CHANGING OUR VIEW OF PROTEINS TO DEVELOP NEW THERAPIES
Trisha Brady challenges normative ideas about protein structure and function.
As a high school student in Milford, Connecticut, Trisha Brady was inspired by a science teacher to imagine the possibilities of what science could be used for. This teacher encouraged her to look beyond the norm and find her own ways of helping people through science. As an undergraduate, she was passionate about using forensic science to support the justice system. Her honors thesis work involved studying whether hair samples could be used in criminal cases to identify people based on unique differences in hair composition.
Now she uses chemistry to help improve health. Brady’s undergraduate Principal Investigator Alyssa Marsico encouraged her to apply to the UMass Amherst PhD in Chemistry program. Marisco connected her with Professor Richard Vachet, who focuses on analytical techniques and method development to study tricky biochemical problems. After month-long rotations intended to expose new UMass students to different labs, Brady joined both Vachet’s lab and Professor Jeanne Hardy’s lab. Hardy’s lab studies caspases.
Caspases are proteins that tell cells when it’s time to die. “It sounds morbid, but it’s really important,” Brady explains. “Cells have to turn over for your body to function correctly.” Cancer occurs when unhealthy cells aren’t killed off. Neurodegeneration happens when too many healthy cells are killed. Our bodies need a balance. The protein Brady studies, caspase-9, is an initiator of cell death. If it doesn’t function correctly, there’s a negative domino effect within the body.
“I view proteins as being flexible, dynamic entities. This is one of the big picture ideas I hope other scientists can use to better understand the proteins they study. It could change the way we view everything.”
Brady wants to change the way scientists think about proteins. “Historically, people have thought of proteins as being more static than they are,” she says. “I view proteins as being flexible, dynamic entities. This is one of the big picture ideas I hope other scientists can use to better understand the proteins they study. It could change the way we view everything.”
Proteins can adapt different conformations, as Brady goes on to describe. “If you look at your hands next to each other, you see they have the same mass and composition. But when you open one hand and close the other, they have different conformations,” she explains.
Scientists used to produce one static image of a protein, but modern tools can assess these conformations. Brady uses a method called ion mobility mass spectrometry, which separates proteins by size, shape, and conformation.
By studying a protein’s structure, Brady learns more about its function. Different conformations may have distinct functions. For example, caspase-9 appears to have built-in security layers, akin to two-factor authentication. In a healthy system, this should function to prevent a signal from being sent on accident. Caspase-9 has functions that scientists aren’t fully aware of yet.
Brady’s research aims to understand these functions enough to create inhibitors that target caspase-9 and tell it not to be active. “Targeting specific conformations may help in the future of developing new therapies,” she says. For people dealing with neurodegeneration, a caspase-9 inhibitor might improve their mental health and well-being.
As much as Brady enjoys the science, it’s the people who keep her motivated. She became a joint student in two labs because the people were so friendly. “It felt like they really wanted to mentor me, and they wanted me to be there,” she reflects. “I had never done molecular biology or biochemistry before. They all came from other backgrounds and knew how to relate to me.” By encouraging her questions, they made her feel like she belonged.
This welcoming environment extends beyond her labs. At the Lederle Graduate Research Center and the Life Sciences Laboratories, there’s always someone who can teach her how to do something new. The Biotech Training Program and the Chemistry-Biology Interface Program have provided her with new collaborators, training, and funding. These programs host retreats and social events, including debates on hot topics and “Chalk Talks” where researchers share their work with each other. Brady is also co-secretary and member of the Association for Professional Development in Chemistry.
Now in year three of her program, Brady knows that teaching and using science to help people will be part of her future. She has returned to high school to tell that science teacher how he motivated her thinking and where she is now. “Everyone deserves good teachers,” she says. “They really do make a difference on where you end up.” Whether she ends up in academia or industry, Brady says she wants to mentor others and inspire new perspectives—on the way we view proteins and the possibilities of using science for good.
Written by Shannon Callaham, PhD student in Environmental Conservation, as part of the Graduate School's Public Writing Fellows Program.