Oxygen’s importance in cellular processes has long been known. But the work to understand how cells sense and adapt to changes in oxygen levels has led to medical insights and potential treatments for anemia, cancer, and more—and today, it has turned into the 2019 Nobel Prize in Medicine.
William Kaelin Jr., Sir Peter Ratcliffe, and Gregg Semenza are credited with identifying the molecular machinery that regulates the activity of genes in response to changes in oxygen levels.
Semenza, a professor of medicine at Johns Hopkins University, studied the gene that encodes a protein used to produce erythropoietin (EPO), a kidney hormone that promotes the formation of oxygen-carrying red blood cells. One of the body’s responses to hypoxia, or low oxygen levels, is a rise in EPO. His research showed how DNA segments located next to the EPO gene mediated the response to hypoxia, the Nobel Committee said. Semenza discovered a group of proteins that play a role in the body’s response to low oxygen. He called these proteins hypoxia-inducible factor (HIF).
Ratcliffe is a British physician and cell and molecular biologist. Like Semenza, he studied how oxygen levels affect the EPO gene. The Nobel Committee said groups led by Semenza and Ratcliffe both found that this oxygen-sensing mechanism was present in virtually all tissues, not just kidney cells.
Kaelin, a professor of medicine at Harvard University and Boston’s Dana-Farber Cancer Institute, was honored for his work showing how the HIF proteins that Semenza discovered are regulated. Kaelin’s initial focus was on von Hippel-Lindau (VHL) disease, a rare inherited disorder. That research revealed that the VHL gene plays a role in controlling cellular responses to low oxygen levels. Kaelin’s research also furthered understanding about protein degradation, a process that cells use to rid themselves of damaged or disease-causing proteins. Protein degradation uses molecular “tags” to mark unwanted proteins for disposal. The Nobel Committee said Kaelin’s research helped show how these tags bind to proteins in an oxygen-dependent way.
Ratfcliffe discovered yet another connection between VHL and protein degradation. He found that VHL physically interacts with the HIF-1a protein, helping break it down.
According to the Nobel Committee, Kaelin and Ratcliffe furthered their research by showing how cells sense changes in oxygen levels and respond to those changes. This sensing allows cells to adapt their metabolism to low-oxygen conditions, such as periods of intense exercise. Oxygen sensing also controls the processes for growing new blood vessels and creating red blood cells. Diseases and medical conditions affected by oxygen sensing include anemia, cancer, and stroke.
The growing understanding about the role of oxygen levels in disease has paved the way for a number of new companies. Arvinas (NASDAQ: ARVN), Nurix Therapeutics, Kymera Therapeutics, and Cedilla Therapeutics are among the biotechs developing protein degradation drugs for cancer, autoimmune diseases, and more. Peloton Therapeutics, a company developing cancer drugs that target HIF-2a, reached a deal to be acquired by Merck (NYSE: MRK) for $1 billion earlier this year.