Scientists know a lot about which microbes live in the human gut, but not what they do
Emily Balskus, 38
Chemistry and microbiology
Balskus, 38, originally imagined a career making complex molecules in the lab. “She can do chemistry that very few people in the world can do,” says synthetic chemist Eric Jacobsen, her Ph.D. adviser at Harvard.
But she became intrigued by how microorganisms make molecules with such ease, when synthesizing those molecules can be so challenging. As a postdoctoral fellow at Harvard Medical School, Balskus attended a seminar on the human microbiome — the catchall term for the trillions of invisible beings that live in and on us. She was hooked.
“I just thought it was fascinating,” she says. “We have all these microbes living in us from the time we are born. They’re such an intricate part of our bodies. They’re interacting with us, yet we know so little about them.”
A growing body of evidence links several illnesses to changes in the body’s microbial communities. While many researchers are out cataloging what these microbial residents are, Balskus is taking a different approach. Rather than focusing on the whodunit, she is interested in the howdunit.
“We really don’t understand … how they are exerting their influence,” Balskus says of the body’s microbes. “It’s a major obstacle and it’s what makes this work so exciting.”
An interest in the “how” emerged early for Balskus: During elementary school in Cincinnati, she and her classmates designed an experiment to prove that green food coloring diluted in water was still there, even when it was no longer visible. “I came up with the idea that we could boil down all the water and get the food coloring back,” she recalls. It worked.
Fast-forward to 2011 when Balskus used more advanced chemistry skills to solve a century-old puzzle. She had read a report linking high blood levels of a compound called TMAO to heart disease. Since the early 1900s, scientists had known that gut microbes convert the essential nutrient choline into the gas TMA, a precursor to TMAO. But how the conversion came about was unknown.
“This was the first time that I was like, ‘This is something I can do, I can figure out how this happens,’” Balskus says.
The essential dietary nutrient choline is broken down in the human gut by the microbial enzyme CutC (surface representation of structure shown), Balskus discovered. Studies of mice suggest that this enzyme’s activity can limit the availability of choline during pregnancy, when it is needed by developing fetuses.
Researchers already knew that choline-digesting microbes kick off the process by cutting a carbon-nitrogen bond. That reaction looked familiar to Balskus. Some bacteria use a particular enzyme to cleave that very bond in an unrelated reaction. And the genes behind that bond-cutting enzyme had been identified. So Balskus combed through catalogs of bacterial DNA looking for similar genes whose functions were unknown.
The approach worked. Balskus found a cluster of genes that appeared to be responsible for the enzyme that was chopping up choline. She and her then graduate student Smaranda Craciun showed in 2012 in the Proceedings of the National Academy of Sciences that numerous microbes, including ones in the gut, also carry genes for the previously unknown choline-metabolizing enzyme.
“She’s sort of like a detective that’s looking at a mix of different clues,” says molecular geneticist and collaborator Peter Turnbaugh of the University of California, San Francisco. “She’s got this chemical logic that really informs what to go after.”
While much of her work to date has revealed microbes behaving badly, Balskus hopes that some will prove to be a force for good. In a 2018 commentary in ACS Infectious Diseases, Balskus and then graduate student Abraham Waldman detailed how elucidating microbial chemistry could change medicine, turning antibiotics, for example, into highly precise tools for fighting ills, rather than the blunt instruments they are today. Other small molecules made by microbes, or delivered to perturb them, may be part of the microbial intervention landscape of the future that could work against infections like HIV, tuberculosis and malaria, Balskus says.
Her work has revealed new mysteries to solve. A 2017 report in Cell Host & Microbe by Balskus and others suggests that activity by the choline-cutting microbes could play a role in obesity and may diminish availability of the nutrient to mom and fetus during pregnancy. How this activity interacts with diet and genetics in any one person is not yet clear. In time, perhaps chemistry will tell.
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