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Discovery of Molecular Switch for How Cells Use Oxygen

Wins 2019 Nobel Prize in Medicine

Research by William Kaelin, Jr., Peter Ratcliffe and Gregg Semenza led the way for applications in treating anemia, cancer and other diseases

Discovery of Molecular Switch for How Cells Use Oxygen Wins 2019 Nobel Prize in Medicine
Credit: Kitti Boonnitrod Getty Images
This year’s Nobel Prize in Physiology or Medicine was awarded to three researchers who helped reveal the mechanism by which cells in the body sense and adapt to oxygen availability. William Kaelin, Jr., Peter Ratcliffe and Gregg Semenza shared the prize for their work, which has played a critical role in understanding—and ultimately treating—diseases such as anemia and cancer. The scientists will share the prize, worth nine million Swedish kronor ($907,695).
“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.”
Oxygen levels can fall throughout the body—for example, at high altitudes or during exercise—or in a local area, such as at a wound site. Low oxygen levels, or hypoxia, lead to new blood vessel formation, blood cell formation, or glycolysis (anaerobic fermentation). Hypoxia was known to trigger a rise in the hormone erythropoietin (EPO), which is involved in producing red blood cells, but the prizewinning scientists revealed the mechanism for how this process works.
The hypoxia response affects many aspects of physiology, including conditions such as anemia, cancer, stroke, infection and heart attack. Cancer cells, for instance, need a blood supply in order to grow, and they can hijack this oxygen-sensing system to create more blood vessels. The research is already leading to the development of new treatments.
Semenza, who is at Johns Hopkins University, showed that hypoxia triggers expression of the EPO gene. Using genetically modified mice, he revealed that certain DNA segments next to this gene regulate its response to low oxygen levels. Semenza discovered a protein complex called hypoxia-inducible factor (HIF), which is composed of two transcription factors—proteins that control the transcription of DNA into RNA—called HIF-1α and ARNT. When oxygen levels are high, HIF-1α is constantly degraded. But when oxygen is low, HIF-1α increases, binding to the EPO gene and other genes and triggering red blood cell formation. Ratcliffe, who is at the University of Oxford and the Francis Crick Institute in England, also studied how oxygen regulates the EPO gene. Both his team and Semenza’s demonstrated this mechanism was present in all cells.
Meanwhile Kaelin, who is at the Dana-Farber Cancer Institute in Boston, was studying an inherited syndrome called von Hippel-Lindau (VHL) disease, which greatly increases the risk of certain cancers in some families. He showed that the VHL gene encodes a protein that prevents cancer from developing, and that cancer cells lacking this gene also had high levels of activity in genes regulated by hypoxia. When the VHL gene is introduced to these cells, it restores the activity levels of the genes to normal. But scientists still did not know how oxygen levels regulated this molecular switch. In 2001 Kaelin and Ratcliffe simultaneously demonstrated that when there is enough oxygen present, hydroxyl groups are added to HIF-1α, allowing VHL to bind to it and leading to its degradation.
The research is already leading to clinical applications. Lowering the expression of the HIF-1α gene could limit a tumor’s ability to grow a new blood supply. By contrast, increasing its expression could help treat people with anemia.
“It’s a good day for [Johns] Hopkins,” Semenza said on Monday in a livestreamed press conference at the university. The message he had for every scientist training today was: “I was once where you are now, and someday you will be where I am now. We’re very lucky to have this career where we get to follow our interests and dreams wherever they lead.”
“I’m honored and delighted at the news,” Ratcliffe said in a statement. “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.”
“I will confess, like most scientists, I did allow myself to dream that maybe one day this would happen,” Kaelin said in a livestreamed press conference at Dana-Farber on Monday. “When I was young, my father’s favorite activity was fishing; part of the secret is knowing where to fish. One thing I got right was understanding that von Hippel-Lindau disease was right place to go fishing.”
Kaelin’s colleagues praised the work. The discoveries “fundamentally defined how cells in the body sense oxygen, and how the cells respond to an abundance of oxygen or an absence of oxygen,” said Betsy Nabel, president of Brigham Health, where Kaelin is a senior physician, at the Dana-Farber press conference. At the same event, George Daley, dean of Harvard Medical School, added that the work “is a powerful reminder of how critical discoveries and transformative therapies flow from [the] deepest understanding of basic mechanisms.”
The awardees were, in some ways, a surprise. There had been speculation that this year’s prize would honor the discovery of the gene-editing tool CRISPR, of receptors for immune cells called T cells, or of optogenetics—a technique for using light to control living cells.
Last year’s prize was awarded to immunologists James P. Allison and Tasuku Honjo for their work showing how the immune system can be harnessed to fight cancer
Editor’s Note (10/7/19): This story was updated after publishing to include quotes from Gregg Semenza of Johns Hopkins University, William Kaelin, Jr., of the Dana-Farber Cancer Institute, Peter Ratcliffe of the Francis Crick Institute, Betsy Nabel of Brigham Health and George Daley of Harvard Medical School.
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