Early this morning, the Nobel Assembly at the Karolinska Institutet notified three researchers, two Americans and a British scientist, they will be awarded the Nobel Prize in Physiology or Medicine for their work revealing how cells sense and adapt to oxygen availability. The research has not only illuminated details of human physiology, but has paved the way for treating medical problems including anemia and cancer.
The joint prize is being split between William G. Kaelin, Jr., a doctor and medical researcher at Harvard University and the Dana-Farber Cancer Institute, Peter J. Ratcliffe, an Oxford professor with the Francis Crick Institute, and Gregg L. Semenza of Johns Hopkins University School of Medicine.
Each research team worked independently for over two decades to determine the response of cells to oxygen abundance. Mitochondria, the little organelles found in the cells of almost every living thing, need oxygen to produce energy. But if they receive too much or too little oxygen, they don’t perform their job well. So the body has developed molecular “machinery” that helps regulate oxygen when environmental levels are too low or too high. This type of oxygen regulation occurs when the body acclimates to higher altitudes, allowing cells to adjust to the lower levels of oxygen in the environment.
Much of that regulation, previous research established, is controlled by a hormone called erythropoietin (EPO), which boosts the concentration of oxygen-carrying red blood cells. Just how varying oxygen levels caused the EPO genes to turn on and boost oxygen levels, however, was unknown.
Using gene-modified mice, Semenza and his team found that bits of DNA next to the EPO gene were responsible for mediating the body’s response to oxygen levels. Semenza and Ratcliffe both found that oxygen-sensing mechanisms were also located in almost every type of tissue in the body. In particular, they identified a protein complex called hypoxia-inducible factor (HIF), composed of two proteins, HIF-1 alpha and ARNT, that can bind themselves to the DNA, signaling low oxygen levels and stimulating the production of EPO.
Kaelin, meanwhile, was researching an unusual disorder called von Hippel-Lindau’s disease (VHL disease), a genetic condition that dramatically raises the risk of some cancers in families with the mutations. In particular, report Gina Kolata and Megan Specia at the New York Times, the cancers are associated with overproduction of blood vessels and increased production of EPO. “I thought it had something to do with oxygen sensing,” Kaelin says.
He was right, and his work helped to further flesh out the body's processes to sense and adjust oxygen levels. “It is one of the great stories of biomedical science,” George Daley, dean of Harvard Medical School tells the Times. “Bill is the consummate physician-scientist. He took a clinical problem and through incredibly rigorous science figured it out.”
The research not only fills in gaps about the oxygen-sensing process, but it also opens up new avenues for combating common diseases. In chronic renal failure, for instance, reduced EPO expression often leads to anemia. Many cancers highjack the oxygen-sensing system to stimulate blood-vessel growth and make conditions right for the spread of cancer cells. Research is currently underway to develop drugs that can activate or block these oxygen sensors to combat these diseases.
Randall Johnson, prize committee member, said in a video interview that though some of these discoveries were made in the mid 1990s, the trio is receiving the award now because further research has illuminated the oxygen-sensing process. “Scientists often toss around this phrase ‘textbook discovery,’” he says. “I’d say this is essentially a textbook discovery. This is something basic biology students will be learning about when they study, at age 12 or 13 or younger, biology, and learn the fundamental ways cells work.”
According to Reuters, Thomas Perlmann, a member of the Nobel Assembly who phoned the three men, said they were all very excited by the honor. “They were extremely happy, and happy to share the prize with each other,” he says.
Kaelin, he says, was almost speechless, and Semenza was still asleep when the call came. Ratcliffe, meanwhile, was in his office, working on a grant proposal. The prize ceremony will take place on December 10, on the anniversary of Alfred Nobel’s death.