Three researchers who studied how cells sense oxygen levels have won the 2019 Nobel Prize in Medicine

The Nobel Prize Committee in Physiology or Medicine at the Karolinska Medical Institute in Sweden has announced the awarding of the 2019 prize to William Kaelin, Sir Peter Ratcliffe and Greg Semenza

The Nobel Prize in Physiology or Medicine for 2019 was awarded jointly and in equal parts (one-third each) to William Kaelin, Sir Peter Ratcliffe and Greg Semenza, for their discoveries in the oxygen level sensing processes of the cells necessary for life.
The three recipients of the award received it thanks to their research that examined how cells adapt to oxygen levels in changing situations, such as: pregnancy, staying at high altitudes, cancer and even wound healing. The unique discoveries for which the three won the prize focus on the molecular mechanisms that determine exactly how the cells adapt when the oxygen supply decreases or increases.
For their discoveries, these prize winners, as every year, receive a cash prize of 1.5 million dollars.

Animals need oxygen in order to convert food into available energy. The basic importance of oxygen has been self-evident for centuries, but the way in which cells adapt to changes in oxygen levels has been a mystery for a long time.
William Kaelin, Sir Peter Ratcliffe and Greg Semenza revealed how cells are able to sense and adapt to changes in oxygen availability. They identified a molecular mechanism that regulates gene activity in response to changing levels of oxygen in the cells.
The important discoveries of this year's Nobel laureates revealed the mechanism of one of life's most essential adaptive processes. They set the foundation for our understanding of how oxygen levels affect cellular metabolism and physiological activity in the body. Their discoveries also pave the way for the development of new effective strategies designed to fight anemia, cancer and many other diseases.

Oxygen in basic processes

Oxygen, which has the chemical formula O2, makes up about a fifth of the Earth's atmosphere. Oxygen is an essential element for animal survival; It is used in the mitochondria organelle present in almost all living cells where it is used in converting food into available energy. Otto Heinrich Warburg, who won the Nobel Prize in Physiology or Medicine in 1931, discovered that this conversion is carried out with the help of an enzymatic process.
Enzymatic.
During evolution, mechanisms were developed to ensure a sufficient supply of oxygen to tissues and cells. The body of the carotid artery (also called the carotid artery), adjacent to large blood vessels on both sides of the neck, contains specialized cells that sense the oxygen levels in the blood. The 1938 Nobel Laureate in Medicine researcher Corneille Jean-Francois Hymans was responsible for the discoveries showing how blood oxygen levels measured by these bodies control our breathing rate by interacting directly with the brain.

HIF (Hypoxia-inducible factors) enter the arena

In addition to the rapid adaptation to low levels of oxygen (hypoxia) based on the carotid body, there are other basic physiological adaptation mechanisms. An important physiological response to a lack of oxygen in the body is the increase in the levels of the hormone erythropoietin (Erythropoietin) which causes an increase in the production rate of red blood cells (erythropoiesis). The importance of hormonal control of the erythropoiesis mechanism was already discovered at the beginning of the twentieth century, but how this process itself is controlled by oxygen remains a mystery.

Greg Semenza studied the gene responsible for erythropoietin and how it is regulated by changing oxygen levels. By using a mouse whose genes had undergone changes, the researcher showed that specific DNA segments located near the erythropoietin gene are the ones that mediate the response to low oxygen. Sir Peter Ratcliffe also studied oxygen-dependent regulation of the erythropoietin gene, and both research groups discovered that the oxygen-sensing mechanism exists in all tissues, and not only in kidney cells where it is normally produced
rythropoietin. These were important findings showing that the mechanism is a general mechanism and functions in many different cell types.

The researcher Semenza wanted to identify the cellular components that mediate this response. By using liver cells that were grown in culture, he found a protein conjugate that binds to those DNA segments that had already been identified under conditions of low oxygen. He called this coupling the oxygen deficiency inducible factor (HIF). At this point, many efforts began to isolate this coupling, and in 1995, the researcher Semenza published some of his important findings, including the identification of the genes coding for this factor. It was found that this coupling consists of two different proteins that bind to DNA. These proteins, which belong to a family of transcription factors (a protein that binds to a specific DNA sequence), were named HIF-1α and ARNT from this stage. Now, the researchers could start trying to crack this attachment, and understand what other components are involved in this mechanism, and how it functions.

VHL: An Unexpected Partner
When oxygen levels are high, the cells contain a low concentration of HIF-1α. However, when the oxygen levels are low, the amount of this factor increases so that it can bind more and subsequently regulate the gene levels of the erythropoietin hormone, as well as the levels of other genes that contain DNA segments that bind to the factor (Figure 1). Several research groups have shown that the HIF-1α conjugate, which normally degrades rapidly, is protected against degradation in a state of low oxygen (hypoxia). When the oxygen levels are normal, a cellular mechanism known as the proteasome, discovered by the 2004 Nobel Prize winners in chemistry, the Israelis Aharon Chakhanover and Abraham Hershko and the scientist Irwin Rose, breaks down the HIF-1α conjugate. Under these conditions, a small protein, called ubiquitin, is added to the HIF-1α protein. The ubiquitin protein functions as a tag for proteins destined for degradation within the proteasome structure. How the protein ubiquitin binds to the HIF-1α conjugate in an oxygen level-dependent manner remains a major research question.
The solution came from an unexpected direction. Around the same time Semenza and Ratcliffe were looking at the regulation of the erythropoietin protein, cancer researcher William Kaelin was studying a genetic syndrome called von Hippel-Lindau (VHL) disease. This genetic disease leads to a significantly increased risk for the development of certain types of cancer in families where there are mutations in the genes responsible for the disease. Kailin showed that the VHL gene encodes a protein that prevents the development of cancer. Kaelin also showed that cancer cells lacking the functional VHL gene express abnormally high levels of hypoxia-regulated genes; However, when the gene is inserted into cancer cells on the one hand, the normal levels are restored. This finding was an important clue showing that VHL is somehow involved in controlling the response to hypoxia. Additional clues came from several research groups that showed that VHL is part of a conjugate that tags proteins with ubiquitin, marking them for degradation in the proteasome. Ratcliffe and his research group then made an important discovery: they showed that VHL is able to physically react with HIF-1α and is required for its degradation under conditions of normal oxygen levels. This finding linked these two components: VHL and HIF-1α.

Oxygen shifts the balance
Many parts of the assembly have been assembled in their proper place, but how oxygen levels regulate the interaction between the two components VHL and HIF-1α has not yet been explained. The research went on to focus on a specific part of the HIF-1α protein that was found to be essential for VHL-dependent degradation, and the two researchers Kaylin and Ratcliffe suspected that the key to oxygen sensing was somewhere in this protein part. In 2001, in two widely published articles, researchers showed that under conditions of normal oxygen levels, hydroxyl groups are added at two specific locations in the HIF-1α component (Figure 1). This chemical change in the protein, known as prolyl hydroxylation, allows VHL to recognize and bind to the HIF-1α component, and this finding explains how normal oxygen levels control the rapid degradation of HIF-1α with the help of enzymes sensitive to the presence of oxygen (prolyl hydroxylases). Further research by Ratcliffe et al identified the enzymes responsible for this mechanism. They also showed that the gene activation role of HIF-1α is regulated by oxygen-dependent hydroxylation. The Nobel laureates have now revealed the oxygen sensing mechanism and shown how it works in its details.

Oxygen is responsible for physiology and pathology
Thanks to the groundbreaking research work of these Nobel laureates, we now know much more about how different oxygen levels regulate basic physiological processes. Oxygen sensing allows cells to adjust their metabolism to low oxygen levels, for example, in our muscles, during vigorous exercise. Other examples of adaptive processes controlled by oxygen sensing include, among others, the formation of new blood vessels and the production of red blood cells. Our immune system, and many other physiological functions, are also regulated by an oxygen sensing mechanism. Oxygen sensing has been demonstrated to be essential even during fetal development, in order to control the growth of normal blood vessels and the development of the placenta.

Oxygen sensing is a central mechanism in a large number of diseases (Figure 2). For example, patients with chronic kidney disease often suffer from severe anemia due to reduced expression of erythropoietin. Erythropoietin is produced in kidney cells and is essential for controlling the production of red blood cells, as explained above. Moreover, the oxygen regulatory mechanism has an important role in cancer. In tumors, the oxygen regulator mechanism is used to speed up the production of red blood cells and change their metabolism to increase the rate of production of cancer cells. Significant research efforts in academic laboratories and pharmaceutical companies are now focused on the development of drugs capable of disrupting the various disease states by activating or inhibiting the oxygen sensing mechanism.

William G. Kaelin, Jr.
William Kaelin was born in 1957 in New York. He received his medical degree from Duke University, Durham. He specialized in internal medicine and oncology at Johns Hopkins University in Baltimore. He established his own research laboratory at the Dana-Farber Cancer Institute and became a full professor at Harvard Medical School in 2002.

Sir Peter J. Ratcliffe
Sir Peter Ratcliffe was born in 1954 in Lancashire, United Kingdom. He studied medicine at Cambridge University and specialized in nephrology at Oxford University. He founded an independent research group at the University of Oxford and became a full professor in 1996. He is the director of clinical research at the Francis Crick Institute in London and a member of several other research institutes in the field of cancer.

Gregg L. Semenza
Greg Semenza was born in 1956 in New York. He received his graduate degree in biology from Harvard University in Boston. He completed his MD/MD at the University of Pennsylvania School of Medicine, Philadelphia in 1984 and specialized in pediatrics at Duke University. He did his post-doctoral work at the Johns Hopkins University in Baltimore, where he also founded his own independent research group. He became a full professor at Johns Hopkins University in 1999, and since 2003 has been the Director of the Vascular Research Program at the Cell Engineering Institute at Johns Hopkins University.