Kaelin, Ratcliffe, and Semenza have solved the mystery of how cells adapt to changing oxygen levels. Their work provides a base for further research into treating anaemia and cancer.

On 7 October, scientists William Kaelin Jr, Sir Peter Ratcliffe and Gregg Semenza were awarded this year’s Nobel Prize in Medicine for their exciting research into how human cells sense and respond to varying oxygen availability in the blood. Until now, these exact physiological mechanisms weren’t fully understood – but independent research from Kaelin, Ratcliffe, and Semenza over the last 20 years has been pieced together to solve the mystery!

Oxygen is vital to life. Animals require oxygen for respiration – the conversion of the foods we eat into the energy we can use to maintain the multitude of metabolic processes that keep us alive. Research by Corneille Heymans outlined how the carotid body, a concentration of specialised cells located near the carotid arteries of the neck, responds to oxygen availability by communicating with the brain to regulate respiration. When the body experiences low oxygen availability (hypoxia), it can react rapidly to cope with this change. The Nobel Prize in Medicine was awarded to Heymans for this work in 1938. 

Another important physiological response to hypoxia is the rise in levels of the hormone erythropoietin (EPO). EPO stimulates increased production of red blood cells to carry more oxygen around the body. This response is controlled by regulation of the EPO gene. 

Semenza studied this gene and found that just one protein-complex, hypoxia-inducible factor (HIF), both controls how the EPO gene works and responds to changing oxygen levels. This protein is abundant when oxygen levels are low but virtually disappears when they are high. Both Semenza and Ratcliffe’s independent research found that this oxygen sensing mechanism is present in almost all tissues and not only in the kidney cells where EPO is normally produced. Another protein, called VHL, was identified by cancer scientist, William Kaelin Jr., and was found to be responsible for destroying HIF when oxygen levels are high. The combination of these findings outlines the molecular ‘switch’ that exists for responding to varying oxygen levels.

Randall Johnson, Nobel Prize committee member, commented on the significance of this research – expressing how “this is really a textbook discovery”. He also predicted that this “basic aspect of how a cell works” is something that biology students will soon be learning about from age 12 or even younger. 

The significance of this year’s prize-winning research is that it highlights the mechanism for oxygen sensing on a cellular level whereas, before, the details were much less clear. There is no doubt that this discovery will benefit the development of promising new strategies in tackling anaemia, cancer and many other diseases.

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