The 2018 Meira and Shaul G. Massry Prize has been awarded to William G. Kaelin Jr., MD, of Harvard Medical School; Sir Peter Ratcliffe, FMedSci, FRS, of Oxford University, the Francis Crick Institute London and the Ludwig Institute for Cancer Research; and Gregg L. Semenza, MD, PhD, of Johns Hopkins Medicine. The three scientists discovered how mammals respond and adapt to oxygen levels in the environment. This crucial research has led to a series of unexpected findings and the potential for new drugs to treat anemia, cardiovascular disease and even cancer.
The Meira and Shaul G. Massry Foundation, which promotes education and research in nephrology, physiology and related fields, established the Massry Prize in 1996 to recognize outstanding contributions to the biomedical sciences and the advancement of health. Fifteen Massry Prize recipients have gone on to win Nobel Prizes.
Oxygen is the key to life on Earth, forming the basis of cellular metabolism to provide the energy that allows animals to survive. Animals trap oxygen in red blood cells and deliver it to all tissues in the body, so that cells have the energy to function. But oxygen is both a blessing and a curse. Too much and cell death pathways can be activated; too little and the cell runs out of energy.
One of the basic responses to oxygen deprivation in our bodies is increased respiration and increased production of red blood cells through the release from the kidney of a hormone called erythropoietin. This response is vital to human survival. But how do cells “sense” the amount of oxygen around them to induce erythropoietin release? This core question was addressed by Semenza and Ratcliffe more than 20 years ago. Semenza discovered a protein called hypoxia-inducible factor (HIF-1) that was uniquely responsive to cellular oxygen levels. When oxygen levels are low, HIF-1 attaches to DNA and activates expression of genes near its DNA binding sites, including the erythropoietin gene. This was the discovery of the key to cells’ ability to sense oxygen.
The discovery of HIF-1 was the start of a long journey to understand oxygen-sensing in cells. In addition to activating genes associated with red blood cell production, Semenza and Ratcliffe discovered that HIF-1 activated many other genes throughout the body. For example, there was direct induction of vascular endothelial growth factor (VEGF), crucial for blood vessel formation. Like a conductor bringing an orchestra together, HIF-1 coordinates red blood cell production, blood vessel growth and a range of other responses that constitute the adaptive body symphony when oxygen levels are lowered. But how does low oxygen change HIF-1 levels?
Enter Kaelin and his research on a rare human disorder: von Hippel-Lindau (VHL) Disease, which involves the formation of blood vessel-rich tumors and cysts along with high erythropoietin levels. Recognizing that a VHL gene mutation results in a deficient VHL protein and this somehow raises blood levels of erythropoietin, Kaelin discovered that the VHL protein is essential for cells to sense the oxygen levels. Another key observation was when Ratcliffe found that VHL interacts with HIF-1 but only when oxygen levels are high. Kaelin then showed that VHL binds to HIF-1 and initiates an assembly structure.
Starting from these seminal observations, many modulators of this oxygen sensing system and the subsequent regulation of cell function have been discovered by the Massry Prize winners and other scientists. Armed with this knowledge, it is now possible to manipulate oxygen sensing and response systems to improve human health. For example, increasing HIF-1 complex regulation could potentially increase red blood cells to help patients with anemia and could potentially increase cardiac vascularization to ward off heart attacks. Decreasing HIF-1 activity and reducing vascularization might slow cancers that need new blood vessels to feed their growth.
“The work of Kaelin, Ratcliffe and Semenza uncovered one of nature’s most important secrets: how oxygen is sensed by animal tissues and how cells modulate their responses to reduced oxygen,” said Shaul Massry, MD, professor emeritus of medicine and physiology & biophysics at the Keck School of Medicine of USC. “This fundamental discovery will have continued impact on medicine for the future.”
The winners will provide lectures on their work at 12:30 p.m. Thursday, Sept. 20, at Mayer Auditorium on the Health Sciences Campus. Lunch will be served before the lecture. RSVP at http://www.usc.edu/esvp, Code: Massry2018.