Nobel Prize in Medicine Awarded to 3 for Work on How Cells Manage Oxygen

The Nobel Prize in Physiology or Medicine was jointly awarded to three scientists — William G. Kaelin Jr., Peter J. Ratcliffe and Gregg L. Semenza — for their work on how cells sense and adapt to oxygen availability.

The Nobel Assembly announced the prize at the Karolinska Institute in Stockholm on Monday.

Their work established the genetic mechanisms that allow cells to respond to changes in oxygen levels, and has implications for treating a variety of diseases, including cancer, anemia, heart attacks and strokes.

“Oxygen is the lifeblood of living organisms,” said Dr. George Daley, dean of Harvard Medical School. “Without oxygen cells can’t survive.” But too much or too little oxygen also can be deadly, so the question was, how do cells regulate their responses?

The investigators uncovered detailed genetic responses to changing oxygen levels that allow cells in the bodies of humans and other animals sense and respond to fluctuations, increasing and decreasing how much oxygen they receive.

The discoveries reveal the molecular mechanisms that control such things as adaptation to high altitudes and also how cancer cells manage to fuel their metabolisms by hijacking oxygen. Randall Johnson, a member of the Nobel Assembly, described the work as a “textbook discovery” and said it would be something students would start learning at the most basic levels of biology education.

“This is a basic aspect of how a cell works, and I think from that standpoint alone it’s a very exciting thing,” Mr. Johnson said.

The work also has implications for treating various diseases including anemia, heart attacks, and strokes, in which there is too little blood, and also cancers that are fed by and seek out oxygen.

William Kaelin, professor of medicine at Dana-Farber Cancer Institute and Brigham & Women’s Hospital Harvard Medical School, was drawn to science for its purity.

“I like mathematics, medicine, and science because I like solving puzzles, and I like answers that are objectively verifiable,” he said when he shared a Lasker award in 2016 with Dr. Ratcliffe and Dr. Semenza.

But he had an unprepossessing start. When he was a pre-med student, hoping to become a physician researcher, his professor wrote, “Mr. Kaelin appears to be a bright young man whose future lies outside of the laboratory.”

He eventually prevailed. He became intrigued by a rare genetically induced cancer, von Hippel-Lindau disease, that is characterized by a profusion of extra blood vessels and overproduction of EPO.

“He was studying a very rare cancer predisposition syndrome,” Dr. Daley said. “It is not a public health menace but it is a fascinating point of curiosity.”

Dr. Kaelin, in an interview this morning, explained: “Like any scientist I like solving puzzles.” And this cancer, he said, “was really fascinating.” It had such unusual features, like causing the body to make a substance, vegF, that stimulates the formation of blood vessels. And the cancer can cause the body to make too many red blood cells by increasing the production of EPO.

He had a hunch about what was going awry.

“I thought it had something to do with oxygen sensing,” he said.

Of course he was right.

“It is one of the great stories of biomedical science,” Dr. Daley said. “Bill is the consummate physician-scientist. He took a clinical problem and through incredibly rigorous science figured it out.”

Gregg L. Semenza is professor of genetic medicine at Johns Hopkins and has been the director of the Vascular Research Program at the Johns Hopkins Institute for Cell Engineering since 2003. He quoted the words of Mary Lasker in as he accepted the Lasker prize in 2016: “I am opposed to heart attacks and cancer the way one is opposed to sin.”

To which he added, “Amen.”

He, like many other researchers, said he pursues his work with “a religious fervor.”

He set out to understand what cancer cells are searching for when they spread from tumors into surrounding tissues, and then to blood vessels that let them travel around the body.

His guess, he said, is that they are searching for oxygen.

The work started when he wondered about the gene for EPO. How was that switch turned on when the body is deprived of oxygen? Once it is activated, the body makes more oxygen carrying red blood cells. But what was the molecular signal that set the process in motion?

His hope, he said during the Lasker talk, was that uncovering the mechanisms that control cells’ responses to oxygen will lead to drugs to increase oxygen sensitivity to treat anemia and cardiovascular diseases. And drugs that do the opposite — decrease oxygen sensitivity — will be developed to treat cancer.

Peter J. Ratcliffe, the third Nobelist, is the director of clinical research at the Francis Crick Institute in London, the director of the Target Discovery Institute at Oxford and a member of the Ludwig Institute for Cancer Research. He became a medical researcher only by chance.

“I was a tolerable schoolboy chemist and intent on a career in industrial chemistry. The ethereal (but formidable) Headmaster appeared one morning in the chemistry classroom. ‘Peter’ he said with unnerving serenity ‘I think you should study medicine’. And without further thought, my university application forms were changed,” he said in 2016.

He became a kidney specialist, fascinated by the way the organs regulate production of EPO in response to the amount of oxygen available. Some colleagues, he said, felt this was “a niche area” and not very important. But he persisted, intrigued by the scientific puzzle. That led him to the discoveries that resulted in a Nobel Prize.

The Nobel Prize Twitter account posted a photo of Dr. Ratcliffe writing a grant proposal on Monday, after learning of his award.

“I’m honoured and delighted at the news. I’ve had great support from so many people over the years,” he said in a statement released by Oxford. “It’s a tribute to the lab, to those who helped me set it up and worked with me on the project over the years, to many others in the field, and not least to my family for their forbearance of all the up and downs.”

Dr. Kaelin said he knew, of course, that today was Nobel Prize Monday. But, he said, “I try to not pay attention.” The chances, he added “are so astronomically small,” that he stuck with this usual routine and went to sleep.

He had a dream, though, that it was 5:30 a.m. and because he had not gotten a 5 a.m. call from Sweden he knew he had not won. He woke up, looked at the time, and saw that it was 1:30 a.m. So he went back to sleep.

Then his phone rang at 5 a.m.

He had won.

The prize last year went to James P. Allison of the United States and Tasuku Honjo of Japan for their work on immunotherapy, or unleashing the body’s immune system to attack cancer. This breakthrough has resulted in an entirely new class of drugs and brought lasting remissions to many patients who had run out of options.


Michael Wolgelenter contributed reporting.