Three scientists have been awarded the Nobel Prize in Physiology or Medicine for their work discovering how cells sense and respond to oxygen, a necessary process for all animal life.
William Kaelin of the Dana-Farber Cancer Institute at Harvard University, Sir Peter Ratcliffe of Oxford University, and Gregg Semenza of Johns Hopkins University were jointly awarded the prize for their discoveries identifying the molecular machinery enabling cells to respond to varying levels of oxygen.
Their research has clinical applications in treating anemia, as well as potentially finding new ways to thwart the growth of tumors in cancer.
"These fundamental findings have greatly increased our understanding of how the body adapts to change, and applications of these findings are already beginning to affect the way medicine is practiced," Randall Johnson of Karolinska Institute, who is on the Nobel prize selection committee, said in Stockholm on Monday morning. "This year's three laureates have greatly expanded our knowledge of how physiological response makes life possible."
Oxygen powers all animal cells, a necessary ingredient in the process of converting food into usable energy. In 1931, the Nobel Prize was awarded to Otto Warburg, for his research showing that this conversion is an enzymatic process requiring oxygen.
What wasn't known was how individual cells sense and respond to fluctuations in oxygen levels. Cells are constantly experiencing changes in oxygen availability, such as when muscles work during exercise, during altitude changes, or even in a localized way when a wound interrupts the local blood supply.
Low oxygen levels — also known as hypoxia — trigger a spike in the hormone erythropoietin (EPO), which leads to increased production of red blood cells.
The earliest work of the three Nobel Prize winners, by Semenza of Johns Hopkins University, showed that this increase in EPO during hypoxia was due to a specific part of the EPO gene called the hypoxia-response element (HRE). Using genetically modified mice, Semenza was able to show that HRE responded to shifting oxygen levels.
Semenza used this part of the gene to isolate the proteins controlling the expression of the EPO gene, including a crucial DNA-binding protein called HIF-1α. This protein degrades rapidly when oxygen levels are high, but when oxygen levels are low, the amount of HIF-1α increases, leading cells to produce more of the EPO needed for increased production of red blood cells.
Both Semenza and Ratcliffe's group at Oxford showed that this oxygen sensing mechanism is ubiquitous across all cells in the body.
Separately from Semenza and Ratcliffe's work on the EPO gene, Kaelin of the Dana-Farber Cancer Institute at Harvard was studying a genetic disease called von Hippel-Lindau's (VHL) disease, linked to a greatly increased risk of certain cancers. Kaelin showed that mutations in the VHL gene were linked to higher expressions of hypoxia-regulated genes, connecting the VHL gene to the hypoxia response as well. Ratcliffe later showed that the VHL gene physically interacts with the protein that he and Semenza had been studying, HIF-1α, showing how it degrades the protein at normal oxygen levels.
"We didn't really foresee the broad impact of this system when we started the work," Ratcliffe said in a telephone interview with the Nobel Prize after the ceremony. "It's important that scientists have the courage and are allowed to derive knowledge for its own sake, independent of the perceived value at the point of creation."
The work of the three scientists is now also making its way into drug development, including in drugs to increase HIF used to treat anemia and to suppress HIF used to treat some forms of cancer. Tumors have increased HIF expression to help them cope with low levels of oxygen in their interiors, and new drugs are experimenting with ways to inhibit HIF in order to cause tumors to shrink.
"This is such a fundamental aspect of how our cells deal with getting oxygen and then adapting to its use, that one can almost imagine that the applications will be, I don’t want to say endless, but very, very wide," Johnson said.
The three scientists will share the prize of 9 million Swedish kronor for their work, roughly equal to $908,000.
The other Nobel prizes in the sciences will be announced later this week, with physics on Tuesday and chemistry on Wednesday.