The mechanism studied affects a broad range of physiological responses and is now the focus of intense study by the pharmaceutical industry.
Three physician scientists whose work revealed how cells sense changing oxygen levels and adapt to them today were awarded the 2019 Nobel Prize in Physiology or Medicine. They are William G. Kaelin, Jr., MD, of Dana Farber Cancer Institute; Sir Peter J. Ratcliff, MD, of Oxford University; and Gregg Semenza, MD, PhD, of Johns Hopkins University.
The citation highlights fundamental research that explained a mechanism essential for animals to convert food to energy and to adapt to changing environments, and one that in recent years has been harnessed to develop treatment for anemia and has implications for the treatment of cancer. The announcement took place in Stockholm, Sweden, at 5:30 am ET, shortly after all 3 winners received word by phone that they would share the most prestigious prize in science.
When oxygen levels are low, a condition called hypoxia, the body adapts in several key ways. One is the rise of a the hormone erythropoietin (EPO), which in turn increases the production of red blood cells. Semenza studied how the EPO gene regulated oxygen and used specially modified mice to demonstrate how DNA next to the EPO gene affect the hypoxia response. He then identified the protein complex that binds the DNA segment as oxygen levels rise and fall, which he named hypoxia-inducible factor, or HIF.
Further research to isolate HIF showed it actually consisted of 2 proteins, ARNT and HIF-1α, the latter of which drops when oxygen levels are high and rises as oxygen falls. This aspect is being applied in the clinical setting, as therapies are in development to regulate HIF-1α to treat cancer. Thus, the HIF complex is both essential to life and can also fuel the growth of cancer tumors.
“That may be difficult to conceptualize that something can be both bad and good,” said Randall Johnson of the Karolinska Institute during the presentation of the Nobel citation. But Johnson said that is the nature of basic discovery, which Nobel Committee Secretary Thomas Perlmann said is what Alfred Nobel sought to recognize with the prize for physiology or medicine.
Work by both Ratcliff and Semenza showed how the oxygen-sensing qualities of the EPO gene and its mechanism were at work across nearly all tissues. And Kaelin’s work on the inherited syndrome, von Hippel-Landau’s disease, (VHL), showed that the VHL gene contains protein that can block the onset of cancer; he additionally found that the presence or absence of a VHL gene in cancer cells affected hypoxia levels, and in turn linked VHL to HIF-1α. Subsequent papers by Ratcliff and others clarified the processes through which VHL recognizes and binds to HIF-1α.
The mechanism uncovered by the 3 Nobel winners affects a range of physiological processes—from how the body responds to exercise, to how it adapts to different altitudes, to how EPO produced in the kidney regulates the formation of red blood cells. Translating this knowledge to pharmaceutical targets is an area of intense focus, according to information from the Nobel Committee. Semenza’s lab has taken part in a phase 1 study involving the regulation of HIF-1α in the treatment of liver cancer.
“This is a momentous day for all of us at Johns Hopkins, and we are immensely proud,” said Johns Hopkins University President Ronald J. Daniels in a statement. “Gregg’s passion for discovery and the energy with which he pursues that passion exemplify Johns Hopkins’ commitment to create new knowledge that helps make a better and humane world.”
The trio previously shared the Lasker Award in 2016, and that year Kaelin was honored with the Science of Oncology award by the American Society of Clinical Oncology.