Why It's Time to Map the Microbiome

The group's goal is to develop next-generation technologies to unlock the secrets of microbiomes, complex ecosystems of microorganisms – from bacteria and viruses to algae and fungi – that inhabit nearly every square inch of the planet and have densely colonized our bodies.

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

But to achieve that, researchers 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. And they need instruments to further study microbial genomes and the chemical signals microorganisms use to communicate, as well as new computer science tools to analyze the data these techniques produce.

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 and its effect human health and development. He holds appointments at the University of California, San Diego School of Medicine and Department of Computer Science and Engineering, where he develops bioinformatics systems to classify and interpret large sets of biological data.
• Janet Jansson – is chief scientist of biology in the Earth and Biological Sciences Directorate at Pacific Northwest National Laboratory (PNNL) and sector lead for PNNL research in the Department of Energy's Biological Systems Science Division. She coordinates two of PNNL’s biology programs: the Microbiomes in Transition (MinT) initiative to study how climate and environmental changes impact natural and human microbiomes and the DOE Foundational Scientific Focus Area, Principles of Microbial Community Design.
• Jeff F. Miller – is director of the California NanoSystems Institute, a multidisciplinary research organization, and the corresponding author of the consortium’s Science paper. Based at University of California, Los Angeles, Miller holds the Fred Kavli Chair in NanoSystems Sciences and 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 about 10 times more microbial cells in and on our bodies than we have human cells, and those microbes encode about 100 times more genetic information than our human DNA. Microbes are also everywhere in the environment, where they carry out such important processes as cycling carbon and other nutrients, promoting plant growth, and preventing disease.

Jeff Miller: Microbiomes also 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 big questions is whether they will begin converting vast amounts of carbon in the permafrost into carbon dioxide, methane and other greenhouse gases. At a time when we are talking about 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 change our diet to alter our microbiome.

Moreover, we're born with our human genes, but our microbes continue to change 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 and a society.

Miller: 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 about metabolic syndrome, type 2 diabetes, inflammatory bowel disease, autism and other conditions? There's so many unknowns that are likely to have a tie to the microbiome and its interaction with the environment.

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

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

Knight: Right. DNA sequencing has got 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 and 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 and environmental applications. We are calling for a unified initiative to bring together different fields of research, government agencies, private enterprise and private foundations to make that possible.

"We have about 10 times more microbial cells in and on our bodies than we have human cells, and those microbes encode about 100 times more genetic information than our human DNA."—Janet Jansson

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

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

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

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

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

Jansson: 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.

Miller: Actually, digoxin is a perfect example of what Janet is talking about. It is a heart drug that can be metabolized and destroyed by certain microbes that live in some human gastrointestinal microbiomes but 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, and infused into someone who lacks a protective microbiota in their gut and has C. difficile disease. The treatment is between 85 and 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.

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 and computer scientists. What did they contribute?

Jansson: What's important here, at least to me, is that a community composed of many different disciplines realizes the importance of the microbiome and is calling for us to do something on a grand scale. For example, I’ve been advocating for improved mass spectrometry to get higher throughput measurements of proteins and metabolites, the molecules microbes use to interact with their environment. We also 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 refer to as the worst-case scenario. It's one of the most diverse microbial environments. The cells live in dense communities and aggregate around soil particles and pores. We can tell what kind of microorganisms are there by sequencing their genes, but we lose all that spatial information about where they live in the soil matrix. It is a really difficult habitat to study, but an extremely interesting and important one.

Knight: Physicists bring quantitative techniques they have perfected for understanding dynamical systems. Engineers want to use that knowledge to control and 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, and on different scales.

Miller: Exactly. And while, as Rob mentioned, the quantitative sciences are extremely important, we are also going to need people to commercialize these discoveries, as well as ethicists and legal experts.

"Many people attribute obesity to lack of willpower, but what if it's primarily based on your microbes? Where is the boundary between what's an intrinsic attribute of 'you' versus what's an attribute you 'have' based on your microbes?"—Rob Knight

TKF: Why ethicists and legal experts?

Miller: 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 and so dynamic, we need to ensure we understand it well enough to justify that manipulation. It is an exciting prospect, and also a somewhat daunting one.

Knight: There are also 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, and on your plants? If researchers begin to extract commercial value from the microbiome, we need to pay much more attention to those issues.

Jansson: Then there is an issue of personal microbiome integrity. Our microbiomes are like fingerprints, and some researchers are studying them for forensic applications. Will this have the potential to infringe on our own personal identity, and 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?

Knight: 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 also 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 and ethicists are going to have a lot to discuss, and valuable contributions to make.

Miller: That's why we have to be really careful about 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?

Knight: 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 and brain development. While the links between the microbiome and metabolism have certainly been very surprising, what surprised me the most has been the links between the microbiome and behavior. This was not even on the radar 10 years ago.

TKF: Could you give us an example?

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

"The idea of potentially engineering Earth’s microbial ecosystems raises very legitimate questions. The prospect for doing harm is there."—Jeff Miller

TKF: Jeff, you study microbial evolution and diseases. Will Rob’s research help move your work forward?

Miller: 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 and incoming disease-causing organisms behave.

I'm also 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 and 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 about the gut. What about you, Janet? Is this work going on in the human gut relevant to your studies of microbiomes in permafrost and on beaches after oil spills?

Jansson: Compared to what we have learned about human microbiomes over the past decade, we are further behind in understanding complex environmental microbiomes. Those answers are important because we don’t understand how our climate will change when those permafrost microbes begin 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, but 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?

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

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

Miller: I'm a molecular biologist, and I like to study molecular mechanisms. I've been waiting for tools that us me not only characterize the organisms in microbiomes, but run controlled tests to see how they behave when we change only one variable at a time.

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

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

Knight: 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, and what this looks like in a living environment.

Jansson: My team is actually working with Rob, and we have different kinds of data sets. When you're dealing with millions of genes and thousands of proteins and 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?

Jansson: I've mentioned tracking metabolites and proteins, but our goal is to understand how microbes occupy different metabolic niches and then communicate with other microbes to get their needs met. When I first heard Jeff talk about his research, I started thinking about some of the networks and keystone species that we see. I had an "ah-ha" moment, and 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 about it if I hadn't met Jeff.

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

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

Miller: 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?

Knight:I think we'll have much better ways to diagnose disease and 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 and interactions. I think we'll make substantial progress towards harnessing microbes to improve industrial processes in the energy sector and to remediate depleted farmland.

Jansson: 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 also interested in designer diets. This is a personal interest. Our whole family got our microbiomes sequenced. We got a family discount, and it only cost something like $49.99 per person. So when we got our microbiomes back, we noticed that all of us fell into the normal range, except one of my daughters. She has a lot of Firmicute bacteria, which make it harder for her to maintain her weight. While she looks great, she has to think about 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."

Miller: Isn't the cure to that to eat complex sugars?

Jansson: Right, but 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 and butter. This is a practical application of how we should think about modifying our microbiomes, and I think that designer diets to achieve different types of results could be possible within a 10-year horizon.

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

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

We can also start to get 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 and 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 get 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 about yet, but microbiomes have a major influence on plant yield, water usage, carbon availability and sequestration. We would like to use less fertilizer and fewer pesticides, and to grow crops in regions impacted by climate change. It's hard to say whether that is five, 10, or 15 years off, but they seem like tractable problems.