William Kaelin displays a model of the VHL protein, which is involved in the groundbreaking research for which he was honored.

Early Monday morning, William G. Kaelin Jr., MD, a senior physician-scientist at the Brigham, received one of the most thrilling calls a scientist can get. The call from Stockholm revealed that Kaelin had been awarded the 2019 Nobel Prize in Physiology or Medicine.

“Like most scientists, I did occasionally dream that maybe one day this would happen,” said Kaelin. “I try to ignore that most days, but when I was younger, my late wife and I would have fun together talking about what would that be like. I’m accepting this prize partly on behalf of my late wife, Carolyn Kaelin. I like to think she’s smiling down and nodding.”

Kaelin, who is the Sidney Farber Professor of Medicine at Dana-Farber and Harvard Medical School, and a Howard Hughes Medical Institute Investigator, joined the Brigham in 1991 and currently has a research staff appointment in the Division of Medical Oncology in the Department of Medicine.

Kaelin is being honored jointly with Sir Peter J. Ratcliffe, MD, of the University of Oxford, and Gregg L. Semenza, MD, PhD, of Johns Hopkins University for their discoveries of how cells sense and adapt to oxygen availability. Their contributions and insights have paved the way for new strategies to treat diseases such as heart disease, anemia and cancer.

“As part of the Dana-Farber/Brigham and Women’s Cancer Center, we have great pride in the scientific research, discovery and innovation that occur at the Dana-Farber Cancer Institute. That pride extends to taking those basic discoveries and translating them into new advances for patients to improve their lives on a daily basis,” said Betsy Nabel, MD, president of Brigham Health. “There are broad applications for this oxygen sensing mechanism across many fields — heart and vascular disease, pulmonary disease, kidney disease and many other organ systems. Bill’s advances extend to cancer and far beyond, and for that, we are enormously grateful.”

The Path to Discovery

In his laboratory based at Dana-Farber, Kaelin’s work focuses on how mutations in genes known as tumor suppressors can lead to cancer. When Kaelin first established his lab, he read about the identification of a mutation in a tumor suppressor gene that leads to von Hippel-Lindau (VHL) disease. Patients with this rare, hereditary syndrome are at heightened risk for developing tumors in the kidneys, adrenal glands or pancreas.

Kaelin’s lab found that the VHL protein prevents the onset of cancer and helps control responses to low oxygen levels by regulating another protein that can trigger or suppress the production of red blood cells and the formation of new blood vessels. Cancer cells with VHL mutations can take advantage of this mechanism to surround themselves with new blood vessels that can fuel their growth. This process is known as angiogenesis and has become a target for combating many diseases, including cancer.

Oxygen sensing is essential for many different functions, including fetal development, metabolism, immune response, and exercise. When oxygen sensing goes amiss, it can lead to many diseases, including anemia, cancer, stroke, infection, heart attacks and more. Kaelin’s contributions to the fundamental understanding of how cells sense and respond to oxygen have led to the development of new drugs that can manipulate oxygen-sensing machinery to treat various diseases. Kaelin said he is continuing to search for new, promising targets.

“My mentor David Livingston, MD, taught me to think, ‘The most important thing you’re ever going to discover lies ahead of you,’” said Kaelin. “I still try to adhere to David’s advice.”

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