Medicine Nobel Prize: Decoding how cells sense oxygen

Nobel Prize winners - Medicine 2019-Optimized

Nobel Prize winners – Medicine 2019

In the case of health people who have normal red blood cell count, the use of external erythropoietin is highly likely to make the blood viscose leading to increased risk of heart disease, stroke, and cerebral or pulmonary embolism.

This year, the Nobel Prize for Physiology or Medicine was awarded to three scientists — William G. Kaelin Jr from Howard Hughes Medical Institute, Maryland, U,.S., Sir Peter J. Ratcliffe from Francis Crick Institute, London and Gregg L. Semenza from the Johns Hopkins University School of Medicine, Maryland, U.S. — for their discovery of how cells sense and adapt to oxygen availability. The three scientists have uncovered the genetic mechanisms that allow cells to respond to varying levels of oxygen.

Why is this discovery important?

Oxygen is used by all cells to convert food to useful energy. While oxygen is essential for the survival of cells, excess or too little oxygen can have adverse health consequences. It is therefore essential to maintain optimal level of oxygen at all times.

Oxygen supply temporarily reduces in muscles during intense exercise and under such conditions the cells adapt their metabolism to low oxygen levels. Proper growth of the foetus and placenta depends on the ability of the cells to sense oxygen.

Drugs have already been developed to treat anaemia by making the body to produce increased number of red blood cells. Similarly, drugs to increase oxygen availability in people with heart disease and lung cancer are being tested. Many diseases can be treated by increasing the function of a particular pathway of the oxygen-sensing machinery. At the same time, inhibiting or blocking the pathway will have implications in treating cancer, heart attack, stroke and pulmonary hypertension.

Cancers are known to hijack the oxygen-regulation machinery to stimulate blood vessel formation and also reprogramme the metabolism in order to adapt to low oxygen conditions. The reprogramming of metabolism gives the cancer cells the plasticity to shift from state where they have limited potential to cause cancer to a state when they have greater potential for long-term growth. Efforts are under way to develop drugs that can block the oxygen-sensing machinery of cancer cells to kill them.

What is already known?

The rate at which we respire depends on the amount of oxygen being carried in the blood. Specialised cells present next to large blood vessels in the neck sense the blood oxygen level and alert the brain to increase the rate the respiration when the oxygen level in the blood goes down. This discovery won a Nobel Prize in 1938.

At the beginning of the last century, scientists knew that specialised cells present in the kidneys make and release a hormone called the erythropoietin. When oxygen level is low, as in high altitudes, more of this hormone is produced and released leading to increased production of red blood cells in the bone marrow. Increased amount of red blood cells in the blood helps the body adapt to reduced oxygen level at high altitudes. Besides increasing red blood cells, the body also grows new blood vessels to increase blood supply.

What are the main contributions by the three prize winners?

Both Prof. Semenza and Sir Ratcliffe independently studied how the erythropoietin gene is regulated by varying oxygen levels. Both researchers found that the oxygen-sensing mechanism is not restricted to kidneys where the erythropoietin is produced but by diverse cells in tissues other than the kidney. Prof. Semenza identified a pair of genes that express two proteins. When the oxygen level is low, one of the proteins (HIF-1α) turns on certain genes, including the erythropoietin gene, to increase the production of erythropoietin. The hormone, in turn, increases the oxygen availability by boosting the production of red blood cells.

Prof. Kaelin Jr, who was studying an inherited syndrome called von Hippel-Lindau’s disease (VHL disease) found that people had increased risk of cancer when they inherited VHL mutations. He found the VHL gene seemed to be involved in how cells respond to oxygen.

The function of the HIF-1α protein, which turns on the genes to produce more of erythropoietin, is blocked and is rapidly degraded when the oxygen level is normal but remains intact when oxygen level is low. Sir Ratcliffe found that VHL interacts with the HIF-1α protein and degrades it when the oxygen level is normal. This ensures that excess red blood cells are not produced when the oxygen level is normal. In 2001, Prof. Kaelin Jr and Sir Ratcliffe both elucidated more details on the mechanism of degradation of HIF-1α protein by VHL when the oxygen level is normal but not when the oxygen level is low.

Are athletes using erythropoietin to cheat at greater health risk?

Athletes have been found to use erythropoietin, synthetic oxygen carriers and blood transfusions for blood doping. Each of the three substances or methods is banned by the World Anti-Doping Agency (WADA).

Lance Armstrong who had won seven Tour de France titles and Olympic medals had in 2013 confessed to using erythropoietin.

While the use of erythropoietin in people who are anaemic due to chronic kidney disease helps in increasing the oxygen level in the blood, the use of the hormone by normal, healthy people can lead to serious health risks. In the case of health people who have normal red blood cell count, the use of external erythropoietin is highly likely to make the blood thick (increase viscosity) leading to increased risk of heart disease, stroke, and cerebral or pulmonary embolism (clot that blocks the flow of blood). “The misuse of recombinant human erythropoietin may also lead to autoimmune diseases with serious health consequences,” warns WADA.

Published in The Hindu on October 13, 2019