William G. Kaelin, Jr. - Recipient of the 2019 Nobel Prize in Physiology or Medicine
7 October 2019: William G. Kaelin Jr., Peter J. Ratcliffe and Gregg L. Semenza are this year's recipients of the Nobel Prize in Physiology or Medicine "... for their discoveries of how cells sense and adapt to oxygen availability."
When I joined the faculty at Duke University, I was investigating tumor oxygenation and blood flow regulation. At that time, third year Duke medical students were required to perform a research project. Bill Kaelin asked to do research in my lab in the early 1980s because of his early interest in tumor oxygenation. He demonstrated that the calcium antagonists verapamil and flunarizine significantly increased tumor blood flow, indicating their potential usefulness in improving cancer treatment with both chemotherapeutic agents and ionizing radiation.
Ultimately, his interest in the regulation of tissue oxygenation led to his seminal discovery that the von Hippel-Lindau tumor suppressor protein (pVHL) binds to the hypoxia-inducible factor (HIF) when a conserved proline residue is hydroxylated (Ivan et al, Science, 2001). This finding provided the first evidence that oxygen-induced modification of HIF plays a key mechanistic role in mammalian oxygen sensing, for which he won the Nobel Prize in Medicine.
Recent findings indicate that these intricate oxygen sensing pathways are not only changed through genetic mutations during disease formation, but can also be modified epigenetically (Dick et al, The Lancet, 2014; Pfeiffer et al, Sci Rep, 2016), bringing this area of research into the growing field of environmental epigenomics.
One of Bill Kaelin's undergraduate Duke University premed professors wrote when he was hoping to be become a physician researcher that "Mr. Kaelin appears to be a bright young man whose future lies outside of the laboratory." In contrast, I thought from the beginning that Bill had the intelligence, creativity, and drive required to be a pioneering research scientist. It is an honor to know Bill and to have had a small part to play in his scientific career. I am truly proud of him and his scientific contributions!
