The 2019 Nobel Prize in Physiology or Medicine has been awarded by the Nobel Assembly at the Karolinska Institute to William Kaelin, Sir Peter Ratcliffe, and Gregg Semenza for their discoveries of how cells sense and adapt to oxygen availability.
The three scientists discovered the molecular switch that allows our cells to adapt when oxygen levels drop. This adjustment is necessary because oxygen levels change (from changing altitude to doing exercise, to getting a cut) and this delivers a hypoxic response.
Our bodies can deal with this in several ways. New blood vessels might form, blood cell production might increase, and our cells might even have to cope with certain metabolic changes. The lactic acid in muscle cells during strenuous exercise is an example of the latter.
Oxygen is used by cells to release the energy trapped in food in a reaction known as aerobic respiration. Cells can also bypass the use of oxygen by carrying out anaerobic respiration, but for humans, this is not a sustainable solution in the long term and it is not as efficient. The ability to switch from one mode to the other is what these three Nobel laureates and their collaborators discovered.
Scientists have known that in low-oxygen environments and in anemic people an increase in the erythropoietin hormone (EPO) is produced by the kidneys. EPO stimulates the production of red blood cells. Semenza, who works at Johns Hopkins University, showed that the increase in EPO is regulated by a specific gene called the hypoxia response element, or HRE.
The gene produces certain proteins and one of them, called HIF-1α, was discovered to be oxygen sensitive. It disappears from cells when oxygen is abundant. At the same time, William Kaelin and his group from the Dana-Farber Cancer Institute, in collaboration with others, discovered that cells lacking the von Hippel-Lindau gene (connected to cancer) were more likely to show signs of hypoxia.
Ratcliffe, who works at Oxford University and the Francis Crick Institute, and his group made the connection between VHL and HIF-1α. Without the gene, the protein cannot be destroyed. Kaelin and Ratcliffe’s group also uncovered the molecular details of how these mechanics unfold.
The role played by HIF-1α is wide-reaching. From general metabolism and exercise response to the development of embryos and the workings of the immune system. But it also impacts conditions such as anemia, cancer, strokes, and heart attacks. EPO is currently being studied as a potential avenue to fight off cancer cells by starving them of nutrients and oxygen.
