Stanford University: Newly minted Nobel laureate Carolyn Bertozzi melds chemistry and biology to advance medicine
Bioorthogonal chemistry, for which professor of chemistry Carolyn Bertozzi, PhD, was awarded the Nobel Prize Oct. 5, is a complicated name for what is a relatively simple (and elegant) concept: engineering two molecules, bobbing separately in the molecular sea of a living cell, so they have eyes only for each another. When their paths cross, they consummate their relationship with a tight embrace.
The method can be used to bring many kinds of molecules together, affixing fluorescent tags to sugar molecules to track their location on or inside a cell, to snap together components of disparate proteins to jolt the immune system into action inside a tumor, or to assemble a neurological-cancer-fighting drug after its individual components have slithered across the blood-brain barrier.
A sister method, click chemistry, is a no-fuss way specially engineered molecular building blocks snap together in a test tube to bring about specific chemical reactions. (Bertozzi shares her prize with the co-inventors of click chemistry.) But bioorthogonal chemistry works in living cells without disrupting their normal function. And Bertozzi, the Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences, and the inventor of bioorthogonal chemistry, is an expert in it.
Bertozzi, who has courtesy appointments in Stanford School of Medicine’s departments of radiology and of chemical and systems biology, is an expert in a lot of things. As the Baker Family Director of Stanford’s Sarafan ChEM-H, which was created to explore the interface between chemistry and human biology, she’s collaborated with researchers and clinicians at Stanford Medicine to advance research in tumor biology, cancer immunotherapies and even COVID-19.
Medical move
Bertozzi has always wanted to make a difference. An article in Stanford Magazine details how she moved her laboratory from UC Berkeley in 2015 to take advantage of Stanford’s on-campus hospital and proximity to Silicon Valley. The change, she hoped, would help her move her chemistry research from the laboratory to the real world. Almost immediately, she was recruited to research a rare disease caused by a defect in a sugar-processing gene called NGLY1. As one of the world’s leading experts in the way sugars coat the outside of living cells, or glycobiology, she was eager to help. Soon she and her lab identified how the mutation caused a buildup of cellular trash that affected the function of the cell, and clinical trials of a resulting gene therapy for the disease are expected to begin in 2023.
Carolyn Bertozzi
Hours after learning she had won a Nobel Prize, Carolyn Bertozzi said she keeps a Christmas tree in her house year-round because “Every day is Christmas … Today is definitely Christmas.”
Andrew Brodhead
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Since her arrival at Stanford, Bertozzi and her lab have contributed to a number of research projects exploring cancer immunotherapies, the virus that causes COVID-19, immunology and tumor biology. The impact of her participation is hard to overstate.
“Having Carolyn at Stanford was game-changing for my lab,” said Sylvia Plevritis, PhD, chair of the Department of Biomedical Data Science. “She ran experiments for us that could be done at only a few places in the world.”
Plevritis and her lab members were studying how lung cancer cells accumulate sugars on their surface to help them evade the immune system, allowing them to proliferate and metastasize. They’d come up with a solid prediction for what they thought was happening but were struggling to validate their findings. “It was tremendously exciting to realize that the world’s expert in the pathway we were studying was just steps away in the next building,” Plevritis said. “We couldn’t have completed the project without her participation.”
Early in the COVID-19 pandemic, assistant professor of pathology Ansuman Satpathy, MD, PhD, and his lab were trying to learn more about interactions between the virus’s RNA and the proteins from the infected cell. Researchers in Bertozzi’s lab had recently identified an entirely new type of molecule on the surface of cells — a glycoRNA, or a membrane-bound RNA molecule modified by a sugar molecule.
Working collaboratively and building on the RNA expertise developed in Bertozzi’s laboratory, Satpathy’s lab was able to show that the host proteins that coated the viral RNA act primarily to block viral replication in the cell. “My laboratory is focused on immunology and genomics, whereas Carolyn and her lab members were thinking a lot more about RNA and how to study it,” Satpathy said. “This is a great example of ChEM-H and the collaborative environment it, and she, foster.”
Tumor applications
Efforts to understand tumor biology and develop new ways to prompt the immune system to tackle cancer cells have also benefited from Bertozzi’s work. Researchers in the laboratory of Jennifer Cochran, PhD, the Shriram Chair of the Department of Bioengineering, used bioorthogonal chemistry techniques to create a synthetic, hybrid immunotherapy molecule, one portion of which homes to tumor sites throughout the body and another that, once in the tumor, activates the immune system to fight the cancer. A single dose of the molecule induced complete tumor regression in 5 out of 10 mice with an aggressive triple-negative breast cancer.
“We’ve gotten striking results in these animal models, and we’re eager to bring this approach to benefit patients,” Cochran said. “This collaboration was key to our joint success. As molecular engineers, we’re experienced in working with proteins, but we don’t have the chemical expertise or infrastructure to synthesize this molecule on our own. By working together we were able to advance this work in ways that neither one could have done alone.”
Other researchers have collaborated with the Bertozzi lab to design a one-two antibody treatment for devastating childhood cancers, to study how sugar-linked molecules called glycopeptides modulate the activity of immune cells called T cells, and to learn how and why some proteins are better than others at crossing the blood-brain barrier that hampers treatment of neurodegenerative disorders.
“Carolyn Bertozzi has transformed our understanding of how the human body functions on a molecular level,” medical school dean Lloyd Minor, MD, said in a statement about the award. “A consummate scientist, Carolyn’s curiosity, collegiality and relentless pursuit of discovery place her firmly in the top echelons of her field, inspiring colleagues and students around the world to push the boundaries of scientific knowledge.”
Bertozzi’s colleagues say that she brings researchers from different disciplines together to synergize research findings and clinical advances that are more than the sum of their individual efforts. It might not be a stretch to suggest that she is the human embodiment of the bioorthogonal chemistry for which she was honored.
“She was so gracious when I reached out to her,” Plevritis recalled. “I can still remember that day. She said, ‘Sure, come on over,’ and several of us walked over to her office. It was so fun to watch her jump up, go to the white board and think in real time about the research. She has such a willingness and an unparalleled ability to take scientists from different backgrounds and bring them into her world.”