Unlocking cellular secrets to better treat diseases

Sophie Lockwood

Sophie Lockwood, PhD ’23, uncovered a complex biological mechanism that could potentially help in drug development

May 22, 2023 – During her PhD studies, Sophie Lockwood has spent most of her time in the lab doing research focused on unpacking the nitty-gritty mechanisms of how proteins interact inside cells.

“My work is so mechanistic it often becomes very myopic, and I lose sight of the bigger picture of the impact,” she said.

But there is one particular moment of clarity that sticks in Lockwood’s mind, which happened at a scientific conference a few years ago. The proteins that she studies are involved in many different diseases, including a lung disease called lymphangioleiomyomatosis, which can worsen during pregnancy. Patients affected by the disease came to the conference to share their experiences with the researchers.

“I remember feeling so heartbroken for these women and their partners, especially as my husband and I were starting to think about having kids at that exact point in time,” Lockwood said. “I was incredibly inspired by their dedication and determination to find a cure and felt a very strong sense of connection to them as well, knowing that my work was so directly tied to their disease.”

Lockwood, a doctoral candidate in the Department of Molecular Metabolism at Harvard T.H. Chan School of Public Health, will graduate in May with a PhD in Biological Sciences in Public Health. As a student, she has sought to understand the biological mechanisms involved when cellular processes go wrong during disease. After graduation, she plans to join a consulting firm, where she will focus on creating strategies for how biotechnology companies can commercialize drugs and bring them to patients.

A winding path to research

Lockwood’s passion for science began in high school, thanks to great teachers. She majored in molecular and cellular biology at Colorado College, where she delved into a unique science curriculum that sparked her interest in lab research. Each course only lasted three-and-a-half weeks and required students to complete both coursework and a research project.

“It allows you to really go deep, and in a lot of ways it’s what you do in a PhD,” Lockwood said. “You’re just doing research all the time and thinking about science all the time.”

At that time, Lockwood was interested in attending medical school. After graduating, she gained a year of relevant experience as a volunteer for a ski patrol in Jackson Hole, Wyoming, providing EMT services to skiers who needed medical care. Lockwood then moved to Boston to work as an ophthalmic assistant in Tufts Medical Center’s ophthalmology department, where she hoped to figure out whether she wanted to be a doctor.

But while working at Tufts, Lockwood observed how clinicians chose certain drugs to prescribe over other ones, and as a result became interested in the details of how different drugs work inside cells. “Why is it this drug is better than that drug? At the mechanistic level, what is one drug doing versus the other? And how can we improve drugs to make them better?” she found herself asking.

To pursue these questions about drug development, Lockwood took a job as a researcher for Mitobridge, a biotechnology company in Cambridge, Mass., focused on diseases caused by mitochondria malfunctioning inside cells, such as acute kidney injury and muscular dystrophy. Lockwood used biochemistry methods to study the mechanisms of how potential drugs behaved inside cells, such as how the compounds affected genes that are involved with mitochondrial function.

“I found that I really enjoyed learning about how things work—it is just how I am as a person,” she said.

While attending scientific seminars at Mitobridge, Lockwood learned that her research touched on topics that were similar to those being investigated by Harvard Chan School faculty in the Department of Molecular Metabolism. She was also drawn to the idea that doing research on drug development at a mechanistic level could lead to helping patients on a larger scale, thus advancing public health. So when she decided to pursue a PhD degree, she set her sights on Harvard Chan School.

A black-and-white discovery

At Harvard Chan School, Lockwood has worked in the lab of Brendan Manning, professor of molecular metabolism and acting chair of the Department of Molecular Metabolism. Manning’s lab focuses on a cell signaling pathway called mTOR, a complex network of proteins that senses environmental cues outside the cell, such as nutrient and energy levels, in order to determine whether the cell grows or not. Mutations in the pathway can lead to a wide range of diseases, including tuberous sclerosis complex, in which benign tumors grow in the brain and other parts of the body.

Within the signaling pathway, Lockwood homed in on two proteins called TSC2 and Rheb. They were previously known to interact with each other at one important region of TSC2, but whether other interactions existed between the proteins was unclear. Lockwood discovered that the two proteins also bind to each other at a different location on TSC2, and that the interaction is important for regulation of the mTOR signaling pathway.

One of the main methods that Lockwood used in her research was extracting the proteins from cells so that she could study them alone, removing the noise of everything else happening in the cell. “Being able to recapitulate something that happens inside the cell—to be able to purify those proteins and study them outside the cell—is really cool,” she said.

Studying the proteins in a simplified system meant that experiment results could be more easily interpreted. “Biochemistry is very black and white in a lot of ways,” Lockwood said. “Once you get things optimized, it’s really amazing to get a yes or no answer.”

“Sophie took on and embraced a project that sat dormant for years due to the challenging biochemical nature of it,” Manning said. “Her paradigm-shifting discoveries have greatly advanced our molecular understanding of a core pathway that functions in all cells to control metabolism and growth and that underlies a diverse array of human diseases, including neurological disorders and cancer.”

Lockwood said her research could help pave the way for more effective drugs. “By improving our mechanistic understanding of this signaling pathway, we can ultimately develop new therapeutic strategies to specifically target mutations within the pathway that underlie numerous disease states,” she said.

Taking a broader view

At the same time that Lockwood was conducting research in the lab, she sought to tackle the challenge of drug development from a different angle. She participated in the Harvard Office of Technology Development’s Business Development Fellowship program, spending one year as a fellow and then returning for a second year to mentor new fellows.

In the program, Lockwood participated in developing strategies to commercialize new discoveries or technologies from the lab so that they can ultimately be used to treat patients.

For one of her projects, Lockwood analyzed a nanoparticle drug delivery system developed by Samir Mitragotri, a professor at Harvard John A. Paulson School of Engineering and Applied Sciences. Her first step was to delve into the science behind the technology and learn the technical details of how it worked, and then present the information in a digestible way to business development experts in the office. Afterward, Lockwood evaluated potential challenges to commercializing the technology, such as competing groups working on similar technologies. She also recommended ways to move the technology forward, such as creating a start-up company or licensing the technology to an already existing one.

“I really enjoyed the fact that I was able to be exposed to so many different types of projects,” she said.

After graduate school, Lockwood will work at at Putnam Associates, a life sciences consulting firm. “I could continue to hone that skill set of being able to synthesize a huge diversity of different technologies, and then think about how those technologies could then be used for the treatment of specific diseases,” she said.

Lockwood’s long-term career goal is to return to the biotechnology industry and help guide drug development. “Ultimately down the line, I would love to go back into biotech, but less on the research side and more on the corporate strategy and the pipeline development aspect—focusing more on the bigger picture of where the biotech is going,” she said.

– Jay Lau

Photo courtesy of Sophie Lockwood