The 2019 Nobel Prize in Physiology or Medicine was shared by three researchers, William Kaelin, Gregg Semenza and Peter Ratcliffe, for their work in identifying the molecular mechanisms by which cells adapt and regulate to changing oxygen levels.
Their research paves the way for a better understanding of how cells adapt to oxygen and for “promising new strategies to fight anaemia, cancer and many other diseases”.
Randall Johnson of the Nobel Assembly described the significance of their research: “Scientists often toss around this phrase, textbook discovery. I’d say this is really and essentially a textbook discovery. This is something that basic biology students will be learning about when they study at age 12 or 13 or younger biology and learn the fundamental ways in which cells work.”
The Nobel Institute's press release provided a detailed explanation of the findings that led to the Nobel.
Essentially, when your body’s oxygen levels are low, a hormone named erythropoietin (EPO) starts to stimulate the production of red blood cells, carrying oxygen from your lungs to the rest of your body.
While scientists long knew the importance of EPO, they did not know exactly how oxygen regulated it. Semenza, director of the Vascular Research Program at the John Hopkins Institute for Cell Engineering, wanted to study the gene that regulated the hormone. At the same time, Sir Ratcliffe of Oxford Unvirsity was studying the O2 -dependent regulation of the same gene.
Both research groups found that the oxygen-sensing mechanisms was a general function present in all tissues. The next step was to find the cellular mechanisms that made it possible.
In 1995, Semenza discovered the protein-complex that activates the DNA-mechanism that regulates hypoxia (low-oxygen levels). He called it the hypoxia-inducible factor (HIF) and showed how it increases in quantity when oxygen levels are low. He identified two proteins that were a part of HIF: HIF-1α and ARNT.
Kaelin, while studying the genetic disease von Hippel-Lindau’s (VHL) syndrome, which increases the risk of developing kidney and pancreatic cancer, found that VHL genes seemed to reduce the number of hypoxia-related genes.
Meanwhile, Sir Ratcliffe’s research showed that VHL physically interacted with HIF-1α and destroyed it under normal oxygen levels. Other research groups showed that VHL was part of a complex that could label proteins with a marker that triggered their destruction in the proteasome (another complex of protein that breaks down unnecessary proteins using chemical reactions).
The combination of their findings led to a greater understanding of how protein-complexes reacted in low-oxygen scenarios, and of the role of VHL, but they still needed to know how oxygen-sensing mechanisms functioned to make it all work together. They later identified the hydroxyl groups that modified HIF-1α to make VHF genes, the chemical processes that regulated oxygen-sensitive enzymes, and how HIF-1α.’s gene-activating function was regulated by the oxygen-dependent process.
The overall effect was to comprehensively explain the “molecular switch”, as Johnson described it to reporters, that regulates how cells adapt when oxygen levels are low.
The three scientists will share the prize total of nine million Swedish kronors ($914,000) and will receive the prize from Swedish King Carl XVI Gustaf at a ceremony in Stockholm on December 10—the anniversary of Alfred Nobel’s death.
