Mitchell has been working with samples collected by a local biotech company developing biotherapeutics for the gut. Its probiotic products, which are used to treat recurrent C. diff infections, contain eight closely related microbial strains belonging to the order known as Clostridiales. The company gave one of its products to 56 human subjects and collected stool samples over time. Mitchell is using genetic sequencing techniques to track how three of the microbial species evolved in 21 of the subjects. Identifying person-specific differences and similarities might reveal insights about the host environment and could help explain why some types of mutations allow some microbes to survive and thrive. The project is still in its early phases, but Mitchell has a working hypothesis.
“The model that I have in my mind is that people have different [gut] environments, and microbes are either compatible with them or not,” she says. “And there’s a window in which, if you’re a microbe, you might be able to stick around but maybe not thrive. And then evolution kind of gets you there. You might not be very fit when you land there, but you’re close enough to hang around and get there. Whereas in other people, you’re totally incompatible with what’s already there, and the resident microbes beat you out.”
Her work is just one of many projects using new approaches developed by Lieberman, who worked as a postdoc in Alm’s lab before starting her own in 2018. As a graduate student at Harvard, Lieberman gained access to more than 100 frozen samples collected from the airways, blood, and chest tissue of 14 patients with cystic fibrosis, a genetic disease that causes mucus to build up in the lungs and creates conditions ripe for infections. The patients were among those who had developed bacterial infections during an outbreak in the 1990s.
Lieberman and her colleagues recognized a perfect opportunity to use genetic sequencing technologies to study the way the genome of the Burkholderia dolosa bacterium evolved when she cultured those samples. What was it that allowed B. dolosa to adapt and survive? Many of the surviving microbes, she discovered, had developed similar mutations independently in different patients, suggesting that at least some of these mutations helped them to thrive. The research indicated which genes were worthy of further study—and suggested that this approach holds promise for understanding what it takes for microbes to grow well in the human body.
Lieberman joined Alm’s lab in 2015, aiming to apply the same experimental paradigm and the statistical techniques she had developed to the emerging field of microbiome research. In her own lab, she has developed an approach to figuring out how the pressures of natural selection result in mutations that may help certain microbes to engraft. It involves studying colonies of bacteria that form on the human skin.
“The idea is to create a genetically engineered metabolite factory in the gut.”
Daniel Pascal
In the gut, Lieberman explains, hundreds of different species of microbes coexist and coevolve, forming a heterogeneous community whose members interact with one another in ways that are not fully understood. This creates a wide array of confounding variables that make it more difficult to identify why some engraft and others don’t. But on the skin, the metabolic environment is less complex, so fewer species of bacteria coexist. The smaller number of species makes it far easier to track the way the genomes of specific microbes change over time to facilitate survival, and the accessibility of the skin makes it easier to figure out how spatial structure and the presence of other microbes affect this process.
One discovery from Lieberman’s lab is that each pore is dominated by just one random strain of a single species. Her group hypothesizes that survival may depend on the geometry of the pore and the location of the microbes. For example, as these anaerobic microbes typically thrive at the hard-to-access bottom of the pore, where there is less oxygen, the first to manage to get there can crowd out new migrants.
“My vision, and really a vision for the microbiome field in general,” Lieberman says, is that one day therapeutic microbes could be added to the body to treat medical conditions. “These could be microbes that are naturally occurring, or they could be genetically engineered microbes that have some property we want,” she adds. “But how to actually do that is really challenging because we don’t understand the ecology of the system.” Most bacteria introduced into a person’s system, even those taken from another healthy human, will not persist in the new person’s body, she notes, unless you “first bomb it with antibiotics” to get rid of most of the microbes that are already there. “Why that is,” she adds, “is something we really don’t understand.”
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