Uniting Diverse Sciences to Tackle the Microbiome

BACTERIA AND OTHER MICROBES interact in diverse populations everywhere from the human gut to the oceans. Scientists are eager to understand these communities, called microbiomes, in the hopes of benefiting human health, feeding the planet and protecting the environment.

Governments, within and beyond the United States, have picked up on the microbiome excitement, too. In May, the White House Office of Science and Technology Policy announced the National Microbiome Initiative, a collaboration between several federal agencies, universities and private foundations. Its goals are to support microbiome research, get the public involved in the project, and develop new technologies to study microbe communities.

Those new technologies are critical. Right now, there is a dearth of tools to help us learn about microbes in groups. Scientists can use DNA sequencing to identify the microbes in a community, but lack the techniques to go much beyond that census. The Kavli Foundation’s $1-million Microbiome Ideas Challenge, launched in support of the national initiative, will provide funds for scientists to start inventing the new tools they need.

It’s not just a job for scientists who study microbes. That’s why The Kavli Foundation has asked the American Society for Microbiology, in conjunction with the American Chemical Society and American Physical Society, to select the most promising, interdisciplinary groups working on tools that could help microbiome research. The Foundation will announce the winners, who will receive funding to take their ideas further, later this year.

The Kavli Foundation spoke to three of the six scientists on the Scientific Advisory Board for the Kavli Microbiome Ideas Challenge, each representing a different scientific discipline. In the roundtable, they discussed the importance of the microbiome, the necessity for collaboration across different fields of science and where they hope the science is leading.

The participants were:

• TIM DONOHUE – Director of the Great Lakes Bioenergy Research Center, Donohue s a Professor of Bacteriology and the UW Foundation Chairman Fetzer-Bascom Professor at the University of Wisconsin-Madison
• JULIE BITEEN – Assistant Professor of Chemistry at the University of Michigan, Biteen is also affiliated with the university's Biophysics, Applied Physics, and Chemical Biology programs.
• TERRY HWA – Co-director of the Quantitative Biology PhD Specialization at the University of California, San Diego, where he is a Presidential Chair Professor in the Department of Physics. He also holds a joint appointment as Professor in the Division of Biological Sciences and is a Distinguished Visiting Professor at the University of Hong Kong.

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: The study of microbes is hardly new, but most scientists study one type at a time, growing in the lab. What kinds of things are they missing by not looking at the bigger picture of a microbiome?

Tim Donohue, Director of the Great Lakes Bioenergy Research Center; Professor of Bacteriology and the UW Foundation Chairman Fetzer-Bascom Professor at the University of Wisconsin-Madison. (Credit: Matt Wisniewski, Wisconsin Energy Institute) .

TIM DONOHUE: They’re missing out on all the interactions that happen in the group—just like a family interaction is very different from an individual sitting alone in his or her bedroom. They’re also missing out on how those interactions determine where these organisms can live, and what other microbes can live in the same neighborhood, whether it’s the soil or the oceans or an animal or a human body.

JULIE BITEEN: One of the big gaps is that we tend to study bacteria that we know how to handle in the lab. For example, we’re a lot better at studying bacteria that grow in air compared to bacteria that need a special environment because they can’t live in oxygen. And we know a lot more about bacteria that we can actually grow in a test tube rather than bacteria with more specialized needs. Most bacteria, in fact, don’t grow well in the lab. We need tools to study microbes in the wild, where they do live in groups.

TERRY HWA: I think the new study of the microbiome will show us two new aspects of microbial life: One is about the phenomena that only emerge when microbes are together in a group; another is about the phenomena that only make sense in the context of a group. It is like a team sport. You do not understand the role of the quarterback in a football team until you see them working with receivers. For example, in waste-water treatment plants and oil refineries, there are groups of microbes that work together in an assembly line, each eating the waste products of the preceding one, leading to the final processing of waste into something like methane that is released into the environment.

BITEEN: The group it lives in can even affect whether a bacterium can survive. It might require a certain type of nutrient that it gets from other species. So it can live in a harsh environment as long as the other bacterial species are also around. TKF: Over the last decade, there have been advances in technology, such as DNA sequencing, that have allowed scientists to delve into the microbiome. What have each of you found to be the most surprising discoveries so far about these microbe communities?

HWA: For me, the biggest surprise has been the mindboggling diversity of microbes and how much that matters. For example, we now know that healthy people tend to have a more diverse microbiome, whereas the diversity is rather limited when one is sick. Yet when we grow groups of bacteria in a lab, or try to represent their growth in a computer program, eventually a few species take over. So what is the secret for maintaining diversity?

Julie Biteen is an Assistant Professor at the University of Michigan, where she uses microscopy to understand how individual molecules move and interact in bacteria. (Credit: Daryl Marshke, University of Michigan)

BITEEN: We hear a lot about the human gut microbiome, but what is really interesting to me–and I only appreciated it recently—is that microbiomes are everywhere. Their environments range from the human gut to the oceans, and even include man-made structures like buildings.

DONOHUE: It’s really changed how I think about microbes. When I was a student, I became interested in microbes because they were presented to me as these very interesting yet simple organisms, which scientists could isolate to understand how they worked. But if you look at a community behavior, whether it’s in the human gut or a waste-water treatment plant, you see that they are acting as a team. This team has figured out how to extract life-saving energy and nutrients from the soup that they live in.

When they’re acting in this team, they’re not the simple organisms that I learned about 40 years ago. In real nature, they’re much more like a family—those few families that are functional, not the dysfunctional ones! Julie is correct in saying that these families are important for everything that each and every one of us requires. They’re also going to be important for things that humankind wants to accomplish in the next 100 years, such as producing medicines, food, chemicals and fuels, as well as making sure our children inhabit a planet that can support their activities.

TKF: Terry, you’re a physicist by training. What interests you about the microbiome and how can physics help us understand it?

HWA: Not only am I a physicist, I was trained as a theoretical physicist, so I didn’t even do experiments when I started out. But I have been studying microbiology for the last 10 or 15 years. I think the most fascinating thing about the microbial community to me is that you’ve got a community working together. Each species is, in part, out for its own benefit, yet they have to figure out how to work together. I think we have a lot of lessons to learn from how these microbes work together, maybe even some social lessons we should consider in human groups.

Physicists can contribute to microbiome research in a number of ways. For one, in developing devices that might allow biologists to make measurements about microbiomes.

Terry Hwa's lab has been working on quantitative descriptions of how genes, proteins and chemicals work together to coordinate the physiological responses of the gut bacterium E. coli, and is more recently studying the interaction of gut microbes with each other and with the host environments. (Courtesy: T Hwa)

There’s also a more theoretical component, because microbes are very complex systems. A physicist has experience working with complexity, with connecting the properties of the parts to those of the whole. For the last 50 years, one of the major themes of physics has been how emergent properties come out of complex interactions at a smaller level, and that’s just what I predict we’ll see with microbiomes. So physicists are particularly well-equipped to help analyze that kind of group.

DONOHUE: I would add, physicists, biophysicists, and others who think in quantitative terms have already contributed greatly to the study of individual microbes. Decades ago, they really give birth to the field of molecular biology, by studying viruses that infect bacteria and understanding how microbes work. Physicists helped us figure out what mutations were, and how to measure and understand bacterial or viral growth. In so doing, they helped move the field from simply describing microorganisms to investigating what they are doing and how they do it.

TKF: Julie, same question. What attracted you, as a chemist, to the study of microbiomes and what does chemistry offer the field?

BITEEN: Chemists bring skill in understanding how molecules work together. What I think is really interesting is to examine what’s happening in microbial communities starting from their smallest building blocks: the molecules. This requires us to visualize the interactions that are happening at the scale of nanometers, which are billionths of a meter.

TKF: At this point, what are the big gaps in our understanding of how microbes function in communities?

DONOHUE: So, we know a lot about who is in these communities, because we can sequence DNA. I would like to know what they’re doing, and why, and where.

Right now, the study of microbiomes is like looking down at Central Park from the sky. You see all the people walking around, but you don’t know which kinds of people are in different parts of the park, why they’re there, or what they’re doing. Is there a Bruce Springsteen concert? Or are they going ice-skating? How does their behavior, or the inhabitants of this community, change in real time with temperature, or a vendor providing free food at one end of the park?

If you can’t tell, I grew up in New York City!

BITEEN: Tim, would you also add that it would be interesting to know how you could poke those people and see how things change?

DONOHUE: Sure, yeah. We need ways to see how altering microbiomes influences their behavior. That will help us understand them at a level of how they work, beyond just who’s there—the same way changing a gene or two in an isolated microbe helps us understand what that gene is doing.

TKF: The National Microbiome Initiative and the Kavli Microbiome Ideas Challenge make it clear that to study the microbiome thoroughly, researchers need new tools to determine the what, why, and where Tim’s after. I’d like us to put together a little microbiome tool wish list. If cost were no object, what tool would you want to study microbiomes with, that you think is achievable?

At the University of Michigan, Julie Biteen focuses her microscope on molecules in the gut bacterium Bacteroides thetaiotaomicron. By labeling two different proteins in red or green, she can see where they interact (yellow). (Credit: Karunatilaka et al., mBio)

HWA: Keep in mind, so much has been learned about individual microbes because many scientists study the same organisms, such as the gut bacterium Escherischia coli or the harmless soil bacterium Bacillus subtilis. Because of that, the knowledge from different labs can be compared and put together to understand these few organisms really well. I cannot imagine that we’d be making the kind of progress we’re making today without the focus on a few so-called “model organisms.”

We need to apply that approach to studying the microbiome. Yes, it would be nice to see what people are doing in Central Park. But the effect is limited if each scientist studies his or her own favorite version of “Central Park,” for example, a park in a desert somewhere. I think first of all, we need “model microbiomes.” This is more difficult to do for communities than for individual bacteria, but my biggest wish would be to define five or ten model communities that everybody can study, so their discoveries will add to each other.

BITEEN: Chemists can offer several tools for microbiome study that come from important and complementary perspectives. For one, I think there’s a lot to learn from mass spectrometry, which is a method that precisely identifies the molecules in a sample and can provide a broad-scale picture of what chemicals are being used for nutrition or communication by microbes in a community.

On the other hand, imaging tools will provide key information about the physical and chemical interactions in a microbial community. At the very smallest scale, I think that improvements in high-resolution microscopy will be really central for looking at how cells work on the inside. In my lab, we use microscopy to study how individual molecules move around in a bacterium. Because even if we’re studying microbiomes, the things that happen inside individual bacteria that influence the whole group. Maybe that microbe is making a protein or chemical that affects its neighbors, for example.

DONOHUE: A broad range of analytical tools is essential. For example, better imaging tools that would allow us to see where the microbes are, if they are alone and what they are doing. In addition, improved ways to measure the chemical products of microbes would allow us to see what they are making or how they are talking to their neighbors in communities.

I’d also like is to be able to capture data in real time and see how communities change. Think of it this way—I’m sitting here with my Fitbit on and I can tell every time I’ve taken a step, right? Well, what if we could figure out what was going on with my microbiome, all the time? But keep in mind, all that real-time data isn’t going to become useful unless you have people with the physical and computational skills to be able to understand it. We need major advances to figure out how to take all that real-time data, identify the useful components and give you an idea of what your microbiome is up to.

Being able to track microbiomes could change how we think about and approach human and animal health. We could learn the foods we eat affect our microbiome, and how this in turn impacts our body. That way we could consider adjusting our behaviors to keep the microbiome, and by extension ourselves, healthy and happy.

So the tools I think are going to be critical are a broad set of accurate analytic tools, real-time measurements, and computer modeling to understand how microbiomes change over time.

TKF: One way to spur innovative ideas for tools is to have new types of collaboration. What are the new collaborative opportunities for studying the microbiome?

DONOHUE: A big wish, for me, is to fund instruments or tools that can bring together people from different disciplines. Microbiomes should be part of every study in which scientists are studying the performance of animals, plants, people, oceans or other ecosystems, because microbes have a major influence on all aspects of the planet. For example, scientists who study microbes need to be working with animal scientists and physicians to understand what’s driving interactions between microbes and animals, and between different groups of microbes. We need to identify what are all the good things that microbes do, and what are all the bad things they do.

If we can figure out how to get the broad community of animal, plant, environmental, physical, mathematical, computational, and engineering experts to work together on these problems, that will be transformative. That’s a big challenge, but it’s what’s needed if we’re going to realize the potential of understanding all the contributions that microbes make, or could make. In my mind, this is exactly where the Kavli Microbiome Ideas Challenge can help.

HWA: A big issue we’ve noticed is that scientists in one field just don’t know enough about other fields to even predict what they could make together. A main goal of the Kavli Microbiome Ideas Challenge, as we see it, is to spark these collaborations and the unexpected ideas that will arise.

TKF: Down the line, once scientists have come up with these tools, how might the average citizen expect to benefit from new knowledge about the microbiome? What kind of specific applications for health, or other fields, might arise in the next 10 years?

BITEEN: The personalized medicine Tim was hinting at with his Fitbit is a great example.

Right now, I can count calories. A lot of information is available available out there, about the nutritional value of this doughnut or that sandwich. But if I knew how the bacteria in my gut affect me digesting my food, I would have a more complete picture.

Perhaps there will come a time when we can say something like, “This high-fiber meal I’m having is leading to the growth of beneficial bacteria in my stomach.” Or perhaps, “The meals that I’m eating are going to affect my ability to fight cancer—or react well to medicines—because of the way they affect my microbiome.”

That would give me some real feedback into what’s going on in my body and how it affects my health. It’s a little bit science fiction, but I think it would be pretty exciting to be able to understand our microbiome and how it’s responding, and to control it.

HWA: To do that, as Tim said earlier, we need to make microbiome studies a predictive science, and that requires computational modeling. Maybe one day when we know more about the microbiome in the human gut, scientists could develop a computer program to predict how the different types of food we eat, or antibiotics we take, affect the gut microbiome.

That could be important, because antibiotics can damage the good bacteria that we want in our bodies. So with further knowledge about the ideal balance of microbes in the gut, someone prescribed antibiotics might also take probiotics—beneficial bacteria—to maintain that balance. The treatment could be tailored to a person’s individual microbiome.

TKF: Tim, I know you’re interested in photosynthetic bacteria, how they process energy and grow. Would tools for studying microbiomes enable more effective production of biofuels or other useful materials?

DONOHUE: Absolutely, let me give you two examples: one that has been used by farmers since the turn of the last century and one that many scientists are working on right now.

Nodules on the roots of soybeans contain bacteria that help the plants collect nitrogen and give farmers bigger yields. With a better understanding of microbial communities, scientists might further improve crop productivity. (Credit: Courtesy of Pacific Northwest National Laboratory.)

Farmers in the Midwest have been adding microbes to soil to increase their soybean productivity for over 100 years. Farmers and scientists saw that they could promote the growth of young soybean plants by dipping the roots of these plants. We now know this is because those nodules contain bacteria that help the plants to access nitrogen.

We also know that those beneficial bacteria were often in the soil; it’s just that in some places they associated with plants and in other places, they didn’t. What if there are other microbes, in the soil microbiome, that also affect crop yield? What if you could understand soil bacterial communities better and favor the friendly bacteria that would increase crop productivity—and disfavor, if you will, the unfriendly microbes? We might be able to feed the world better if you knew who the members of the microbial communities are, who the friendlies are, and how to enhance their activities.

Now, let me go to the other example. Julie’s probably going to throw something at me for saying this, but microbes have been doing chemistry on this planet for a lot longer than humans have, and I would submit that they’re the master chemists of this planet.

BITEEN: Actually, I agree 100 percent.

DONOHUE: All right, fine. Then we agree that microbes are able to make chemicals and fuels, the same fuels we’re currently making from petroleum products in often environmentally unfriendly ways. So why can’t we tap into the abilities of individual microbes, or the teamwork of microbial communities, to spark a “green” chemical revolution? With the help of microbes, we could decrease our carbon footprint on the planet, by using renewable resources to make a lot of the fuels and chemicals we currently get from petroleum.

It could be one microbe has all the parts to go from compound A to compound B that you want.

HWA: Or it could be a consortium.

DONOHUE: Right, or it could be a consortium. And there are microbiomes like this. Wastewater treatment plants have microbial communities that make methane, natural gas, all the time. And, in the biotech industry, there are certain vitamins made by groups of microbes. So I think there are huge opportunities for improvements in making the chemicals we want by using microbe communities, or by combining parts from different organisms into new microbial “chemists.”

So those two applications, using microbiomes to increase food production and make chemicals, are some of the other the blue-sky things that I can see coming out of microbiome research.

TKF: I want to get back to something Terry said earlier about the emergent phenomena that happen when the bacteria come together. Microbes, individually, have been the source of some of the most powerful tools that we have in society, such as yeast, for making bread and beer, and antibiotics. Are there any abilities bacteria use when they’re in communities that you would be interested in harvesting for human use once you understand them better?

HWA: I think that’s a question we can’t even answer yet. To answer this question, it really requires us to really know better about emerging properties of microbiomes. That’s the kind of thing we’ll find out by inventing these new tools and doing microbiome research.

—Amber Dance, Fall 2016