

J.J.: Then there is an issue of personal microbiome integrity. Our microbiomes are like fingerprints, & some researchers are studying them for forensic applications. Will this have the potential to infringe on our own personal identity, & how do we protect our identities if it does? That's an issue to consider.

TKF: To what extent are our microbiomes part of our identities?

R.K.: That's a really fascinating question. For example, many people attribute obesity to lack of willpower or some other intrinsic feature of the person. But what if it's primarily based on your microbes rather than on your ability to resist that extra slice of chocolate cake? There is moreover new evidence that the microbiome might determine whether you are depressed or happy, or have certain forms of mental illness, or even whether you prefer one food to another.

Where is the boundary between what's an intrinsic attribute of "you" versus what's an attribute you "have" based on your microbes? Philosophers & ethicists are going to have a lot to discuss, and valuable contributions to make. 

J.M.: That's why we have to be really careful approximately manipulating our microbiomes, so we don't create pathological situations.

TKF: Let's switch gears for a moment. Rob, what has surprised you most over the past decade of microbiome research?

R.K.: Remember, 10 years ago, microbes hadn't been linked to any of the things we now know they're involved in, such as obesity, allergies, depression & brain development. While the links between the microbiome & metabolism have certainly been very surprising, what surprised me the most has been the links between the microbiome & behavior. This was not even on the radar 10 years ago. 

TKF: Could you donate us an example? 

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such neurological diseases as Alzheimer's & Huntington's diseases. In an effort to underst …

R.K.: Yes. Paul Patterson, Sarkis Mazmanian & Elaine Hsaio of Caltech injected pregnant female mice with RNA to simulate a viral attack, & their pups were born with behaviors characteristic of autism in humans, such as cognitive & communications deficits & compulsive behaviors. They then treated them with microbes isolated from the human gut & cured many of those symptoms. They then introduced a chemical isolated from the mother mouse's microbiome & the symptoms reappeared. 

My research group is working with researchers at the University of Colorado to test the ability of microbes to inoculate mice against social stress. While the links between the microbiome & human behavior are much less clear, the fact that we can find these links in mice establishes that there is a plausible biological mechanism. It certainly motivates the human research.

TKF: Jeff, you study microbial evolution & diseases. Will Rob's research assist move your work forward? 

J.M.: I'm kind of the outsider here, since I study the molecular mechanisms by which bacteria cause infection. Yet I'm interested in how the microbiome changes how resident & incoming disease-causing organisms behave. 

I'm moreover interested in some of the technologies that could arise from the Unified Microbiome Initiative. Precision antibiotics is one example. One of the problems with drug resistance is that we use broad-spectrum antibiotics that harm beneficial microbes as they kill disease-causing pathogens. Any microbes that survive pass on their antibiotic resistance. 

Now, the Unified Microbiome Initiative Consortium is interested in therapeutics that will specifically target one & only one species or strain, so researchers can run experiments to see how our complex microbiota functions without them. But we could use those same reagents to treat infectious diseases, perhaps preventing some of the consequences of broad-spectrum antibiotic use. 

TKF: You see a link, Jeff. But so far, we've only talked approximately the gut. What approximately you, Janet? Is this work going on in the human gut relevant to your studies of microbiomes in permafrost & on beaches after oil spills?

J.J.: Compared to what we have learned approximately human microbiomes over the past decade, we are further behind in understanding complex environmental microbiomes. Those answers are significant because we don't understand how our climate will alter when those permafrost microbes commence to warm up. We need to know if that microbiome is going to pump greenhouse gases into the atmosphere or store them in the soil.

But going back to what Jeff was talking about, once we understand these environmental processes, we would want to design microbial communities that could fill an environmental function. I see that as a future goal, yet we first need to understand how those interactions work in nature. We don't know that yet.

TKF: For your research, what types of tools are your priorities? 

J.J.: I need tools for high-throughput 'omics. 

TKF: When you say 'omics, you mean something more than just genomics, right? 

J.J.: So specifically, I mean high-throughput proteomics & metabolomics, tools that measure the proteins & the small molecules produced by cells & used for their communication. Also, I need better databases & algorithms to store & interpret the data this equipment produces. They're parallel concerns, & they are both huge bottlenecks right now. 

J.M.: I'm a molecular biologist, & I like to study molecular mechanisms. I've been waiting for tools that not only characterize the organisms in microbiomes, yet run controlled tests to see how they behave when we alter only one variable at a time. 

We need a way to visualize dynamic communities living in their normal habitat, with their complexity preserved & with minimal perturbation. We moreover need to observe them over a time scale that lets us see who is there & how they interact with one another & with their environment. 

Technologies that work precisely to delete or add organisms to a microbiome, or alter their genes without having to cultivate them would be enormously valuable. Developing those precision tools appeals to me from the perspective of pure science, & I believe they will eventually enable us to manipulate microbiomes to achieve beneficial outcomes.

R.K.: I agree with Janet, we need better algorithms to interpret the data. We can already survey the genomes of organisms in a microbiome to see who is there. You could imagine improving those algorithms to capture more spatial data over time, so we understand which microbes are influencing the behavior of others, & what this looks like in a living environment.

J.J.: My team is actually working with Rob, & we have different kinds of data sets. When you're dealing with millions of genes & thousands of proteins & hundreds of thousands of metabolites, it's challenging to integrate all that data in ways that provide a picture of what's really happening in the microbiome.

TKF: So you are interested in tracking chemical communications?

J.J.: I've mentioned tracking metabolites & proteins, yet our goal is to understand how microbes occupy different metabolic niches & then communicate with other microbes to obtain their needs met. When I first heard Jeff talk approximately his research, I started thinking approximately some of the networks & keystone species that we see. I had an "ah-ha" moment, & realized we could use some of Jeff's tools to knock out different nodes in these networks in order to test some of our hypotheses. I wouldn't have thought approximately it if I hadn't met Jeff. 

TKF: So just working on this proposal with Jeff & other researchers has changed how you might do research?

J.J.: Absolutely. I mean, I've been feeling like a kid in a candy store. It's been fantastic.

J.M.: I think that's a trend in science in general. As we break out of our silos, we realize that there's so much more to be gained by interacting with colleagues in areas that you might not have interfaced with before.

TKF: The Unified Microbiome Initiative proposes an ambitious tool development agenda for the next 10 years. Where do you think it will lead?

R.K.: I think we'll have much better ways to diagnose disease & perhaps new therapeutics for the large number of microbiome-related diseases. I believe we're going to develop very general technologies that impact a broad range of different microbial processes & interactions. I think we'll make substantial progress towards harnessing microbes to improve industrial processes in the energy sector & to remediate depleted farmland. 

J.J.: If we're looking out 10 years, I would like to work on developing better data on vulnerable microbial ecosystems. I want to know how they react when we reach a tipping point, such as a permafrost thaw or rising seawater levels, so we can predict the impacts of climate change. 

I'm moreover interested in designer diets. This is a personal interest. Our whole family received our microbiomes sequenced. We received a family discount, & it only cost something like $49.99 per person. So when we received our microbiomes back, we noticed that all of us fell into the normal range, except one of my daughters. She has a lot Firmicute bacteria, which make it harder for her to maintain her weight. While she looks great, she has to think approximately it more than the rest of us. On the other hand, if she ever has a problem, she can always say, "It's not me, mom, it's my Firmicutes."

J.M.: Isn't the cure to that to eat complex sugars? 

J.J.: Right, yet her microbes don't want to eat them. Her microbiome is sending signals to her brain that they don't want to eat that. They want to have bread & butter. This is a practical application of how we should think approximately modifying our microbiomes, & I think that designer diets to achieve different types of results could be possible within a 10-year horizon.

TKF: What approximately the next 10 years for you, Jeff?

J.M.: Within five years, I think it's reasonable to expect to have precision antimicrobials for bacteria that cause tooth decay & periodontal disease. 

We can moreover start to obtain a handle on how to prevent infectious diseases of immunosuppressed patients in hospitals. For people getting an organ or bone marrow transplant, for example, we suppress their immune systems & put them on antibiotics. Some studies show that if we look at the microbiome of their stool, using the same $49 technique Janet used to sequence her family's microbiomes, we can obtain predictive, actionable information on the bacteria  that are likely to cause serious bloodstream infections before those infections occur. If we can combine that with precision antimicrobials, we might be able to deal with the threat without disrupting their beneficial microbiota. 

Agriculture's another area we haven't talked approximately yet, yet microbiomes have a major influence on plant yield, water usage, carbon availability & sequestration. We would like to use less fertilizer & fewer pesticides, & to grow crops in regions impacted by climate change. It's complex to say whether that is five, 10, or 15 years off, yet they seem like tractable problems.

Follow all of the Expert Voices issues & debates — & become part of the discussion — on Facebook, Twitter & Google+. The views expressed are those of the author & do not necessarily reflect the views of the publisher. This version of the article was originally published on Live Science.

The Nanotech View of the Microbiome (Kavli Roundtable) Body Bugs: 5 Surprising Facts About Your Microbiome Can Microbes in the Gut Influence the Brain? Copyright 2015 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.ScienceBiologyThe Kavli Foundation

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