Nobel Prize in Medicine Awarded for Research 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. The findings have implications for treating a variety of diseases, including cancer, anemia, heart attacks and strokes.

Why did they win?

“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. The three researchers tried to answer this question: 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.

Why is the work important?

The discoveries reveal the cellular mechanisms that control such things as adaptation to high altitudes and how cancer cells manage to hijack 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 research also has implications for treating various diseases in which oxygen is in short supply — including anemia, heart attacks and strokes — as well as for treatment of cancers that are fed by and seek out oxygen.

Who are the winners?

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

“Like any scientist, I like solving puzzles,” he said in an interview this morning.

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

Eventually he became intrigued by a rare, genetic cancer, von Hippel-Lindau disease, that is characterized by a profusion of extra blood vessels and overproduction of erythropoietin, or EPO, a hormone that stimulates production of the red blood cells that carry oxygen.

The cancer “was really fascinating,” Dr. Kaelin said. It had 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.”

As it turned out, 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.”

Dr. Kaelin said he knew, of course, that today the Nobel Prize would be awarded. But his chances were “so astronomically small” that he stuck with this usual routine and did not stay up last night.

He had a dream, though, that he had not gotten the 5 a.m. call from Sweden. He woke up and looked at the time; in fact, it was just 1:30 a.m.

He went back to sleep, and when it really was 5 a.m., his phone rang.

Gregg L. Semenza, professor of genetic medicine at Johns Hopkins, said his life was changed by a high school teacher, Rose Nelson, who taught biology at Sleepy Hollow High School in Tarrytown, N.Y.

“She was unbelievable,” Dr. Semenza recalled in an interview. “She transmitted the wonder and joy of science and scientific discovery. She set me on a course to science.”

In college, at Harvard, he thought he would get a Ph.D. and do research in genetics. But then a family he was close to had a child with Down syndrome.

“That shifted me from being interested in genetics as kind of a scientific discipline to thinking about the impacts of genetics on people,” he said.

After attending medical school at the University of Pennsylvania, Dr. Semenza set out to understand what cancer cells are searching for when they spread into surrounding tissues, and then into blood vessels that carry them around the body.

His guess was that cancer cells are searching for oxygen.

Dr. Semenza turned his attention to the gene the guides production of EPO. Once it is activated, the body makes more oxygen carrying red blood cells. But how is that switch turned on when the body is deprived of oxygen?

As a geneticist, he was trained to study rare genetic diseases. But his work on cellular responses to oxygen led him to study such common diseases as heart disease and cancer.

At first, he divided his attention between the two conditions. More recently, Dr. Semenza said, he has focused on cancer, looking for ways to use what he has learned to find new ways to attack tumors.

Dr. Semenza was asleep when the call from Sweden came this morning, and did not get to his phone in time to answer it. The phone rang again a few minutes later.

“I heard this very distinguished gentleman tell me I was going to receive the Nobel Prize,” he said. “I was shocked, of course. And I was kind of in a daze. I’ve been in a daze ever since.”

But he added, “It’s been wonderful.”

Peter J. Ratcliffe, the third Nobelist, is the director of clinical research at the Francis Crick Institute in London and director of the Target Discovery Institute at Oxford.

He became a medical researcher almost by chance. “I was a tolerable schoolboy chemist and intent on a career in industrial chemistry,” he said in a speech in 2016. “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 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 not very important.

But he persisted, intrigued by the scientific puzzle. “We set about the problem of EPO regulation, which might have been seen, and some did see, as a niche area,” he said in a telephone interview posted by the Nobel Committee on Twitter.

“But I believed it was tractable, it could be solved by someone. The impact of that became evident later.”

The research is an illustration of the value of basic research, he added: “We make knowledge, That’s what I do as a publicly funded scientist. It is good knowledge. It is true. It is correct.”

But, he added, “We set out on a journey without a clear understanding of the value of that knowledge.”

When the call from Sweden came, Dr. Ratcliffe was writing a grant proposal. Today he will continue working on it.

“I’m happy about it,” he said of the Nobel Prize. But also was not enthusiastic about being thrust into the public eye.

“I’ll do my duty, I hope,” he said.

“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,” he said in a statement released by Oxford.

Who won the 2018 Nobel for medicine?

The prize last year went to James P. Allison of the United States and Tasuku Honjo of Japan for their work on immunotherapy, for 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.

When will the other Nobel Prizes be announced?

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Michael Wolgelenter contributed reporting.