Two American researchers and one British scientist who independently discovered how cells sense and adapt to oxygen levels won the 2019 Nobel Prize in medicine or physiology on Monday.
Thomas Perlmann, secretary of the Nobel Committee and professor of molecular development biology at the Karolinska Institute, announced the award at a ceremony in Stockholm.
Dr. William Kaelin Jr. of Boston’s Dana-Farber Cancer Institute and Harvard Medical School, Sir Peter Ratcliffe of the University of Oxford and London’s Francis Crick Institute, and Dr. Gregg Semenza of Johns Hopkins University identified “the molecular machinery that regulates the activity of genes in response to varying levels of oxygen, … one of life’s most essential adaptive processes,” the committee said in its announcement. The discoveries have paved the way for understanding “how oxygen levels affect cell function in both health and diseases including anemia and cancer.”
The trio, who also jointly won the 2016 Lasker Award for basic medical research, will share 9 million Swedish kronor, or about $900,000.
Before the public announcement, Perlmann reached all three laureates by phone (in Kaelin’s case, after one wrong number), and all were “really happy” (although Semenza was practically asleep), he told reporters. Kaelin was “almost speechless.”
The oxygen-dependent cellular processes that the laureates discovered are “truly fundamental for oxygen-consuming organisms such as ourselves,” Jeremy Berg, editor-in-chief of the Science family of journals, told STAT. They play key roles not only in normal physiology, he said, but also “in cancer, where adjustment of tumors to low availability of oxygen can be a central issue.”
Oxygen-sensing in cells is not only “a core process involved in metabolism and the generation of new blood cells,” biologist Jason Sheltzer of Cold Spring Harbor Laboratory told STAT, but is “also a process that goes awry in many tumors.” The laureates’ discoveries of cells’ oxygen-sensing machinery “explained a fundamental mystery in biology, and it’s also leading to many potential medical applications,” he added. “Treatments that increase production of HIF [a protein involved in cells’ oxygen-sensing machinery] could help individuals with anemia. In contrast, HIF is frequently overactive in cancer, and HIF inhibitors may be useful to treat these cancer types.”
Kaelin is a co-founder of Cambridge, Mass.-based biotech Tango Therapeutics, which develops molecularly-targeted cancer drugs, as well as Cedilla Therapeutics, which is developing drugs to treat cancer by targeting tumor-driving proteins. He has long been on the scientific advisory board of the philanthropic group Stand Up To Cancer and is also a senior physician in the department of medicine at Brigham and Women’s Hospital.
Scientists had known since the 1970s that when oxygen levels are low, the kidney secretes a protein called EPO, which travels to bone marrow and ramps up production of red blood cells. (This is why EPO has become a target of performance-enhancing drugs in sports, as athletes seek to increase their levels of red blood cells in order to boost the delivery of oxygen to their muscle cells.) But how kidney cells know to do that remained a mystery for years.
In the early 1990s, Semenza, now 63, figured that EPO must work like other genes, meaning a nearby piece of DNA must activate it. He discovered the protein produced by this DNA, an “enhancer” that he named hypoxia-inducible factor 1, or HIF-1. When cells are deprived of oxygen, HIF-1 levels rise, he found; when HIF-1 enters cell nuclei, it turns on the EPO gene, with the end result that the bone marrow churns out boatloads of red blood cells to compensate for the low levels of oxygen.
Ratcliffe, 65, and Kaelin, 61, picked up the story from there, looking even further upstream in the cell’s oxygen-sensing machinery to figure out what regulates HIF-1. They independently identified a protein (its name is Von Hippel Lindau, but everyone calls it VHL) that binds to and destroys Semenza’s EPO-activating HIF. No HIF-1, no EPO, no extra red blood cells. The scientists’ key insight was this: a shortage of oxygen must quash VHL. Only in that way can HIF-1 survive and turn on EPO.
Putting the final piece into the puzzle, Ratcliffe and Kaelin figured out how low oxygen levels keep VHL from destroying HIF-1. The short answer: In conditions of low oxygen, enzymes called dioxygenases, which ordinarily hang dangly oxygen molecules on HIF-1 like Christmas tree ornaments, have nothing to hang. It’s the oxygen ornaments by which VHL recognizes and destroys HIF-1. No oxygen, no ornaments on HIF-1, no VHL destruction of HIF-1. HIF-1 lives another day, entering the nucleus and activating the EPO gene.
“Thanks to this research we know much more about how different levels of oxygen impact on physiological processes in our bodies,” said Bridget Lumb, president of the 4,000-member Physiological Society. “This has huge implications for everything from recovery from injury and protection from disease, through to improving exercise performance.”
The process of choosing the medicine laureate began last year, when the Nobel Committee for Physiology or Medicine invited nominations from more than 3,000 experts: the 50-member Nobel Assembly at Karolinska Institute, members of the medicine and biology divisions of the Royal Swedish Academy of Sciences, past laureates in medicine or chemistry, and full professors of medicine at about a dozen institutions around the world, among others. In an effort to increase gender diversity, the Nobel Assembly has in recent years been increasing the number of women it invites to submit nominations.
The three 2019 winners bring to 219 the number of medicine laureates, of whom 12 have been women.
After nominations (typically 300 or so, since many people suggest the same researchers) closed in January, the five-member committee reviewed them, asked international experts to write reports on the candidates, and in September recommended a handful (the exact number is a secret) to the Nobel Assembly. The Assembly voted on Monday morning, Swedish time, with the announcement coming soon after.
This story has been updated with additional expert comment and detail on the laureates’ research.