The 2019 Nobel Prize in Medicine or Physiology – Recipients, Subject and Importance

The winners in Physiology and Medicine of the Nobel Prizes, regarded as the world’s most prestigious scientific awards, have been announced: from Oxford University and the Francis Crick Institute in London, Sir Peter Ratcliffe, from Harvard University in the USA, William Kaelin , and from John Hopkins University, Gregg Semenza, for their discoveries concerning cells’ oxygen-sensing mechanisms , were awarded the 2019 Nobel Prize in Physiology or Medicine. These discoveries are enabling revolutionary treatments for diseases including cancer, anemia and stroke. Let us explore the exciting discovery leading to the Nobel Prize.

Oxygen is fundamental to life and is required to convert nutrients into energy. Despite its known importance, how our cells respond to changes in oxygen remained mysterious. Three distinguished scientists, William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza, discovered how our cells sense oxygen availability and how they adapt to it.

They identified molecular pathways regulating gene activity according to changing oxygen levels. This discovery is important because it elucidates life’s most fundamental adaptive process. It also enabled understanding of how oxygen levels affect cell metabolism and physiological functions.

Oxygen has always been central to biological research and is vital for human and animal life. Scientist Otto Warburg won the Nobel Prize in Physiology or Medicine in 1931 for discoveries about how oxygen is used in mitochondria and related enzymatic processes.

Our bodies have developed many physiological adaptations to low oxygen (hypoxia). The most important is an increase in erythropoietin (EPO). Increased EPO raises red blood cell numbers (erythropoiesis). Hormonal control of erythropoiesis has been known since the early 20th century, but how oxygen controls this remained mysterious.

Gregg Semenza studied how different oxygen levels control the EPO gene. Using specially designed mouse models, he discovered that the EPO gene provides the response to hypoxia.

Sir Peter Ratcliffe investigated the EPO gene’s oxygen dependence. Both groups found that the oxygen-sensing mechanism occurs not only in kidney cells but in all tissues.

Semenza tried to identify cellular components involved in oxygen sensing. In laboratory liver cells, he discovered an oxygen-dependent protein complex binding to a specific DNA segment. He named it hypoxia inducible factor (HIF). After intensive work to purify the HIF protein complex, he published initial results in 1995 and identified genes encoding HIF. HIF-1α consisted of two different DNA-binding proteins (transcription factors), named HIF-1α and ARNT. Further research continues.

When oxygen is high, cells contain little HIF-1α. When oxygen falls, HIF-1α levels rise and HIF-1α can bind the EPO gene and regulate it and related genes. Different research groups discovered that HIF-1α is rapidly degraded under normal conditions but protected from degradation in hypoxia. At normal oxygen levels, HIF-1α is degraded in cellular machines called proteasomes. The proteasome discovery received the Nobel Prize in Chemistry in 2004. Ubiquitin, a small peptide, is attached to HIF-1α as a signal for degradation. How ubiquitin binds HIF-1α depending on oxygen remained mysterious. The answer came from an unexpected direction.

While Semenza and Ratcliffe investigated EPO regulation, cancer researcher William Kaelin Jr. focused on the hereditary syndrome Vol Hippel Lindau (VHL). It greatly increases certain cancer risks in families with inherited VHL mutations. Kaelin discovered that the VHL-encoded protein prevents cancer development. He also found that cancer cells without a functional VHL gene had abnormally high hypoxia-related gene activity. Introducing a normal VHL gene restored that activity to normal. These results demonstrated the relationship between VHL and HIF-1α and explained that VHL is needed for HIF-1α degradation.

Many pieces had fallen into place, but how oxygen regulated the relationship between VHL and HIF-1α remained unknown. Research focused on the region of HIF-1α important for VHL-dependent degradation. Kaelin and Ratcliffe thought the oxygen sensor lay somewhere in this region. Two papers published in 2001 reported that at normal oxygen levels hydroxyl groups were added at two specific sites on HIF-1α. This modification is called prolyl hydroxylation. It enables VHL to bind HIF-1α. Further research by Ratcliffe discovered the enzymes responsible. The gene governing HIF-1α activity was also found to be controlled by oxygen-dependent hydroxylation. The oxygen-sensing mechanism was thus elucidated.

Thanks to the 3 Nobel-winning scientists, we know more about how oxygen levels govern fundamental physiological events. Oxygen sensing enables cells to adapt metabolism to low oxygen, as seen in muscle cells during intense exercise. Formation of new blood vessels and production of red blood cells also involve cellular oxygen-sensing mechanisms. Our immune system is likewise regulated by oxygen sensors. Oxygen sensing also plays a role in blood vessel and placenta formation during fetal development.

Oxygen sensing contributes to many diseases. Patients with chronic kidney failure develop severe anemia because EPO gene activity decreases. EPO is produced in kidney cells and controls red blood cell production. Oxygen-dependent molecular events are also important in cancer. In tumors, oxygen-sensing mechanisms contribute to blood vessel formation and metabolic remodeling. Intensive efforts have recently sought to develop cancer drugs targeting oxygen-sensing mechanisms.