Researchers who advanced understanding of how cells sense and adapt to oxygen availability have won the 2019 Nobel Prize in physiology or medicine. The decision partly reflects the potential for the research to inform development of new treatments for diseases including anemia, cancer and stroke.
Harvard Medical School’s William Kaelin Jr., the University of Oxford’s Sir Peter Ratcliffe and Johns Hopkins University’s Gregg Semenza shared the prize for their independent work into the interaction between cells and oxygen. Collectively, the researchers, working with collaborators not honored by the Nobel Assembly, identified the molecular machinery that acts to regulate the activity of genes in response to changes in oxygen levels.
The scientific research narrative plotted out by the Nobel Assembly covers Ratcliffe and Semenza’s research into oxygen-dependent regulation of the EPO gene, which showed that the vast majority of tissues share an oxygen-sensing mechanism. Semenza went on to identify the hypoxia-inducible factor (HIF) and show that the protein complex undergoes oxygen-dependent binding to a DNA segment.
Kaelin worked in a different area, cancer, but made discoveries that informed the oxygen field. When researching a rare genetic disease associated with increased cancer risk, Kaelin linked the VHL gene to the mechanism for controlling responses to oxygen deprivation. Subsequently, Ratcliffe showed that VHL is involved in the degradation of the transcription factor HIF-1α.
Kaelin and Ratcliffe went on to describe the mechanism by which VHL identifies and binds to HIF-1α, thereby explaining the role oxygen levels play in the degradation of the transcription factor.
The body of research improved understanding of physiological processes including metabolism and immune response. In doing so, the researchers also pointed to new ways to treat disease. The Nobel Assembly highlights anemia, cancer, stroke, infection, wound healing and myocardial infarction as areas of healthcare that could be affected by the research.
That broad potential is reflected in the pipeline of drugs targeting pathways related to the research. Companies including AstraZeneca see inhibitors of HIF-prolyl hydroxylase as a better way to treat renal anemia, while Merck illustrated the excitement about the potential of the research in cancer by paying $1.05 billion upfront to buy Peloton Therapeutics for its HIF-2α inhibitor.