Discovery of the Molecular Switch for How Cells Use Oxygen has Won the 2019 Nobel Prize in Medicine

Photo by julian mora on Unsplash
By Teodor Teofilov

The 2019 Nobel Prize in Physiology or Medicine was awarded to three researchers who discovered the mechanism that cells use to sense and adapt to changing oxygen levels in the body, announced the Nobel Prize Committee in Stockholm on October 7. William G. Kaelin Jr, Sir Peter J. Ratcliffe, and Gregg L. Semenza identified molecular machinery that regulates the activity of genes in response to varying levels of oxygen and will share a third of the 9 million Swedish kronor (about $907,173) prize.

“Oxygen is essential for life, and is used by virtually all animal cells in order to convert food to usable energy,” said Randall Johnson of the Karolinska Institute, a member of the Nobel Committee, at a press conference in Sweden announcing the award on Monday morning. “This prize is for three physician scientists who found the molecular switch that regulates how our cells adapt when oxygen levels drop.”

Kaelin is a professor at Harvard Medical School and the Dana-Farber Cancer Institute. He was born in 1957 and obtained his M.D. from Duke University, Durham. Kaelin trained in internal medicine and oncology at Johns Hopkins University and the Dana-Farber Cancer Institute.

Ratcliffe was born in 1954. He studied medicine at Cambridge University and completed nephrology training at Oxford. Subsequently he became the Nuffield Professor of Clinical Medicine at Oxford and the Director of Clinical Research at the Francis Crick Institute in London, Director for Target Discovery Institute at Oxford, a Member of the Ludwig Institute for Cancer Research, and knighted.

Semenza is a professor of Medicine at Johns Hopkins University and Director of the Vascular Research Program at the Johns Hopkins Institute for Cell Engineering. He was born in 1956, got both an MD and a PhD from the University of Pennsylvania and completed residency training in pediatrics at Duke University and a postdoc at Johns Hopkins University.

Their discovery is “the mechanism for one of life’s most essential adaptive processes” and has already led to promising new strategies for treating anemia and cancer, among other diseases.

Animals and humans need oxygen to make use of the energy in food and without it there would be no life. The oxygen we breathe breaks down chemical bonds in calories and realeases the energy that our cells use. This process has been understood for centuries, but what wasn’t known was the process of how cells adapt and respond to differing oxygen levels.

Oxygen levels throughout the body can fall — for example during exercise or at high altitudes. These low oxygen levels (hypoxia) can lead to new blood vessel formation, blood cell formation or glycolysis (anaerobic fermentation). Although many people might know about hypoxia, Ratcliffe has called it “an important component of many human diseases including cancer, heart disease, stroke, vascular disease, and anemia.”

The prize winning scientists have revealed the mechanism for how hypoxia triggers a rise in the hormone erythropoietin (EPO), which is involved in the production of red blood cells.

“Cells and tissues are constantly experiencing changes in oxygen availability,” Johnson said. “As an embryo grows and develops, as muscles work, the oxygen available changes as the tissues themselves change. Cells need a way to adjust to the amount of oxygen they have, while still doing their important jobs.”

According to the committee, these discoveries are of vital importance and could lead the way for new strategies to fight anemia, cancer and many other diseases.

Below is the interview by freelance journalist Lotta Fredholm with Professor Randall Johnson, Member of the Nobel Assembly.

Oxygen in the spotlight

About a fifth of the Earth’s atmosphere is made up of oxygen and it is essential for the existence of life. It is used by the mitochondria (the powerhouse of the cell) to convert food into energy. Otto Warburg, awarded the 1931 Nobel Prize in Physiology or Medicine, revealed that his conversion is an enzymatic process. Corneille Heymans received the 1938 Nobel Prize in Physiology or Medicine for showing that the carotid arteries in the neck have special cells that sense the blood’s oxygen levels and control our respiratory rate in response.

Semenza added another key physiological adaptation to hypoxia — that when oxygen levels drop EPO rises in the body and sends a signal to increase the production of red blood cells (red blood cells carry oxygen around the body).

“The importance of hormonal control of [red blood cells] was already known at the beginning of the 20th century, but how this process was itself controlled by O2 remained a mystery,” the Nobel committee said in a press release.

Semenza used genetically-modified mice to figure out that DNA segments near the EPO gene control the cell’s response to low oxygen levels.

Ratcliffe built on that work. He also studied “O2-dependent regulation of the EPO gene, and both research groups found that the oxygen sensing mechanism was present in virtually all tissues, not only in the kidney cells where EPO is normally produced.”

Semenza discovered that a protein he named “hypoxia-inducible factor,” (HIF) mediated the oxygen response and by 1995, he had also identified the genes that encode HIF: HIF-1a and ARNT.

At about the same time as Semenza and Ratcliffe were making their discoveries about the EPO gene, Kaelin was studying the Von Hippel-Lindau disease(VHL), and inherited syndrome. He found another genetic response to changing oxygen levels. This genetic disease leads to dramatically increased risk of certain cancers in families with inherited VHL mutations. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer. He noticed that when cancer cells don’t have a working VHL gene they had “abnormally high levels of hypoxia-regulated genes,” but when the gene was reintroduced normal levels were restored.

This finding was an important clue showing that VHL was somehow involved in controlling responses to low oxygen levels.

In 2001, two in two simultaneously published articles Kaelin and Ratcliffe showed that a type of protein modification, known as prolyl hydroxylation, allowed VHL to recognize and bind to HIF-1a, which was another part of the puzzle of understanding the mechanism of sensing oxygen and how it worked.

“Thanks to the groundbreaking work of these Nobel Laureates, we know much more about how different oxygen levels regulate fundamental physiological processes,” the Committee said. “Oxygen sensing allows cells to adapt their metabolism to low oxygen levels: for example, in our muscles during intense exercise.”

The Committee added that “oxygen sensing is central to a large number of diseases.”

“The work by Ratcliffe, Kaelin and Semenza has been crucial to our understanding of how cells sense and respond to changes in oxygen levels,” Dr Alex Greenhough at the University of the West of England who works on cancer biology said to the Guardian. “Their work is of huge significance to diseases that feature an impaired blood supply, which includes important solid tumours such as breast, colorectal and pancreatic cancers. Their outstanding work on the fundamental mechanisms of oxygen sensing will pave the way for future therapies that will be able to exploit the disease-specific nature of hypoxia for clinical benefit”

The committee said that labs and pharmaceutical companies around the globe are racing to develop drugs “that can interfere with different disease state by either activating, or blocking, the oxygen-sensing machinery.”

“Scientists often toss around this phrase ‘textbook discovery’” said Johnson in an interview with freelance journalist Lotta Fredholm. “But I’d say this is really a textbook discovery.”

You can watch the announcement ceremony below.

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