Why in news?
The Nobel Prize in Physiology or Medicine for 2019 has been jointly awarded to William G. Kaelin, Sir Peter J. Ratcliffe, and Gregg L. Semenza, for ‘their discoveries on how cells sense and adapt to oxygen availability.’
What is the discovery all about?
- The discovery by scientists aims to identify the molecular machinery that regulates the activity of genes in response to varying levels of oxygen and understand how underlying cells adapt to such variations in oxygen supply.
- Oxygen is used by the mitochondria present in virtually all animal cells in order to convert food into useful energy. The carotid body, adjacent to large blood vessels on both sides of the neck, contains specialized cells that sense the blood’s oxygen levels.
- In addition to the carotid body-controlled rapid adaptation to low oxygen levels (hypoxia), 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).
- He is credited with identifying a set of DNA-binding proteins called hypoxia-inducible factor, or HIF, which spur the hypoxia response and activates the genes that make EPO.
- HIF was found to consist of two different DNA-binding proteins, called transcription factors, now named HIF-1a and ARNT. When oxygen levels are high, cells contain very little HIF-1a. However, when oxygen levels are low, the amount of HIF-1a increases so that it can bind to and thus regulate the EPO gene.
William Kaelin, Jr:
- His research is about a genetic syndrome, Von Hippel-Lindau’s disease (VHL disease) which leads to dramatically increased risk of certain cancers in families with inherited VHL mutations. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer.
- But cancer cells lacking a functional VHL gene express abnormally high levels of hypoxia-regulated genes but that when the VHL gene was reintroduced into cancer cells, normal levels were restored. This was an important clue showing that VHL was somehow involved in controlling responses to hypoxia.
Sir Peter J. Ratcliffe:
- Ratcliffe and his research group discovered that VHL can physically interact with HIF-1a and is required for its degradation at normal oxygen levels. This conclusively linked VHL to HIF-1a.
- Oxygen sensing is central to a large number of diseases. E.g. patients with chronic renal failure often suffer from severe anemia due to decreased EPO expression.
- When oxygen levels are low in the cells, this mechanism signals the kidneys to produce more red blood cells, which carry the vital molecule throughout the body.Thus the three scientists focused on developing drugs that could treat diseases by either activating or blocking the body’s oxygen-sensing machinery.
How is the discovery useful?
- Researchers hope new advances in this field can ultimately develop treatments that help mitigate the effects of hypoxia-related illnesses, such as coronary heart disease and anemia.
- People with chronic kidney disease can’t make erythropoietin and therefore have hypoxic cells. Now, erythropoietin can be produced in the lab and injected into patients.
- An oral treatment for anemia called roxadustat, which prevents the breakdown of HIF and subsequently makes more erythropoietin, is in the middle of a clinical trial in China. These types of treatments could even be used to treat neurodegenerative diseases or help repair the brain after a stroke.
- Most chemotherapy drugs are currently designed to kill well oxygenated cells, but there’s a dearth of approved treatments that target hypoxic cancer cells. Now drugs that will inhibit HIF activity as an addition to existing cancer therapies can be developed.