The Season of the Prize

The Nobel Prize season starts today with the 2019 award in Physiology or Medicine. This year’s prize goes to three individuals, two Americans and a Brit, for their work on how the body maintains homeostasis during changes in oxygen levels. Drs. William G. Kaelin Jr. (Harvard University), Peter J. Ratcliffe (Oxford University), and Gregg L. Semenza (Johns Hopkins University) received the announcement early this morning. This same trio also received the Lasker Award in 2016, an award that is often considered a predictor of future Nobel Prize winners.

Oxygen is obviously critical for human life, but how does the body adjust to changes in oxygen levels?  The amount of oxygen available to our cells changes as altitude varies. It also changes during many diseases or even while exercising.  Too much or too little oxygen can be toxic, so how do our cells compensate for these changes?  Scientists knew that mechanisms must exist to regulate these levels exquisitely, but the molecular details were unknown. Thanks to independent studies from the labs of these three scientists, key steps in the regulatory process have been identified and characterized. At the center of the process is a protein called hypoxia-inducible factor, HIF for short, which acts as an oxygen sensor. At normal oxygen levels the HIF protein is chemically modified by oxygen (in the form of an added -OH group). Addition of the -OH group to HIF causes HIF degradation, so under standard oxygen levels the amount of HIF in the cells is normally low. As available oxygen decreases then there is insufficient oxygen to modify the HIF molecules, so HIF is not degraded and instead accumulates in the cells. Increasing levels of HIF turn on many of our genes that help cells survive low oxygen. In particular, genes are activated which stimulate formation both of new red blood cells to carry more oxygen and new blood vessels to get the red blood cells to our tissues more effectively. If oxygen levels rise again then HIF becomes modified, it undergoes degradation, and the target genes turn back off.

Not only is this HIF work important for understanding a fundamental process in cell physiology, but it also has wide-ranging clinical applications for diseases. Cancer, stroke, heart attacks, anemia, lung diseases, and wound healing are all conditions where there are issues with tissue oxygen levels. Already there are new drugs in development that target the HIF pathway to modulate oxygen levels in the tissues. Increasing oxygen levels would be beneficial for heart attacks, strokes, anemia, lung diseases, and wound healing. Alternatively, decreasing oxygen levels in cancer cells could help kill tumors that are critically dependent on high oxygen levels for their growth. Once again, studies of a basic physiological process have identified new drug targets and new potential therapeutic approaches to a wide range of diseases. Congratulations to our newest Nobel Laureates.

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