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Nobel Assembly member Randall Johnson (far right), announce the winners of the 2019 Nobel Prize in Physiology or Medicine: Gregg Semenza, Peter Ratcliffe, and William Kaelin.
JONATHAN NACKSTRAND/AFP via Getty Images
The 2019 Nobel Prize in Physiology or Medicine has been awarded to three scientists for their research into how cells detect oxygen and react to hypoxia—conditions when oxygen is low in tissues. The fundamental physiology work has led to a better understanding of how more than 300 genes in the body are regulated, including the one for the hormone erythropoietin (EPO), which controls the production of red blood cells.
Oxygen sensing is integral to many diseases and numerous drugs are being developed to alter the response of this system to treat everything from cancer to anemia. “Applications of these findings are already beginning to affect how medicine is practiced,” Randall Johnson of the Karolinska Institute in Sweden, who studies hypoxia and was on the prize selection committee, told a press conference in Stockholm announcing the winners.
“How oxygen is sensed by both normal tissues and tumors is an incredibly important discovery that is highly deserving of a Nobel Prize”, says Amato Giaccia, a cancer researcher at the University of Oxford. “It’s a fundamental aspect of nature.” Many of the genes that are turned on when oxygen is scarce are also turned on in tumor cells, he notes.
The three new Nobel laureates are William Kaelin Jr at the Dana-Farber Cancer Institute in Boston, Peter Ratcliffe of the University of Oxford in the United Kingdom and Gregg Semenza of Johns Hopkins University School of Medicine in Baltimore. The Nobel committee praised the trio for “for their discoveries of how cells sense and adapt to oxygen availability.”
In the 1980s scientists already knew that low oxygen levels increased transcription of the gene for the hormone erythropoietin (EPO) in the kidney, which in turn boosted production of oxygen-carrying red blood cells. But how the body sensed a lack of oxygen was unclear.
In 1992, Semenza pinpointed a protein he called hypoxia-inducible factor (HIF). It binds to the regulatory region of the EPO gene when there is little oxygen. HIF is made up of two parts: HIF-1alpha and HIF-1beta (or ARNT). Only HIF-1alpha senses oxygen directly and Semenza, Ratcliffe and Kaelin showed how in independent lines of research: Under normal oxygen conditions, two amino acids of the HIF-1alpha protein are chemically modified by enzymes called prolyl hydroxylases. The modified HIF-1alpha can then bind to a protein called VHL and that complex is tagged for destruction in the cell’s garbage disposal, the proteasome.
Under low oxygen conditions, however, the enzymes that chemically modify HIF-1alpha become inactive. Instead of binding to VHL and being destroyed, HIF-1alpha migrates to the cell’s nucleus, where it unites with HIF-1beta and binds to certain parts of the genome, regulating transcription of hundreds of genes including the one for EPO.
Kaelin, a cancer researcher, came into the topic by researching an inherited syndrome, von Hippel-Lindau’s disease, that increases the risks of certain cancers. It’s caused by mutations in the gene for VHL and Kaelin found that cancer cells lacking the protein turn on hypoxia-related genes.
The cancer connections to this oxygen sensing system have only expanded. Some of the genes controlled by HIF are used by tumor cells to produce blood vessels to nourish themselves, others directly act on cell proliferation or metastasis. Several compounds that inhibit HIF-1alpha or the closely related HIF-2alpha are being tested in clinical trials to treat cancer patients. Another class of drugs inhibits the enzymes that modify HIF (they are called HIF prolyl hydroxylase inhibitors).
When oxygen levels are low (hypoxia), HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4).
Courtesy Karolinska Institute
One of these, roxadustat, was approved in China in 2018 for the treatment of anemia in people with chronic kidney disease. And even before that, two cyclists were suspended for using the substance to enhance their performance by boosting red blood cell production.
Celeste Simon, a cellular biologist at the University of Pennsylvania Perelman School of Medicine in Philadelphia, says it is hard to overestimate the role hypoxia plays in disease. “Oxygen limitation is a part of virtually all diseases, not just solid tumors or stroke, but inflammation, wound healing, peripheral arterial disease. All of these involve decreased oxygen.” She says one of the main goals of the field now is to show that the knowledge can be used to help patients.
“There’s HIF in virtually every cell of the body, in the nervous system, in the blood vessels, the immune system,” notes Johnson, who also has a lab at the University of Cambridge. Its role in the immune system may turn out to be particularly critical, he says, because immune cells invade inflamed tissue, which is usually hypoxic. But it also means that any manipulation of HIF will have numerous effects. “These drugs that influence the hypoxia pathway will be very powerful, but they will also have to be looked at very carefully,” says Johnson.
A 2004 feature in Science covered much of the history of prize-winning work. And in a feature just last month, Science visited a mountaintop city to explore how low oxygen levels ravage the body.
“Believe it or not, this has been a really lousy year for me,” Semenza surprisingly noted at the start of a press conference in Baltimore this morning, explaining that he had fallen down stairs in May and broken his neck (A Hopkins neurosurgeon handled his care and he has few problems resultings from the fall). On a lighter note, Semenza added that he didn’t wake up fast enough to answer the first phone call from the Nobel committee.”I’m a deep sleeper.”
Ratcliffe, who also has a position at the Francis Crick Institute in London, was racing to finish a grant application when he got the news, according to a tweet from the Nobel committee.
“Grant proposal deadlines wait for no-one!”
Sir Peter Ratcliffe sitting at his desk working on his EU Synergy Grant application, after learning he had been awarded this year’s Nobel Prize in Physiology or Medicine.
Photographer: Catherine King pic.twitter.com/np0ty6SLi9
— The Nobel Prize (@NobelPrize) October 7, 2019
Related content from Science, Science Signaling, and Science Translational Medicine
H. E. Nicholson et al., “HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species,” Science Signaling 12, 601 (01 Oct 2019)
N. Masson et al., “Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants,” Science 365, 6448 (05 Jul 2019)
A. A. Chakraborty et al., “Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate,” Science 363, 6432 (15 Mar 2019)
A. A. Chakraborty et al., “HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase,” Science Translational Medicine 9, 398 (12 Jul 2017)
G. Yuan et al., “H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea,” Science Signaling 9, 441 (16 Aug 2016)
J. W. Bullen et al., “Protein kinase A–dependent phosphorylation stimulates the transcriptional activity of hypoxia-inducible factor 1,” Science Signaling 9, 430 (31 May 2016)
G. Yuan et al., “Protein kinase G–regulated production of H2S governs oxygen sensing,” Science Signaling 8, 373 (21 Apr 2015)
M. E. Hubbi et al., “A Nontranscriptional Role for HIF-1α as a Direct Inhibitor of DNA Replication,” Science Signaling 6, 262 (12 Feb 2013)
Y. A. Minamishima et al., “Reactivation of Hepatic EPO Synthesis in Mice After PHD Loss,” Science 329, 5990 (23 Jul 2010)
G. L. Semenza, “Life with Oxygen,” Science 318, 5847 (05 Oct 2007)
M. Ivan et al., “HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing,” Science 292, 5516 (20 Apr 2001)
P. Jaakkola et al., “Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation,” Science 292, 5516 (20 Apr 2001)
Related content from News from Science
M. Enserink, “Hypoxia city,” Science (12 Sep 2019)
J. Marx, “How Cells Endure Low Oxygen,” Science 303, 5663 (05 Mar 2004)