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Dr. Melody Campbell, a structural biologist at Fred Hutchinson Cancer Center, was named today a 2022 Pew Scholar in the Biomedical Sciences by The Pew Charitable Trusts. Pew awards these prestigious grants to early-career investigators of outstanding promise who are exploring some of the most pressing questions in health and medicine.
Campbell studies how cells communicate and interact with their surroundings, focusing on proteins that infection-fighting immune cells use to move through the body, find pathogens and fight them. She is a world expert in a protein-imaging technique called cryogenic electron microscopy, or cryo-EM, that helps her understand how proteins’ forms contribute to their functions. Such insights could help inform the development of drugs designed to correct protein mutations.
Campbell joins more than 1,000 scientists who have been named Pew Scholars since 1985, including several fellow Fred Hutch faculty members. The four-year, $300,000 award will give her more scientific flexibility, she said.
“I’ll be able to try things that are a little bit wilder, that might be a little bit more high risk,” Campbell said. “The award will allow me to not only try more things, but also explore higher risk projects without hesitation.”
Understanding how cells interact with the world around them
Our cells need to be able to sense and respond to what’s going on around them. Campbell’s studies focus on a family of proteins called integrins, which are long, flexible proteins that span the cellular membrane and help connect what’s inside a cell with what’s outside it.
“Integrins can signal from inside of the cell out, and outside of the cell in,” Campbell said. “It’s called by bidirectional signaling, and it’s something that makes them a little bit unique.”
She works to understand how integrins’ shapes inform how they work.
“Integrins undergo one of the most dramatic conformational [shape] changes of any protein,” Campbell said. “They can go from completely splayed out and open, to crunched up into this little L-shaped ball.”
Integrins undergo these changes as they help cells sense, respond to and communicate with their environments. But integrins’ dynamic nature makes it difficult to study them using X-ray crystallography, a standard protein-imaging technique that requires proteins to take on a rigid, repeating crystalline structure. That’s why Campbell uses cryo-EM, which can generate images of proteins that aren’t firmly aligned.
Large, flexible proteins and proteins that cross the membrane (many of which are potential drug targets) don’t crystallize well — if they crystallize at all. Cryo-EM makes it much more straightforward to study their shapes and how they interact with other proteins and potential therapeutics, Campbell said. The technique, which she has played a major role in refining, gives scientists insight into the different shapes that a protein can assume.
“And for me, seeing how the protein is moving and changing — these dynamic flexible proteins — that's half the story,” she said. “So you can capture certain [conformational] snapshots in crystallography, but you can't observe this dynamic continuum the way you can in cryo-electron microscopy. By using this alternative technique, you’re filling in even more of the story.”
Cryo-EM has advanced to the point that scientists can see the individual amino acids that make up a protein, and see how a mutation or an interaction with a drug could change a protein’s shape and how it works. Campbell is using the technique to shed more light on the link between protein form and function, by gaining a deeper understanding of an integrin's normal state and how a mutation can gum up the works. And as scientific director of the Hutch’s Electron Microscopy shared resource, she is also working to make this powerful technology available to investigators at the center and beyond.
Twenty-four different types of integrins, many of which play several biological roles, dot cells across the body. And mutations that affect integrin function can also affect our health, so there’s no shortage of questions to ask. Defective integrins have been linked to many health problems, including a type of muscular dystrophy, a bleeding disorder, susceptibility to infections and even cancer.
Much of Campbell’s work focuses on an integrin called Mac1, which helps white blood cells find and fight off pathogens. Immune cells rely on integrins like Mac1 to crawl through the body and identify the right cells or pathogens to engulf. Mutations in Mac1 that prevent their white blood cells from performing these tasks leave people more vulnerable to infections. What Campbell learns about how Mac1 interacts with its different target proteins, and how mutations affect its ability to bind these targets or adopt different conformations, will be important information for scientists looking to design compounds to help mutated integrins work properly.
In addition to continuing her studies of Mac1, Campbell is expanding her research to other integrins, including one that helps blood vessels grow and could potentially be co-opted by tumors that need to grow a new blood supply.
“We're trying to understand how cells are communicating with each other via integrins by understanding which proteins are talking to each other, how they're talking to each other, and what that communication is important for,” Campbell said. “Basically, from a broad perspective, how is the cell communicating with everything around it?”
