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Nobel Prize

Three researchers who uncovered how cells respond to oxygen awarded 2019 Nobel Prize in Physiology or Medicine

William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza share award for discovering how cells sense and adapt to oxygen availability

by Laura Howes and Megha Satyanarayana
October 7, 2019

 

20191007-medicinemugs.jpg
Credit: Courtesy of HHMI; Oxford University; Johns Hopkins Medicine
William Kaelin Jr. (left), Sir Peter Ratcliffe, Gregg Semenza won this year’s Nobel Prize in Medicine or Physiology.

The 2019 Nobel Prize in Physiology or Medicine has been awarded to three researchers whose work on the role of oxygen in cellular biology has been described as paradigm shifting.

William G. Kaelin Jr. at the Dana Farber Cancer Institute, Sir Peter J. Ratcliffe of the University of Oxford and the Francis Crick Institute, and Gregg L. Semenza of Johns Hopkins University School of Medicine will share the roughly $1 million prize for their discoveries of how cells sense and adapt to a lack of oxygen.

While most life on Earth has evolved to metabolize oxygen to survive, too much or too little of the gas in cells can be catastrophic. Kaelin, Ratcliffe, and Semenza identified the proteins that are involved in cellular oxygen sensing and how they interact. Their work has contributed insights to fields such as developmental biology and cancer research and led to drugs to treat cancer and anemia.

The effects of their work range across almost every aspect of physiology, said Randall S. Johnson, professor of molecular physiology and pathology at Cambridge University during a press conference in Stockholm this morning. This year’s Nobel laureates “have greatly expanded our knowledge of how physiological response makes life possible,” he said.

Sam McBrayer, a cancer and metabolism biologist at the University of Texas Southwestern Medical Center and a former postdoc under Kaelin, agrees and says that the prize validates the importance of oxygen sensing in physiology. He says that medicines, such as cancer drugs Torisel and Zortress, are the results of the scientists’ work, and “there is no greater validation than that result.”

Both Semenza and Ratcliffe worked to understand how and why a specific gene for the hormone erythropoietin turns on when oxygen levels are low. Erythropoietin triggers a range of physiological responses such as making more red blood cells to try to get more oxygen to cells in need.

In 1991, Semenza found the protein responsible, called hypoxia-inducible factor (HIF). While working on an inherited disease called von Hippel-Lindau’s disease that causes cysts and tumors in the body, Kaelin found another part of the oxygen sensing system, called VHL, in 1996. Kaelin showed that cells without a functional VHL gene dial up a low oxygen response even under normal-oxygen conditions. Ratcliffe and his team then found that the VHL protein interacts with one of the components of HIF, HIF-1α, marking it for destruction by the cellular machinery that munches up proteins. With HIF-1α gone, the genes involved in a low-oxygen response remain off in normal-oxygen conditions.

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Credit: Wikipedia/Jawahar Swaminathan
HIF-1α is one of the key players in oxygen sensing in cells

The findings “challenged the orthodoxy of cell biology” when first discovered, says Nicholas Forsyth, a researcher in stem cell biology at Keele University, because at the time scientists thought oxygen just played a role in metabolism and didn’t affect the expression of a wide range of genes. But today, he says, “it’s not an understatement to say that Kaelin, Ratcliffe, and Semenza are pillars of the scientific research community.”

Oxygen sensing allows cells to adapt their metabolism to low or high oxygen conditions, which is crucial for cell health, Forsyth explains. Many physiological functions are also fine-tuned by this process and oxygen sensing is central to treatment of disease. For example, Torisel and Zortress target HIF to try to reduce the number of blood vessels that feed tumors in the body.

Daniele Gilkes, a cancer biologist at Johns Hopkins Medicine and former postdoc with Semenza, hopes that this award gets scientists to think about oxygen levels as they design experiments. Many tissue culture experiments are carried out at about 20% oxygen, because that’s the concentration that we breathe, but in some places in the body, like the breast, oxygen levels are more like 8%.

As scientists develop organoids, which are 3-D models of organs that often have different cell types and blood vessels, there is a lot of focus on making sure the right cells and the right architecture are present. But these three researchers’ work highlights how physiological conditions matter, she says, and oxygen concentration is part of that. “People aren’t necessarily looking at oxygen concentration,” Gilkes says. “I think it will be important for mimicking human biology better.”

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Credit: Adapted from the Noble Foundation
At normal oxygen levels, HIF-1α gets hydroxylated, allowing the VHL protein to recognize it and form a complex, leading to HIF-1α degradation. When oxygen levels are low, HIF-1α is protected and it accumulates in the nucleus, where it binds to specific genes, turning them on.

Co-workers and former students of the researchers have been quick to add their praise. Gabriela Pavlínková, who worked with Semenza, is head of the molecular pathogenetics department at the Institute of Biotechnology in the Czech Republic. Semenza, she says, has an extreme focus on detail, but “is very helpful and understanding, especially regarding junior scientists and colleagues.”

In 2016, all three researchers won the Albert Lasker Basic Medical Research Award for their work. The Lasker award is often seen as a precursor to the Nobel Prize, so Forsyth wasn’t surprised the three will receive the Nobel. Still, he’s delighted, adding that sometimes, scientists can grumble about who is included, or left out, when a prize is awarded. But this year’s medicine prize is “perfect” he says. “It’s absolutely on the money.”

2019 had been a “lousy year,” before today’s prize announcement, Semenza said at a press conference today. On May 31, he fell down the stairs and broke four vertebrae in his neck.

The three researchers never formally collaborated, but at another press conference today Kaelin explained that they were aware of each other’s work and read each other’s papers. But more importantly, he said, they saw each other at conferences and discussed their unpublished findings. “That free exchange of information allowed us to hit escape velocity,” he said.

At their respective press conferences, all three researchers emphasized the importance of fundamental research for driving forward innovation. “We make knowledge,” Ratcliffe said. “That’s what we do.”

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Comments
Fang Liu (October 9, 2019 12:19 PM)
I personally appreciate the committee offering the prize to the people working on this great and significant field for understanding one of the critical factors for humans living, aging to dying.

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