When Yimon Aye, Chemistry and Chemical Biology, left her PhD program at Harvard University, she took the first of two big risks in her early career. First, she shifted disciplines for her postdoctoral fellowship from organic chemistry to biology. Then she went on the job market with a proposal, not for derivative research but for a new technology that had the potential to shift paradigms in studies of biological cell signaling. “My proposal was completely different from the research programs I had been a part of,” says Aye.
As a result, many foundations said no. Many schools turned her away.
“It is typical for faculty candidates in biology and biological chemistry to propose something that they have a strong, or at least related, background in,” Aye says. “I failed many grants and had to be thick-skinned. But I felt that I could do it and that it would have an impact.”
Aye was right. Four years later, she has been named a National Institutes of Health New Innovator, an Alfred P. Sloan Foundation Fellow, a Beckman Foundation Young Researcher, National Science Foundation early CAREER awardee, and most recently, the 2016 American Chemical Society Research in Toxicology Young Investigator, among other accolades.
After arriving at Cornell, Aye realized her proposal. She created a platform called T-REX™, which allows researchers to isolate the effects of chemical reduction-oxidation (redox) reactions on specific targeted proteins in living systems. Researchers can then track the effect of these redox reactions, where electrons are transferred from one chemical species to another, and directly read out how individual redox events are linked to biological responses.
Using Aye’s T-REX™ (Targetable Reactive Electrophiles and Oxidants), scientists can now study both the beneficial and harmful impacts of chemical redox reactions in ways they never could before.
Aye says we are exposed to oxidative or electrophilic small molecules all the time—when we breathe in smoke or eat broccoli, for example. Some of these molecules are also present in our bodies, such as very small amounts of hydrogen peroxide. The reactive molecules, in high concentrations, disrupt chemical stability and cause oxidative stress—a proliferation of free radicals. There’s evidence that the deregulation of these reactions contributes to aging, Alzheimer’s, and cancers.
Many of these small molecule reagents, when generated in low amounts at the right place and time, however, actually contribute to human health. “They are incredibly important as signaling cues,” says Aye. “They can perturb individual signaling pathways at a specific time and space that ultimately helps to maintain fitness.”
“My proposal was completely different from the research programs I had been a part of,” says Aye.
Until Aye’s T-REX™ platform, the prevailing technique to study redox reactions included flooding the cells with a given reactive entity, Aye explains. This often results in oxidative stress but obscures the important details of beneficial signaling. “You can imagine, we have thousands of proteins, so you would have no control in trying to understand which pathway is being hit, which target is being modified, because these signals are diffusible and highly reactive chemical entities.”
A Tool with Boundless Implications for New Drug Development
Aye’s technique allows researchers to precisely deliver a particular chemical signal to any redox-responsive protein in living cells and more recently in animal models, perturbing the system to understand the specific biological response. Along with her lab members, she’s created a toolbox that allows users to pick and mix signals and proteins for use in various assays, all to model the system.
The technology has vast implications for new drug development—any redox-responsive protein that is associated with disease can be perturbed with any small molecule reagent to see the pathophysiologic effects.
“Even we were surprised at how well this toolset works,” Aye says. “We’re finding now that the field appreciates this tool because there is such a need for it. I feel encouraged and excited to bring this unique chemical ID to address the latest challenges in the field.”
“Looking back, I don’t regret the risks,” Aye continues. “There are so many big biological questions that you can contribute to as a chemist to combat disease and improve human life.”
With a rush of support and collaborators, Aye is not hubristic in the least but looking ahead. “I tell my students that with these opportunities and grants, we have the responsibility now to think bigger and do better,” she says. “We have so much more to do.”
Aye admits that taking big risks is not for everyone and that her upbringing may have prepared her for the challenge. She grew up in Burma during a time of great unrest and civil strife, which in the 1980s inspired mass student protests. As a result, all schools, even at the elementary level, were closed.
“My mother was a university lecturer,” Aye says, “but when the university shut down, she was able to get a position in an American international school in Rangoon. I was lucky because I was able to receive books that way through my mother. But at seven or eight years old, I was unable to attend a proper school.”
When she was old enough, Aye took the entrance exams for the British school system, and two boarding schools offered her full scholarships. “For me coming from Burma, to have a chance to study in England, to go through Oxford, Harvard, and come to Cornell as faculty, my personal circumstances have already made me realize that you have to believe in yourself and keep trying. And think hard about things,” she says. “I learned not to be afraid of failure.”
Aye fell in love with chemistry because of her high school chemistry teacher, but she hated experiments. “Back in Burma, I’d never done any experiment whatsoever. I’d not seen a basic lab setup, a burette, or pipette—nothing at all,” she says. “I didn’t have the common sense to do simple things.”
Even at University of Oxford, Aye says, she felt behind in teaching labs. “I was always the last one to finish in labs and never got the recrystallized compound or good yield.”
It wasn’t until the summer between her third and fourth year at Oxford that she gained any confidence in the lab. She spent that summer at Massachusetts Institute of Technology. “Number one, I came to experience what cutting edge research was like in the U.S.,” she says. “The second thing was, while I knew I was really bad in the teaching labs, I loved finding unexpected and new things and was the second author on a paper from this 11-week, summer work. That really gave me confidence.”
Now, what makes Aye most happy is her students’ development and accomplishments and that her risk, and the new technology that came out of it, has contributed to science. “We have our own applications and discoveries using the technique, but it’s incredibly exciting to be able to serve the community through a unique technology.
“I’m also grateful to Cornell for believing in me,” she continues. “I still remember the first gel-based discovery that I made, trying to build T-REX from ground zero. It was in my own hands, in my lab here at Cornell. I just could not quite believe that the idea worked. Now I tell my students to have faith and drive forward if you have that gut feeling, because one never knows.”