A fundamental discovery of living cells adapting to varying levels of oxygen that won the coveted 2019 Nobel Prize for physiology or medicine to two American scientists -- Gregg L Semenza and William G Kaelin -- and their British peer Peter J Ratcliffe may offer new strategies to fight a wide range of diseases, including anaemia, cancer, strokes and heart attacks.

It may now be textbook knowledge, but a quarter-century ago even scientists didn’t know how cells managed to sense and adapt to fluctuating levels of oxygen. The levels of oxygen available to cells can vary widely even during situations which are very common in normal life. Rigorous physical exercise or a climb in mountains or a cut resulting in bleeding, for instance, can leave cells in many organs gasping for an adequate supply of oxygen. Unless it is sensed and sufficient remedial action initiated, those affected cells can be lost forever. But, in real life, cells managed to handle the situation reasonably well without any external help. Nevertheless, scientists remained clueless about the underlying mechanism for long.

The puzzle began to unravel slowly around 1995 when Semenza, a Johns Hopkins University professor, discovered and characterised a gene which codes for a protein called hypoxia (low oxygen) inducible factor-1 alpha, or HIF-1a, which is essential for sensing oxygen levels in cells. Subsequent studies by Semenza and also by Ratcliffe, across the Atlantic, figured out that HIF-1a acts as a molecular switch that augments production of red blood cells, which help carry more oxygen to cells.

This didn’t help solve the mystery completely, though. The scientists had also observed that when oxygen levels increase in cells, there is a sudden drop in HIF-1a levels and vice versa. Unless they can manipulate it, there can hardly be any use in clinical settings. Initial clues on how HIF-1a gets degraded when oxygen levels go up in cells came from Kaelin, who is incidentally a cancer researcher.

The fact that many potential therapies exploiting this newly-acquired understanding are round the corner made the trio – who would share the Nobel Prize bounty equally – favourites among the 400-odd individual nominations received from around the world. China, for instance, is close to clinically testing a therapy that would help treat anaemia, a scourge that it grapples with just as much as India. Medical scientists elsewhere, similarly, hope that HIF-1a may offer a magic bullet to deal with some of the most aggressive forms of breast cancer in not so distant future.

Published on October 10, 2019