Trio Wins Nobel for Hypoxia Discoveries

Three scientists—William G. Kaelin Jr., MD, of Dana-Farber/Harvard Cancer Center in Boston, MA; Sir Peter J. Ratcliffe, MD, of the University of Oxford and the Francis Crick Institute in the UK; and Gregg L. Semenza, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, MD—won this year's Nobel Prize in Physiology or Medicine for their research elucidating how cells sense and adapt to changing oxygen levels—work that not only is fundamental to biology, but also has clinical applications for a range of diseases, including cancer.

“This is really a textbook finding,” said Randall Johnson, PhD, of the University of Cambridge in the UK, who is a member of the Nobel Assembly. “This is one of the most basic mechanisms a cell has to adapt to its environment—to be able to counteract whatever oxygen levels it's encountering and … metabolically adjust to them.”

Scientists have long known that hypoxia triggers increased production of erythropoietin, which leads to the formation of more oxygen-toting red blood cells. However, it took the trio of Nobel Laureates, working independently, to untangle the molecular mechanism behind this physiologic response—an effort that also earned them a Lasker Award in 2016 (Cancer Discov 2016;6:1200–1).

Conducting complementary research, the researchers determined that this mechanism centers on the HIF1 protein complex—composed of HIF1α and ARNT/HIF1β—that increases erythropoietin production when it binds to DNA segments near the erythropoietin gene. At normal oxygen levels, hydroxyl groups are added to HIF1α, which allows a complex consisting of the von Hippel-Lindau (VHL) protein, produced by the tumor suppressor VHL, to recognize and tag HIF1α with ubiquitin. This tag tells the cell that HIF1α should be broken down, which decreases the amount of HIF available for DNA binding. However, when oxygen levels dip (or when VHL is mutated, as in the familial cancer syndrome VHL disease), these hydroxyl groups aren't added to HIF1α, so the VHL complex can't recognize and tag it. This prevents the breakdown of HIF1α, making it available for DNA binding, which increases erythropoietin production and oxygen levels.

“It's sort of like a thermostat, if you will, cells have to adjust,” said Kaelin, who studied VHL. “If they're getting too much oxygen or too little oxygen, they have to adjust themselves so that they can tolerate that environment.”

“It is a very elegant and unusual mechanism—it is a really basic finding about how biology works,” Johnson said.

However, the mechanism has applications beyond basic biology. “Many of the common diseases have derangements in the ability to maintain proper oxygen levels,” said Semenza, who discovered HIF1. In cancer, cells rapidly consume oxygen as they divide, yet they can continue dividing in a hypoxic environment by producing more HIFs.

“We find that HIFs play a really critical role in the progression to metastatic disease and the ability of the cancer cells to shield themselves both from the immune system and from therapies,” Semenza said.

Consequently, HIFs have become a therapeutic target: Phase II trials are testing a HIF2 antagonist in renal cell carcinoma, which has high HIF2 levels due to a VHL mutation. The development of this agent “represents a real leap forward,” said Celeste Simon, PhD, of Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

Simon emphasized that research on mechanisms of hypoxia should not stop with HIF. “I think [this award] recognizes a large body of work that has illuminated a highly conserved stress response,” she said. “I just hope that it inspires people working in hypoxia to keep looking at … HIF-independent sensors.”

For the Nobel Laureates, their work illustrates the importance of basic research. “As with almost any discovery science, the impact of that becomes evident later, and we didn't really foresee the broad reach of this system when we started the work,” said Ratcliffe, whose research linked VHL to HIF1α.

“Our story is really one of trying to generate knowledge and to understand how things work,” Kaelin said. “If you go deep enough and you understand things well enough, occasionally opportunities for translation and therapeutic application will arise.” –Catherine Caruso

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