Nobel Assembly member Randall Johnson (far right) announces the winners of the Nobel Prize in Physiology or Medicine: Gregg Semenza, Peter Ratcliffe, and William Kaelin Jr.


Medicine Nobel honors work on cellular system to sense oxygen levels

The 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 Stockholm, who studies hypoxia and was on the prize selection committee, said in a press conference 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 in the United Kingdom. “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, and Gregg Semenza of Johns Hopkins University School of Medicine in Baltimore, Maryland. 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 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 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-1alpha 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-1alpha is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1alpha (3). The VHL protein can then recognize and form a complex with HIF-1alpha 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, 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 in the United Kingdom. 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,” Johnson says.

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.