Discovery of Molecular Switch for How Cells Use Oxygen Wins 2019 Nobel Prize in Medicine - Scientific American

This year’s Nobel Prize in 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 9 million Swedish Krona ($907,695).

“Oxygen is essential for life, and is used by virtually all animal cells in order to convert food to energy,” said Randall Johnson of the Karolinska Institute, a member of the Nobel Committee, at a press conference in Sweden announcing the prize 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 drop 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 works.

The hypoxia response affects many aspects of physiology, including conditions such as anemia, cancer, stroke, infection and heart attack. Cancer cells, for example, need a blood supply in order to grow, and they can hijack this oxygen-sensing system to grow more blood vessels. The research is already leading to the development of new treatments.

Semenza, who did his prize-winning work 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. He discovered a protein complex called hypoxia-inducible factor (HIF), which is composed of two transcription factors—proteins that control the rate of 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, triggering red blood cell formation. Ratcliffe, at Oxford University and the Francis Crick Institute in London, also studied how oxygen regulates the EPO gene, and both his team and Semenza’s showed that this mechanism was present in all cells.

Meanwhile, Kaelin, at the Dana Farber Cancer Institute in Boston, was studying an inherited syndrome called von Hippel-Lindau’s disease (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 these genes to normal. But scientists still did not know how oxygen levels regulated this molecular switch. In 2001, Kaelin and Ratcliffe simultaneously showed that when there is enough oxygen present, hydroxyl groups are added to HIF-1α, allowing VHL to bind to it, 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.

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 immune cells called T cells, or of optogenetics—a technique for using light to control living cells.

Last year’s prize was awarded to James P. Allison and Tasuku Honjo for their work showing how the immune system can be harnessed to fight cancer.

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Discovery of Molecular Switch for How Cells Use Oxygen Wins 2019 Nobel Prize in Medicine - Scientific American
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