A Summer of Protein Degradation and the Beauty of Basic Science
MSRP-Bio student Elizabeth Bond worked in the Baker Lab, investigating the macromolecular machines that roam the cell and gobble up unneeded proteins.
Elizabeth Bond’s greatest summer accomplishment is proudly displayed as the background image on her phone. To the casual observer, it looks like columns of black blobs, but to Bond this stained protein gel signifies that, after two long weeks, she successfully isolated her protein of interest. The snapshot also underscores that she’s found her “people” — the kind who, as she describes, “will freak out with you over a great looking gel.”
A rising senior at UMass Amherst, Bond joined 18 fellow MIT Summer Research Program in Biology (MSRP-Bio) students — collaborating in labs across the biology department and various MIT-affiliated institutes for 10 weeks. Together, they attended seminars, lectures, Q&A sessions, meals, and field trips while living in dorms and bonding over science and life in general.
“You’re with a group of other college students looking towards the future, and you’re all stressing out about what comes next,” she says. “That’s amazing because you’re able to talk about your different insecurities and anxieties. You have a built-in support system that you might not get by staying at your home institution over the summer.”
Bond grew up not too far from MIT in the quiet town of Boxford, Massachusetts. Before setting foot on campus, she expected MIT to be cutthroat and competitive. Instead, she found “a bunch of nerds who are willing to help other nerds learn, make mistakes, and be human beings.” The researchers she met were supportive and eager to share their insights, scientific or otherwise. “In addition to being really interesting, these conversations helped me feel that I fit in with a group of very intelligent scientists,” she says.
As a biochemistry major, Bond appreciates basic science because it allows her to probe biological phenomena with no immediate goal other than to understand the underlying mechanisms. “Maybe 10 years down the line my research will help someone’s translational work, but right now I can pursue knowledge for its own sake,” she says. “The beauty of basic science is that you’re able to study things because they’re cool, while also contributing to the body of work your lab family began before you.”
At UMass Amherst, she serves as an undergraduate research assistant, investigating AAA+ proteases — the same protein degradation machines she studied all summer in Tania Baker’s lab, mentored by graduate student Kristin Zuromski. Back home, Bond examines these proteases in bacteria, using a combination of microbiology and computational biology. As a member of the Baker lab, she studied these macromolecular machines leveraging biochemical approaches.
She likens AAA+ proteases to Pac-Men from the classic arcade game, roaming the cell and gobbling up misfolded, excess, or unneeded proteins. One of the AAA+ proteases studied in the Baker lab is ClpAP, which is comprised of the AAA+ unfoldase ClpA and its partner peptidase ClpP. Bond’s protein of interest this summer was ClpA, a hexameric protein depicted as a cylinder with a central channel. ClpA unfolds and threads protein substrates through its channel, which contains pore loop structures that protrude from the chamber and play important roles in the function of ClpA. From there, the proteins enter ClpP, where they are degraded into small peptide fragments.
There are two types of pore loops in ClpA, D1 and D2, but their respective roles in the recognition, unfolding, and movement of proteins for degradation are not fully characterized. Bond hoped to discern their roles relative to one another.
She introduced a mutation into the gene that encodes ClpA, switching one amino acid for another in the D2 pore loop, in a region thought to be critical for recognizing proteins targeted for degradation. This mutation would, in theory, lead to a variant of ClpA where the D1 pore loop retained normal activity, but the D2 pore loop was unable to function. She used chemical crosslinking to generate a ClpA dimer variant that was half wildtype and half mutant in the D2 pore loops, and monitored the ability of the assembled hexameric AAA+ protease to function.
By observing the degradation activity of this crosslinked ClpA variant containing three active and three inactive D2 pore loops in an alternating order, she hoped to get a better sense of the role the D2 pore loops play in ClpAP protease function.
Although there is still more to be done to answer this particular question, reflecting on the summer Bond feels her project went “surprisingly well,” despite being more challenging than she initially anticipated — primarily due to multi-week protein purification experiments and performing many procedures simultaneously. She arrived with the sole intention of bolstering her biochemistry knowledge, and left with a greater appreciation for the breadth of scientific fields she could pursue.
“MSRP-Bio gave me the chance to talk with students and faculty members working in multiple branches of science,” she says. “I study bacteria, but I can learn a lot from someone researching roundworms or cancer cells, or using computational approaches to biology. Those conversations prompted me to think more critically about my own research.”
Besides feeling integrated into the tightly-knit Baker lab, her favorite aspect of the summer was the bond she formed within her MSRP-Bio cohort. In addition to freaking out over protein gels, they started their own journal club, and they discussed personal struggles, family, where they came from, and where they want to go.
“A lot of students of color who come from underrepresented groups in science, like I do, have this anxiety about not being smart enough or not fitting in,” she says. “The program allows you to bond over these shared feelings and that is part of what makes it really amazing for students who are trying to do great things, but do not often feel fully represented.”
At the beginning of the summer, Bond hadn’t fully admitted to herself that she wanted to apply to grad school. “It was easier for me to be ambiguous about what I wanted to do, because it was scary to admit that grad school was something I might actually want,” she recalls. After a summer at MIT, she’s gained the confidence to apply and state her ambitions out loud.
“My project’s been amazing and great, but now I want to have my own body of work,” she says. “It’s something I have this great urge to do — and, because of MSRP-Bio, I’m ready for it.”