Three scientists were awarded the Nobel Prize in Physiology of Medicine for their discovery of the mechanism of how cells regulate oxygen: William G. Kaelin, MD, an oncologist who is the professor of medicine at Harvard Medical School and the Dana-Farber Cancer Institute; Gregg Semenza, MD, PHD, a scientist at Johns Hopkins; and Peter Ratcliffe, FRS, FMedSci, of the Francis Crick Institute in London.
The key breakthroughs were made through an oncological look into a rare hereditary cancer type, according to the Nobel Assembly at Karolinska Institute.
The Nobel Committee cited that Semenza and Ratcliffe were focused on the rise of the levels of the hormone erythropoietin (EPO) in response to hypoxia (low oxygen levels) in the 1990s. Both Semenza and Ratcliffe were studying the genes controlling EPO in mice – and thereby elucidating the hypoxia-inducible factor, or HIF.
Kaelin, a cancer researcher, was instead studying an inherited syndrome called von Hippel-Lindau’s disease, or VHL. It’s a rare inherited affliction which dramatically increases the likelihood of some tumors. The mutated gene in VHL was eventually shown by Kaelin to show that it controlled the response to hypoxia – and was thus integral in HIF. Kaelin showed that one form of the protein, HIF-2α, is critical in the development of some kidney cancers, and how HIF-1α is hijacked by triple-negative breast cancers, according to a statement by the Dana-Farber Cancer Institute.
The consequent identification of proline hydroxylases of the 3 scientists working independently of one another fully determined how oxygen uptake is regulated, the Nobel officials explained.
“Through the combined work of these 3 laureates it was thus demonstrated that the response by gene expression to changes in oxygen is directly coupled to oxygen levels in the animal cell, allowing immediate cellular responses to occur to oxygenation through the action of the HIF transcription factor,” the Nobel Committee stated.
The 3 scientists were named winners of the Lasker Award for Medical Science in 2016.
The impact to cancer includes possible inhibitors to the HIF pathway – including one found by Kaelin and his colleagues to block the EPAS1 function, thereby slowing tumor growth, as per a 2016 study published in Nature.
Kaelin said in a phone interview with a Nobel interviewer that some of the key breakthroughs were made because they were trying to understand the entire oxygen pathway.
“The clinical features of patients who had mutations in the VHL gene were a curious constellation of findings – but one way to unify them was that there was some abnormality in the way the tumors they were developing were sending and responding to oxygen,” Kaelin recalled. “We thought if we could understand that, we could understand more globally how cells and tissues sense and respond to changes in oxygen.”
“I, like my co-awardees, I’m trained as a physician,” he added, in the early-morning call. “We understood very well the important of oxygen in so many human disease… Now that we understand the pathway we have opportunities for pharmacological intervention in diseases such as cancer.”
The work was made possible, Kaelin added, because the scientists were trying at first to just understand the biology – and they were not focused solely on clinical applicability.
“There are no shortcuts, as far as I’m concerned,” the oncologist said.