Hertz Fellow Ylaine Gerardin Seeks New Evolution-Based Approaches to Antibiotic Drug Development

October 30, 2016

For more than 70 years, antibiotics have been used effectively against harmful bacteria and parasites, reducing deaths and serious diseases. Conversely, the use of antibiotics has become so widespread that bacteria have evolved to resist them, hampering the drugs’ effectiveness. In addition, about 2 million Americans are infected annually with antibiotic-resistant bacteria, resulting in 23,000 related deaths, according to the Centers for Disease Control.

Concerned by the prospect of slipping back into a pre-antibiotic era, Hertz Fellow Ylaine Gerardin, a postdoctoral researcher at MIT, is exploring new avenues to producing novel antibiotics by studying the phenomenon of antibiotic production from an evolutionary perspective.

As the lead author on a paper published in Nature Microbiology in September, Gerardin concludes there’s a surprisingly narrow range of conditions where it is advantageous for certain bacteria to produce antibiotics. Producers can get taken advantage of by antibiotic-resistant strains, or “cheaters,” that aren’t affected by toxic molecules and propagate while other strains are cleared away, Gerardin explained. Eventually, there comes a point where increasing antibiotic production can actually decrease the producers’ selective advantage.

“In evolutionary game theory, we think of this as a ‘cheating’ strategy,” Gerardin said. “The producer has to make sure it receives enough benefit of its own without giving too much benefit away to these cheaters. That restricts not only the conditions under which they produce antibiotics, but there’s also an optimal amount of antibiotics that a producer can produce to maximize its fitness.”

Gerardin hopes the findings can help expand overall understanding of antibiotic production, and inform different approaches to developing more antibiotics, taking advantage of natural evolution to encourage bacteria to produce more, or different, antibiotics in the lab. Instead of screening each individual bacterium when creating a new drug, she said, researchers could mix all the bacteria together, apply selective pressure, and see which ones win out.

“If you’re interested in finding new antibiotics by looking at natural antibiotic producers, it’s something to keep in mind,” Gerardin said. “You might find things in the wild that don’t make as much antibiotics because it actually might be better for them. If you’re trying to increase antibiotic production, they might be able to do it themselves; they might be perfectly self-limiting.”

Ylaine Gerardin Hertz Fellow bacteria colonies
Image: "Colonies of antibiotic-producing bacteria (red) inhibit the growth of competitor colonies (blue), but are taken advantage of by antibiotic-resistant cheater colonies (green). These interactions limit the evolutionary advantage of antibiotic production as a competitive strategy."

Gerardin worked on her latest paper while pursuing her PhD in the Kishony Lab at Harvard University, a lab known for studying the evolution of antibiotic resistance in clinical settings. She’s since moved on to MIT as a postdoc working with Jeff Gore, a Hertz Fellow who was the first person to encourage Gerardin to apply for her fellowship.

Focusing on microbial ecology, Gerardin currently is trying to engineer the microbiome of a tiny transparent worm as a model system for studying gut microbiomes. By feeding the worm a photosynthetic bacteria, she’s hoping to prove it’s possible to create a microbial community inside an animal that could benefit the worm and, through photosynthesis, create a novel symbiotic relationship between gut bacteria and the host animal.

“You could imagine that someday we could be able to do something like this in humans and have bacteria in our gut that we could eat, and these bacteria would be engineered to do something beneficial to humans,” Gerardin said. “Giving people antibiotics wipes out a lot of gut flora, so imagine if in the future you could also take bacteria along with your antibiotic therapy and they would be able to survive and you would still have a healthy gut biome.”

Starting out at MIT as a biology major, Gerardin found she wanted to do something more quantitative, so she pursued a second major in electrical engineering. Her PhD work in systems biology took her to Harvard, where she shared a lab with Hertz Fellow Michael Baym. He made one of the pieces of equipment Gerardin used to measure the growth of antibiotic producers, an imaging system called the "macroscope," which combines a digital camera with colored LED lights and filters. She also collaborated with Boston Children's Hospital to sequence the genomes of bacteria isolated from patients' blood in order to find genes responsible for antibiotic resistance.

In her academic work, Gerardin said she tries to combine her experimental/biological side with her computational/engineering side to find synergistic applications of the two approaches. Out of her many interests, Gerardin said she enjoys microbial ecology because she can create models that accurately predict a system and see them borne out in experiments.

“I like working with bacteria since they have a quick turnaround time due to a fast growth rate,” she said. “Even though they’re the simplest organism, they’re surprisingly complicated and they do these behaviors like creating molecules that kill other bacteria or being resistant. There’s a lot of complexity to them.”

Gerardin said she wants to continue investigating microbes and antibiotics in academia or in private industry, with an emphasis on research that is more applicable to humans.