In molecules, one chemist sees art
In 2020, when she came to MIT for graduate school, Lee spent a virtual lab rotation with Laura Kiessling ’83, a chemist who helped pioneer the field of chemical biology. Unlike biochemistry, which is the study of the chemistry behind biological systems, chemical biology involves applying chemical tools to probe and manipulate biological systems, Lee explains.
GRETCHEN ERTL
Chemistry department students and advisors rank each other in a matching process to determine which labs students join. Lee was thrilled to match into Kiessling’s lab, her top choice. Beyond being drawn to the creative possibilities of the field, she was also excited to be part of a lab made up mostly of women and people of color.
When Kiessling recalls the matchmaking process, she says that Lee had an impressive synthetic chemistry background as well as an interest in working on biological systems. More than that, Kiessling was looking for what she calls “open-minded people willing to try crazy things.”
In her lab, everyone studies glycans—chains of sugar molecules that coat the outside of all living cells. Glycans are one of the main research subjects for scientists studying Mycobacterium tuberculosis, the tuberculosis-causing pathogen, which lives in a quarter of the global population. Its thick, glycan-filled cell wall dampens the body’s usual immune response, allowing the bacterium to go undetected. As a result, people can live years without knowing they’re infected—until tuberculosis launches a devastating attack on the body. The disease causes as many as 1.5 million deaths per year.
Today, most patients are given a “cocktail” of drugs targeting different aspects of the bacterium. But it’s becoming increasingly resistant to existing antibiotics, and designing new drugs is a public health priority. Lee’s work targeting M. tuberculosis’s distinct cell wall could be one key avenue to finding an effective treatment.
When Lee sets to work producing her molecule, she moves around the lab swiftly and decisively—pouring liquids into giant beakers, pulling out a flame torch to evaporate excess moisture that threatens her reactions, and taking measurements with an assortment of the lab’s precisely calibrated instruments. She is following steps that she devised three years ago, when she started trying to figure out how to alter an existing tuberculosis-targeting chemical so that it could breach cell walls like a Trojan horse and reveal details about the sugars within. M. tuberculosis absorbs different kinds of sugars for different purposes. Lee wanted to zero in specifically on mannose-containing glycans, which the bacterium uses to build its cell wall. If Lee could see how it incorporates those glycans into its structure, that could help researchers develop new drugs that disrupt the building process and thus kill the cell. But Lee needed to hit a sweet spot when designing her molecule. It had to be complex enough to fool the tuberculosis bacterium into incorporating it just as it would incorporate mannose-containing glycans, yet simple enough to be made repeatedly in the lab. If the synthetic glycan were too generic, tuberculosis would use it for multiple functions, making it impossible to target the cell-wall-building process she’s studying.
Designing the synthetic route to producing the molecule took a year of troubleshooting—what Lee calls “part of the art.” After much trial and error, she figured out how to optimize the synthesis, running multiple stages at once since some take minutes and others last days. Lee estimates that she’s done the full synthesis around 30 times.
The final tuberculosis-targeting chemical, AzFPM, consists of synthetic sugars mimicking mannose-containing glycans. It’s so close in structure to these glycans that the bacterium incorporates it into the cell wall without noticing.
