The 2019 Nobel Prize in Physiology or Medicine has been jointly awarded to William G. Kaelin, Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza for their discoveries of “how cells sense and adapt to oxygen availability.”
The trio, who also won the 2016 Albert Lasker Basic Medical Research Award, uncovered the mechanisms by which cells respond to varying levels of oxygen, a discovery which laid the groundwork for greater understanding of several biological processes and associated diseases.
William G. Kaelin Jr. is a Professor of Medicine at Harvard Medical School and Dana Farber Cancer Institute. His research focuses on studying the functions of tumor suppressor proteins and how these proteins prevent tumor growth.
Sir Peter J. Ratcliffe is a Professor at the University of Oxford and the Francis Crick Institute, where he studies the mechanisms by which cells sense and signal hypoxia.
Gregg L. Semenza is a Professor at the Johns Hopkins University School of Medicine. His research centres on studying the molecular mechanisms of oxygen homeostasis.
The importance of oxygen sensing
Although it has been known for some time the importance of oxygen in sustaining life and the problems that can occur when levels become too low or high, it wasn’t until the winning trio’s discovery that the molecular mechanisms which enable cells to sense oxygen levels and adapt appropriately to fluctuations were uncovered.
As well as being implicated in several diseases ranging from anaemia to cancer, this adaptive process allows animals to survive at extreme altitudes and has enabled them to colonise a wide range of habitats.
How do cells sense and adapt to oxygen levels?
A decrease in oxygen levels causes an increase in a protein complex called HIF (Hypoxia-Inducible Factor). HIF regulates the expression and levels of the erythropoietin (EPO) hormone, which increases the production of red blood cells. It has also been shown to activate vascular endothelial growth factor (VEGF), which is involved in the formation of blood vessels. As a result, more oxygen can be carried around the body. When oxygen levels are normal, there is no build-up of HIF as it is rapidly broken down by ubiquitination, directed by the von Hippel-Lindau (VHL) assembly.
Video Credit: Flora Lichtman
Towards novel therapies
Understanding more about the oxygen sensing abilities of cells could help develop novel therapies for several diseases. For instance, anaemia could be treated by inhibiting the destruction of HIF and therefore boosting EPO activity and red blood cell production. Cancers could also be targeted, by preventing cancerous cells from creating new blood vessels.