The Karolinska Institute in Stockholm has just kicked off the week of the Nobel Prizes and, as tradition dictates, the first to be announced was the Nobel Prize in Medicine, which this year went to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza for work revealing the molecular mechanisms underlying the way cells adapt to variations in oxygen supply.
The fundamental role that oxygen has for life has been known for centuries, but we are still delving into the mechanisms that lead cells to adapt to changes in the levels of this compound.
As explained by the Swedish academy, William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza discovered how cells can detect and adapt to the changing availability of oxygen, identifying the molecular machinery that regulates the activity of genes. in response to varying oxygen levels. This research work has therefore made it possible to reveal the mechanism that underlies one of the most important adaptive processes for life.
In the practical field, these discoveries have paved the way for promising new strategies to combat anemia, cancer and many other diseases whose cure is a challenge for 21st century medicine.
The carotid body and the hormone erythropoietin
In 1938, Corneille Heymans received the Nobel Prize in Physiology or Medicine for his discoveries about how the carotid body, adjacent to the large blood vessels that exist on both sides of the neck, controls our breathing through direct communication with the brain, as it contains specialized cells that are capable of detecting oxygen levels in the blood.
Another of the physiological responses that control oxygen levels has to do with the hormone erythropoietin (EPO), which leads to increased production of red blood cells in a process known as erythropoiesis. The importance of hormonal control of erythropoiesis was already known in the early 20th century, but how this process was controlled by oxygen remained a mystery. Gregg Semenza studied the EPO gene and how its production is regulated by varying levels of oxygen.
Sir Peter Ratcliffe also studied the oxygen-dependent regulation of the EPO gene, and both research groups found that the oxygen sensing mechanism was present in virtually all tissues, not just kidney cells where EPO is normally produced. These findings demonstrate that the mechanism is general and functional in many different cell types.
What cellular components mediated this response? Semenza, studying liver cell cultures, discovered a protein complex that binds to the identified DNA segment based on oxygen levels. He called this complete hypoxia inducible factor (HIF). Extensive efforts to purify the HIF complex began, and in 1995, Semenza was able to publish some of his key findings, including the identification of the genes that encode HIF.
HIF was found to consist of two different DNA-binding proteins, called transcription factors, which have been called 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-1 increases so that it can bind to regulate the EPO gene and other genes with DNA segments that bind to HIF.
Around the same time that Semenza and Ratcliffe were exploring regulation of the EPO gene, cancer researcher William Kaelin, Jr. was investigating an inherited syndrome: von Hippel-Lindau disease (VHL disease). This genetic disease leads to a very high 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. Kaelin also showed that 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.
By pulling this thread, the three award-winning researchers have continued to make discoveries in their respective research groups that have led to a better understanding of these mechanisms and the role of ubiquitin, a small peptide that is added to the HIF-1 protein. , in the process of oxygen regulation in the cell.
The role of oxygen in physiology and pathology
Thanks to the work of this Nobel Prize laureates, we now know much more about how different levels of oxygen regulate fundamental physiological processes.
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 regulated by the oxygen sensing machine. Oxygen sensing has even been shown to be essential during fetal development to control normal blood vessel formation and placental development.
Oxygen detection is also essential for a large number of diseases. For example, patients with chronic kidney failure often suffer from severe anemia due to decreased expression of EPO which, as already explained, is produced in the kidney and plays an essential role in the control of blood cell formation. red.
In the case of cancer tumors, oxygen-regulated machinery is used to stimulate blood vessel formation and remodel metabolism for effective cancer cell proliferation. Intense ongoing efforts in academic laboratories and pharmaceutical companies are now focused on developing drugs that can interfere with different disease states by activating or blocking the oxygen sensing machinery.
The winners
The 2019 Nobel Prize in Physiology and Medicine has gone to two American and one British researchers:
William G. Kaelin, Jr (New York, 1957) has been an investigator at the Howard Hughes Medical Institute since 1998. In addition, he has his own laboratory at the Dana-Farber Cancer Institute and has been a professor at Harvard Medical School since 2002 .
Sir Peter J. Ratcliffe (Lancashire, UK, 1954) is Director of Clinical Research at the Francis Crick Institute in London and a Fellow of the Ludwig Cancer Research Institute.
Gregg L. Semenza (New York, 1956) is director of the Vascular Research Program at the Johns Hopkins Institute of Cell Engineering and a professor at John Hopkins University.
