The 2019 Nobel Prize for Physiology and Medicine has been awarded to three scientists who discovered how cells sense and adapt to oxygen levels.

Sir Peter Ratcliffe, of the University of Oxford and Francis Crick Institute, William Kaelin, of Harvard, and Gregg Semenza, of Johns Hopkins University share the Nobel.

Oxygen Sensing in Cells

Oxygen levels in cells vary and can be affected by altitude, exercise and injury. Our body tries to maintain oxygen levels to ensure that every cell has enough oxygen to generate sufficient energy. The Nobel research uncovered the molecular mechanisms that regulate gene activity in response to varying oxygen levels.

It has been understood since the early 20th century that the body responds to low levels of oxygen, known as hypoxia, by raising its levels of the hormone erythropoietin. The hormone increases the production of red blood cells to restore the transport of oxygen around the body. However, how oxygen initiates this physiological response was not known.

The Discovery

Semenza and Ratcliffe found the erythropoietin gene, and two oxygen sensing proteins that control its expression. These proteins are known as hypoxia-inducible factor (HIF). When the body is experiencing normal oxygen levels, HIF-1α combines with oxygen molecules and is rapidly degraded by proteasomes. However, when the body experiences hypoxia, HIF-1α cannot degrade as there are no oxygen molecules available. Instead, it accumulates in the nucleus where it binds to ARNT. The HIF-1α/ARNT complex can then bind to a regulatory section of DNA in the erythropoietin gene.

The research therefore demonstrates the mechanism through which oxygen levels can regulate the production of red blood cells.

Future Disease Treatments

Kaelin was studying von Hippel-Lindau (VHL) disease, an inherited condition that causes tumours and the over-production of erythropoietin. He discovered that VHL protein, that is defective in people with the condition, is required to ensure the degradation of HIF-1α under normal oxygen levels. This mechanism could therefore be harnessed by tumours to generate new blood vessels, known as angiogenesis. Tumours create new blood vessels to harvest oxygen and nutrients from the body to ensure their continued growth.

Patients with chronic renal failure can suffer from severe anaemia due to decreased erythropoietin expression. Therefore, inhibiting the HIF-1α degradation pathway could lead to treatments for anaemia, whilst promoting the pathway could prevent tumour angiogenesis and lead to cancer treatments. Drugs that block oxygen sensing enzymes to promote the production of red blood cells are already in late stage clinical trials.

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