Trio win Nobel for hypoxia research

Two Americans and a Briton won the 2019 Nobel Medicine Prize on October 7 for discovering a molecular switch that regulates how cells adapt to fluctuating oxygen levels, opening up new approaches to treating heart failure, anaemia and cancer.

William Kaelin Jr of Harvard University, Gregg Semenza of Johns Hopkins University and Peter Ratcliffe of the Francis Crick Institute in Britain and Oxford University will share equally the 9 million kronor ($918,000) cash award, the Karolinska Institute said.

Why is the discovery so important?

The Nobel Committee said that their work has “greatly expanded our knowledge of how physiological response makes life possible”. They explained that the scientists identified the biological machinery that regulates how genes respond to varying levels of oxygen.

That response is key to things like producing red blood cells, generating new blood vessels and fine-tuning the immune system.

The committee said scientists are focused on developing drugs that can treat diseases by either activating or blocking the body’s oxygen-sensing machinery.

How do cells adapt to changes?

Animals need oxygen for the conversion of food into useful energy. The fundamental importance of oxygen has been understood for centuries, but how cells adapt to changes in levels of oxygen has long been unknown.

Kaelin Jr., Ratcliffe and Semenza discovered how cells can sense and adapt to changing oxygen availability. They identified molecular machinery that regulates the activity of genes in response to varying levels of oxygen.

The seminal discoveries by this year’s Nobel laureates revealed the mechanism for one of life’s most essential adaptive processes.

During evolution, mechanisms developed to ensure a sufficient supply of oxygen to tissues and cells. The carotid body, adjacent to large blood vessels on both sides of the neck, contains specialised cells that sense the blood’s oxygen levels. The 1938 Nobel Prize in Physiology or Medicine was awarded to Corneille Heymans for discoveries showing how blood oxygen sensing via the carotid body controls our respiratory rate by communicating directly with the brain.

In addition to the carotid body-controlled rapid adaptation to low oxygen levels (hypoxia), there are other fundamental physiological adaptations. A key physiological response to hypoxia is the rise in levels of the hormone erythropoietin (EPO), which leads to increased production of red blood cells (erythropoiesis).

In cultured liver cells, Semenza discovered a protein complex that binds to the identified DNA segment in an oxygen dependent manner. He called this complex the hypoxia-inducible factor (HIF).

HIF was found to consist of two different DNA-binding proteins, so-called transcription factors, now named HIF-1α and ARNT.

When oxygen levels are high, cells contain very little HIF-1α. However, when oxygen levels are low, the amount of HIF-1α increases so that it can bind to and thus regulate the EPO gene as well as other genes with HIF-binding DNA segments.

Researchers demonstrated that von Hippel-Lindau’s disease (VHL disease) can physically interact with HIF-1α and is required for its degradation at normal oxygen levels. This conclusively linked VHL to HIF-1α.

Oxygen shapes physiology and pathology

Oxygen sensing allows cells to adapt their metabolism to low oxygen levels. For example, in our muscles during intense exercise. Other examples of adaptive processes controlled by oxygen sensing include the generation of new blood vessels and the production of red blood cells.

Our immune system and many other physiological functions are also fine-tuned by the oxygen-sensing machinery. Oxygen sensing has even been shown to be essential during foetal development for controlling normal blood vessel formation and placenta development.

Oxygen sensing is central to a large number of diseases. For example, patients with chronic renal failure often suffer from severe anaemia due to decreased EPO expression.

EPO is produced by cells in the kidney and is essential for controlling the formation of red blood cells.

Moreover, the oxygen-regulated machinery has an important role in cancer. In tumours, the oxygen-regulated machinery is utilised to stimulate blood vessel formation and reshape metabolism for effective proliferation of cancer cells.

Intense ongoing efforts in academic laboratories and pharmaceutical companies are now focused on developing drugs that can interfere with different disease states by either activating, or blocking, the oxygen-sensing machinery.