Nordic Life Science 1
We need it for converting food into energy that w
e can use. The fact that oxygen is fundamental for life has been known for centuries, but it has long been unknown how cells adapt to changes in levels of oxygen. Too much or too little oxygen can be deadly and cells need to regulate their responses. That is what the three Nobel Laureates in Physiology or Medicine 2019 have discovered and described. They shared the Prize for their discoveries of how cells sense and adapt to oxygen availability, and they have described the molecular machinery that regulates the activity of genes in response to varying levels of oxygen. “The discovery has provided us with a clear molecular understanding about how a cell senses and then adjusts itself to variations in oxygen that occur in the different tissues of the body. This is among the most important physiological variables in a cell’s life and that we now understand and can manipulate the response has a tremendous meaning,” says Randall Johnson, a professor at Karolinska Institutet and a member of the Nobel Assembly. At the press conference he also described the Laureates’ work as a “textbook discovery”. “This is something basic biology students will be learning about when they study biology and learn the fundamental ways cells work. It is a basic aspect of how cells work and I think from that standpoint alone it’s a very exciting thing.” ”It is a great choice! Not least because it clarifies the broad areas of application basic physiological discoveries have. Besides the understanding of how the body’s cells are working this knowledge opens up for the development of new treatments for diseases such as heart attacks, cancer, anemia and chronic wounds, because if we don’t understand the fundamental principles of how our cells are working we cannot anticipate how to treat those who have become ill. It’s as simple as that,” says Mia Phillipson, Professor at the Department of Medical Cell Biology at Uppsala University. In animals oxygen is used by the mitochondria in cells to convert food into energy. During evolution this mechanism developed to ensure a sufficient supply of oxygen to tissues and cells. For example, the carotid body, adjacent to large blood vessels on both sides of the neck, contains specialized cells that sense the blood’s oxygen levels, describes the Nobel Assembly at Karolinska Institutet in their press release. It has been described how blood oxygen sensing via the carotid body controls our respiratory rate by communicating directly with the brain (hypoxia). There are also other fundamental physiological adaptations. An important physiological response to hypoxia is the rise in levels of the hormone erythropoietin (EPO), which leads to increased production of red blood cells. This was known already at the beginning of the 20th century but it was not known how this process itself was controlled by oxygen. Semenza studied the EPO gene and how it is regulated by varying oxygen levels. He used gene-modified mice and showed in 1991 that specific DNA segments located next to the EPO gene mediate the response to hypoxia. At the same time, Ratcliffe, who had also been studying oxygendependent regulation of the EPO gene, found that the oxygen sensing mechanism was present in virtually all tissues, not only in the kidney cells where EPO is normally produced. The two research groups now showed that the mechanism was general and functional in many different cell types. In cultured liver cells Semenza also discovered a protein complex that bound to the identified DNA segment in an oxygen-dependent manner. This complex was called the hypoxia-inducible factor (HIF). He was able to publish some of these findings in 1995, including the identification of the genes encoding HIF. The complex consists of two different DNA-binding proteins, transcription factors, named HIF-1α and ARNT. Results have shown that when oxygen levels are high the cells contain very little HIF-1α and when oxygen levels are low the amount of HIF-1α increases so that it can bind to and regulate the EPO gene, as well as other genes with HIF-binding DNA segments. It was also shown that HIF-1α, normally rapidly degraded, is protected from degradation in hypoxia. At normal oxygen levels, the cellular machinery, the proteasome, degrades HIF-1α. A small peptide, ubiquitin, is added to the HIF-1α protein. Ubiquitin works as a kind of tag for the proteins defined for degradation in the proteasome. How ubiquitin binds to HIF-1α in an oxygen-dependent manner was described by Kaelin, around the same time in 1995. He was investigating an inherited syndrome, von HippelLindau’s disease (VHL disease), a genetic disease associated with dramatically increased risk of certain cancers. He showed that the VHL gene encodes a protein that prevents the onset of cancer. He also showed that cancer cells lacking a functional VHL gene express abnormally high levels of hypoxia-regulated genes, but when the VHL gene was reintroduced into cancer cells, normal levels were restored. This demonstrated that VHL was somehow involved in controlling the response to hypoxia. Other researchers also found VHL to be part of a complex that labels proteins with ubiquitin, marking them for degradation in the proteasome. Ratcliffe and his research group were able to demonstrate, in a crucial experiment, that VHL can physically interact with HIF-1α and is required for its degradation at normal oxygen levels. This finding linked VHL to HIF-1α.