The University’s “Double ‘Hoo” is a meetup for researchers, bringing together pairs of graduate students and undergraduates to collaborate on research projects. This year, Angela Zeigler and Ani Chandrabhatla, both members of Associate Professor Jeff Saucerman’s systems biology lab, were among the 17 teams University-wide selected for the award. They will use their $5,000 grant to test drugs that may help prevent heart failure after a heart attack.
The award was the perfect way for Zeigler and Chandrabhatla to meet their complementary career goals. Zeigler (M.D./Ph.D. ’17) recently decided that her future lay in the lab rather than the clinic.
“One of the responsibilities of a faculty member,” she says, “is managing projects and mentoring aspiring young scientists.” The Double ‘Hoo presented an opportunity for her to gain experience in both.
Chandrabhatla (BME ’19) is trying to determine if a career in research is for him. For his senior science project in high school, he had chosen a project that was wholly experimental—but soon found his schedule dominated by the need to monitor his cells. He thought that a project that mixed computational and experimental research would better suit his temperament.
Zeigler and Chandrabhatla found common ground in taking the cardiac fibroblast model that Zeigler assembled for her dissertation and adapting it for drug discovery. In the immediate wake of a heart attack, disruption in signaling networks in cardiac fibroblast cells causes them to break down collagen in the heart so that inflammatory cells can remove dead tissue. The fibroblasts then replace this dead tissue with new collagen, which forms a scar that holds the damaged heart together. If the fibroblasts destroy too much collagen, the heart can dilate; if they produce too much replacement collagen, the heart stiffens. Both these changes contribute to heart failure.
Under Saucerman’s direction, Zeigler developed a large-scale computational model of cardiac fibroblast signaling in order to identify regulators of fibrosis. The model network integrates 10 signaling pathways, including 91 nodes and 134 reactions.
To use this model as a test bed for drug discovery, Zeigler was looking for someone who already had computational skills. Chandrabhatla fit the bill. He is creating a digital tool that connects to the open source DrugBank database, extracts information about a drug that targets a gene or protein in Zeigler’s model, and simulates the effect of adding the drug to the network. Their goal is to find drugs that interrupt excessive fibroblast activity. They will validate this tool experimentally by observing the effects of the drug on adult cardiac fibroblasts in culture.
Even the process of applying for the Double ‘Hoo award was a learning experience. Chandrabhatla discovered how hard it is to write an effective grant proposal in a limited amount of space—in this case, two pages. “It took many iterations to figure out how to present our ideas clearly, but succinctly,” he says.
Zeigler has also learned some of the techniques of effective mentoring. Adopting a method that Saucerman uses with his graduate students, Zeigler had Chandrabhatla write the first draft of the proposal. “It gave me a chance not only to work with Ani on his writing but also to assess how well he understood the project,” she says.
For both Zeigler and Chandrabhatla, the exciting part of their Double ‘Hoo project is the opportunity to learn these lessons while searching for a new treatment that could save lives.