There was always a good chance William G. Kaelin, Jr., MD, and two other scientists working on the same problem would share a Nobel Prize, as they did on Oct. 7, for deciphering the mechanism that enables cells to sense and adapt to changes in oxygen abundance.
The three had already been honored with two major awards that often presage the most prestigious prize of all. Still, in any given year, one never knows, and Kaelin said he had always tried to tamp down the inevitable expectations.
“Of course, I knew it was Nobel Prize Monday when I went to bed Sunday night,” he said at a Dana-Farber press conference. He fell asleep, then awoke “from a very vivid dream,” he said, “where I looked at the alarm clock and it was 5:45 a.m.. So in my dream I said, ‘OK, another year it didn’t happen, but it’s OK.’”
But then he realized it was only 2:30 a.m. — too early for the announcement — he went back to sleep. When the phone rang just before 5 a.m., he thought: “Is this the dream part, or is this the awake part?”
It was the awake part. Kaelin, along with Sir Peter Ratcliffe of the University of Oxford, and Dr. Gregg Semenza of Johns Hopkins University, had just been awarded the 2019 Nobel Prize in Medicine, for their discoveries of the molecular system by which cells sense and adapt to varying levels of oxygen availability.
“It was just surreal,” he said. “I had this sort of out-of-body feeling of great appreciation and being so thrilled to share this with all the people who have meant so much to me.”
After that overwhelming start to his day, Kaelin fielded calls and conducted interviews before arriving at an 11:30 a.m. press conference at Dana-Farber, where he was introduced by President and CEO Laurie H. Glimcher, MD, and received accolades from Harvard Medical School (HMS) Dean George Q. Daley, MD, and Elizabeth Nabel, MD, president of Brigham and Women’s Hospital (BWH).
Kaelin, the Sidney Farber Professor of Medicine at Dana-Farber and a professor of medicine at HMS and BWH, along with his co-winners Ratcliffe and Semenza, also jointly won the 2016 Lasker Award for basic medical research.
“We’re all incredibly proud of Dr. Kaelin – and hopeful for the promise this means for patients here and everywhere,” Glimcher said. The body’s mechanism for adapting to changing oxygen levels “is essential for survival,” she added, “and understanding it and being able to manipulate it are already being used to develop exciting new treatments for cardiovascular disease and cancer.”
HMS Dean Daley, who works in the field of hematology, called Kaelin “the consummate physician-scientist, the finest that medicine has to offer.” Nabel commented that the advances made by Kaelin and his co-awardees “are in cancer and way beyond.” She said that his achievements aside, Kaelin “is a wonderful, amazing individual and human being.”
Kaelin said at the press conference that he and his late wife, Carolyn Mary Kaelin, MD, MPH, had talked about what would happen if he won the Nobel. Carolyn Kaelin, a breast surgeon at Dana-Farber/Brigham and Women’s Cancer Center, died in 2015. In the years immediately following her death, Kaelin said he had hoped the prize would not come so soon.
“It would be too bittersweet, too crushing to receive it without Carolyn,” he said. “Now I like to think she’s looking down and smiling and saying, ‘See, I told you it was going to happen!”
Kaelin said that while he did not formally collaborate with the other two Nobel winners, he said the research was inherently collaborative.
“They were reading my papers and I was reading their papers, and when we would see each other at scientific conferences we were talking about things that were going to appear in publications six months later,” he said. “In my view, that really accelerated the field.”
He added that “science is done in an ecosystem” of collaborators and other scientists working in related fields. He made special mention of David Livingston, MD, in whose Dana-Farber laboratory Kaelin trained. “He was — and is — my mentor,” Kaelin said. “He taught me how to be a scientist.”
In his Dana-Farber laboratory, Kaelin has focused on why mutations in genes known as tumor-suppressor genes can lead to cancer. One such tumor-suppressor gene called VHL, when mutated, causes von Hippel Lindau syndrome, a rare disorder that makes patients likely to develop kidney cancer, as well as other types of tumors.
Studying VHL led Kaelin and his co-awardees to a landmark discovery – the molecular explanation to a long-standing biological puzzle: How does the body sense and adapt to changes in oxygen — for example, when people adjust to thinner air at high altitudes.
Pursuing this question, he discovered that the VHL protein normally helps regulate the levels of an oxygen-sensitive protein called HIF, which can trigger or suppress the production of red blood cells and the formation of new blood vessels and discovered the molecular switch that renders HIF oxygen-sensitive. Cancer cells with mutated VHL genes commandeer this system to surround themselves with new blood vessels — a process called angiogenesis — to feed their growth.
Kaelin found that mutation of the VHL gene causes kidney tumors to churn out large amounts of a protein, VEGF, which helps provide them with an extra blood supply to fuel the cancer’s growth. His work on the VHL protein (the protein made with the “instructions” provided by the VHL gene) helped to motivate the eventual successful clinical testing of VEGF inhibitors for the treatment of kidney cancer. However, the first drug from his laboratory to receive approval for clinical use is a drug to stimulate the production of red blood cells to treat anemia.
Kaelin discovered that the VHL protein helps control the levels of the protein HIF, which ratchets up or down the response to low oxygen, such as the production of red blood cells and new blood vessels. He showed that one form of the protein, HIF-2α, drives certain kidney cancers, and he subsequently discovered how HIF-1α is hijacked by triple-negative breast cancers. He is developing therapeutic strategies for targeting these molecules. In fact, a HIF-2α inhibitor has now advanced to phase 3 clinical testing based on promising results when used to treat patients with kidney cancer.
“We are thrilled for Dr. Kaelin on this extraordinary honor,” said Glimcher. “It’s a discovery that has already led to important medical applications in areas like cancer, where the availability of oxygen is critical to the way cancer cells grow and survive.”
In addition to the Nobel and Lasker awards, Kaelin and his two Nobel Laureate collaborators earned the 2010 Canada Gairdner International Award and the Grand Prix of the Fondation Lefoulon-Delalande from the Institute of France in June 2012, for contributions to the field of cardiovascular research.
Kaelin also has received the Science of Oncology Award from the American Society of Clinical Oncology, the Princess Takamatsu Award from the American Association for Cancer Research, the Steven C. Beering Award, and the Wiley Prize in Biomedical Sciences. He has also been a Howard Hughes Medical Institute investigator since 1998.