Discovery of how cells sense oxygen wins the 2019 medicine Nobel

Manipulating this molecular switch is being explored for cancer treatment

William Kaelin, Gregg Semenza and Peter Ratcliffe

The trio of winners for this year's Nobel Prize in physiology or medicine, William Kaelin, Gregg Semenza and Peter Ratcliffe (from left), discovered the molecular machinery that allows cells to sense and respond to changes in oxygen levels.

From left: Dana-Farber; Johns Hopkins; Univ. of Oxford

A trio of scientists has won the 2019 Nobel Prize in physiology or medicine for their work on how cells sense and respond to oxygen.

Gregg Semenza of Johns Hopkins University School of Medicine, William Kaelin of Dana-Farber Cancer Institute in Boston and Peter Ratcliffe of the Francis Crick Institute in London made discoveries relating to the HIF system, proteins that fine-tune cells’ response to oxygen. The three researchers will split the prize of 9 million Swedish kronor, or more than $900,000.

Like candles or furnaces, cells need oxygen to function correctly. If oxygen isn’t regulated properly, cells could die. The work has implications for nearly every aspect of physiology from metabolism to exercise, immunity, embryo development and the response to lack of oxygen at high altitudes, Nobel committee member Randall Johnson, noted during the announcement of the prize by the Nobel Assembly of the Karolinska Institute in Stockholm on October 7. The HIF system plays a role in anemia, cancer, heart attack, stroke and other disorders.

“Cells literally and figuratively don’t live in a vacuum,” says Dennis Brown, a cell physiologist at Massachusetts General Hospital and Harvard Medical School in Boston. In fact, “life as we know it wouldn’t exist without oxygen,” he says. For many years, scientists understood that cells could adjust to differing levels of oxygen, but didn’t know how it was done until the three new laureates made their discoveries, says Brown, who is also the chief science officer for the American Physiological Society.

Semenza and Ratcliffe both discovered that all cells can sense when oxygen levels drop. “Your body does all sorts of things to keep the level of oxygen appropriately high in your blood and in your tissues,” says cell biologist Andrew Murray of Harvard University. For instance, at high altitudes where the air is thinner, the body responds to not having enough oxygen, a condition known as hypoxia, by turning on production of erythropoietin. That protein, often called EPO, is a hormone made by the kidneys and signals the bone marrow to make red blood cells. Since red blood cells contain hemoglobin, which ferries oxygen throughout the body, making more red blood cells boosts the amount of oxygen in cells and tissues.

Semenza went on to identify hypoxia-inducible factor, or HIF, a complex of proteins that switches on activity of genes needed to make erythropoietin and other proteins that help cells adjust to low-oxygen conditions.

Hikers on Everest
At high altitudes, such as trekking near Mount Everest (shown), the body responds to low oxygen levels by preventing a key set of proteins from breaking down. That increases levels of the hormone erythropoietin, spurring the production of oxygen-carrying red blood cells. The 2019 Nobel Prize for physiology or medicine was awarded for the discovery of this molecular mechanism.Marc Bruxelle/Shutterstock

Ratcliffe, a kidney physiologist, discovered that cells constantly make the HIF proteins, but if there is enough oxygen, cells promptly chew up those proteins, says Murray. HIF and other proteins slated for destruction get tagged with an “eat me” sign, in the form of a small protein called ubiquitin (SN: 10/13/04).

At about the same time as Ratcliffe made his finding, Kaelin, a cancer biologist and a Howard Hughes Medical Institute investigator, was studying an inherited cancer called von Hippel-Lindau disease. People with this hereditary cancer often have tumors in their pancreases, kidneys and adrenal glands as well as in the central nervous system. Nervous system tumors may resemble tangles of blood vessels and sometimes produce erythropoietin, an indication that the cells are low on oxygen.

Kaelin discovered that proteins, known as the VHL complex because they go awry in these cancers, help affix the “eat me” tag to HIF, triggering its destruction. Kaelin probed how VHL knows when to tag HIF and when to leave it alone. When oxygen levels are normal, HIF sports hydroxyl groups (each a molecule of oxygen and a molecule of hydrogen, or OH). Ratcliffe’s and Kaelin’s groups identified the enzymes responsible for tacking on the hydroxyl groups, which is the signal for VHL to initiate HIF’s destruction. When oxygen levels drop, HIF is bare of hydroxyl groups and VHL ignores it, allowing HIF to trigger production of erythropoietin and other proteins needed to survive low oxygen.

Mutations that inactivate VHL increase HIF levels so cancer cells can boost their oxygen-scavenging activities and encourage blood vessel growth in the tumors, a process called angiogenesis (SN: 2/22/17). HIF also is involved in turning on production of a protein called VEGF, which stimulates blood vessel growth.

That is especially important in cancer because cancer cells grow quickly and exhaust their oxygen supply. Tumors can grow to only about 1 millimeter across without making new blood vessels, because oxygen can diffuse only about half a millimeter away from a capillary before cells consume it, says Murray.

Some researchers are working on therapies that might switch off HIF in cancer cells, suffocating them. Turning on low-oxygen responses also might help limit damage from heart attacks or kidney disease, Brown says.

The drug roxadustat, which manipulates the HIF system, has been approved in China to treat anemia in patients with chronic kidney disease. People develop anemia when the kidneys lose function because the organs don’t produce enough erythropoietin. Roxadustat blocks the enzymes that normally break down HIF, keeping this switch on to increase erythropoietin levels and red blood cell production.

The three researchers didn’t collaborate directly, Kaelin said in a news conference held at Dana-Farber. But “we’d see each other at meetings and talk there, or at bars afterwards, about the things that’d be appearing in the press six months from now, and I think that free exchange of ideas accelerated the field. It allowed us to reach escape velocity and go much faster.”

The trio’s discoveries were made in the 1990s, but it often takes decades before the Nobel Assembly awards the prize as it waits for “the year when the full impact of the discovery has become evident,” according to the late Ralf Pettersson, a former chairman of the Nobel selection committee at the Karolinska Institute.

“It’s very clear that we now understand this fundamental biological switch,” said Johnson. “It seems like a complete and clear story.”

In an interview posted on the Nobel Prize website, Ratcliffe said, “we set about the problem of EPO regulation, which might have seemed — and did seem to some — as a niche area. But I believed it was tractable, could be solved by someone…. As with almost any discovery science, the impact of that becomes evident later. We didn’t really foresee the broad reach of the system when we started the work.”

When it came to winning a Nobel, Kaelin confessed that “I did occasionally allow myself to dream that maybe one day this would happen.” But on Nobel Monday, Kaelin instead dreamed his clock read 5:45 a.m. EST — 15 minutes after the announcement was scheduled to take place in Stockholm — and he’d been passed over for the prize. In fact, he was the last of the three winners reached because the Nobel committee had to call his sister to get his phone number. When Kaelin finally got the call he’d been hoping for, “it was so surreal and I had this sort of out-of-body feeling,” he said.

Semenza, meanwhile, said that until now, “it has been a lousy year.” He fell down stairs in his home on May 31 and broke four cervical vertebrae in his neck. He slept through the Nobel committee’s first attempt to call him, but got to the phone in time when they called back. “I was not able to say much of anything because I was so shocked and surprised,” he said at a news conference at Johns Hopkins.

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