By Alfred Nyakinda

The 2019 Nobel Prize in Physiology or Medicine has been awarded to three scientists for their groundbreaking research into the human body’s response to changes in oxygen levels, which has implications for the treatment of several diseases.

The Nobel Assembly announced its decision on the 7th October, recognizing the contributions of William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza towards describing the mechanism by which cells sense and adapt to changes in oxygen availability.

“These fundamental findings have greatly increased our understanding of how the body adapts to change and applications of these findings are already beginning to affect the way medicine is practiced,” said Prof Randall Johnson of the Nobel Assembly at the announcement, “This year’s three laureates have greatly expanded our knowledge of how physiological response makes life possible.”

The body’s normal response to reduced oxygen levels is known to involve measures such as the production of more red blood cells, the adaptation of the metabolism of cells in response to low oxygen levels, such as in muscle cells during exercise, and even the creation of new blood vessels.

“It’s a system which is required for our body to function normally. Oxygen levels vary in different part of the body, tissues and organs,” said Prof. Patrik Ernfors, Chair of the Nobel Committee for Physiology or Medicine, “this system is dual, it both makes the cell cope during low oxygen levels, but it is also a system that generates an opportunity for the cell to regain normal oxygen levels.”

“When you have this kind of basic fundamental processes in your body, of course those are also really important in diseases such as anemia, cancer, heart attack, stroke or other disorders where you have a reduction in blood supply, and oxygen and nutrient supply,” added Prof. Ernfors.

The scientists’ discovery opened the way for research aimed at developing drugs which will work by either activating or blocking the process described by their work, to be used in the treatment of different diseases.

According to Professor Thomas Perlmann, Secretary of the Nobel Committee for Physiology or Medicine, a tumor in the body often lacks blood supply and may activate the response identified by the scientists so as to attract blood vessel formation to stimulate its growth.

The ability to detect oxygen also has a role in chronic kidney failure where patients suffer from anemia due to decreased levels of the hormone erythropoietin (EPO), which is produced mainly by the kidney and helps control the production of red blood cells in response to low oxygen levels, or hypoxia.

In separate studies of the EPO gene, Semenza and Ratcliffe found that the ability to sense oxygen was present in nearly all tissues and not just in the kidney where the EPO is normally produced.

Semenza identified a protein complex called the hypoxia-inducible factor (HIF) composed of two proteins, one of which is oxygen sensitive is and broken down when oxygen levels are normal, but when hypoxia is experienced it is protected from degradation.

“Semenza and others showed that HIF was present in almost all cells and at this point, HIF was potentially a key regulator of oxygen responsiveness,” said Prof Johnson.

This work was furthered by the findings of cancer researcher William Kaelin, Jr., that provided a link between oxygen sensing and a gene associated with an increased risk of cancer among people suffering from the hereditary von Hippel-Lindau’s disease (VHL disease).

Research by Kaelin showed that cancer cells lacking a functional VHL gene had an abnormally high number of hypoxia-regulated genes, but reintroducing the VHL gene restored normal levels.

“However, we still didn’t know how oxygen regulated this switch. Ratcliffe and Kaelin then simultaneously showed the way by demonstrating that an oxygen dependent reaction seals HIF’s fate in high oxygen conditions,” added Prof Johnson.

Kaelin and Ratcliffe published articles in 2001 explaining how the human body’s oxygen sensing mechanism works through the interaction of the VHL gene and HIF.

Prof Johnson noted that utilization of these findings is on its way to the clinic with potential drugs to increase HIF used to treat anemia and to suppress HIF used to treat some forms of cancer

Oxygen sensing is important in the regulation of the body’s immune system as well as many other physiological functions, such as the increased production of red blood cells to cope with lower oxygen levels at higher altitudes.

Currently, the hormone EPO is used in the treatment of anemia resulting from chronic kidney disease with good results when properly used, according to the World Anti-Doping Agency (WADA).

WADA, however, warns that improper use can lead to serious health risks among athletes who use it to gain a competitive edge, noting it can result in heart disease, stroke and blockages of blood vessels.