NOBEL PRIZE IN MEDICINE AWARDED TO HYPOXIA RESEARCHERS

The prize was awarded to William G. Kaelin Jr., Peter J. Ratcliffe and Gregg L. Semenza for discoveries about how cells sense and adapt to oxygen availability
NOBEL PRIZE IN MEDICINE AWARDED TO HYPOXIA RESEARCHERS

The Nobel Assembly announced the prize at the Karolinska Institute in Stockholm on October 7th 2019.

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 to 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.

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 his 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 Sleepy Hollow, 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 that 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 the 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 inter- view 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 he 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.

How this discovery can help fight diseases

This year's Nobel prize winning oxygen study could result in treatments for a variety of diseases, including cancer, heart attack and stroke. While declaring this year's Nobel Prize in Physiology or Medicine, the award committee said that labs and pharmaceutical companies around the world were racing to develop drugs “that can interfere with different disease states by either activating, or blocking, the oxygen- sensing machinery.”

The discovery means that we now understand the processes behind the generation of new blood vessels, the production of red blood cells, certain immune system functions and even fetal and placenta development. We, therefore, know much more about the diseases arising from these pathways, such as cancers that proliferate using the oxygen-sensing system to grow tumours. All across the globe, there are now ongoing efforts by academics, entrepreneurs and pharmaceutical companies focused on developing drugs that can either inhibit or activate this oxygen-sensing machinery.

Many potential therapies are already exploiting this newly-acquired under- standing. China, for instance, is close to clinically testing a therapy that would help treat anaemia. Medical scientists elsewhere, similarly, hope that HIF-1a may offer a magic bullet to deal with some of the most aggressive forms of breast cancer in the near future.

Roxadustat and daprodustat, treat anaemia by increasing red blood cell production, and similar drugs are aiming to treat patients with heart disease and lung cancer that struggle with hypoxia. More experimental drugs are also blocking blood vessel formation, aiming to prevent tumour growth in some cancers.

Experts say the discoveries were integral to the development angiogenesis blockers like Avastin (bevacizumab), which treat cancer by blocking tumor cells’ ability to trigger the growth of new blood vessels they need to obtain oxygen and nutrients. Angiogenesis blockers are used to treat a variety of cancers, including malignancies of the brain, kidney, lung and colon. In many cases, the drugs are used in combination with other treatments, including chemotherapy.The discoveries could also help lead to the development of new drugs for heart attack and stroke. Both conditions are marked by cell damage resulting from interruption of the delivery of oxygen-rich blood to critical tissues.

© New York Times News Service

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