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which earned one of the three 2019 Nobel Prizes i
n Medicine or Physiology, opened up understanding of the mechanisms in cells that regulate oxygen flow – and the discovery that the mechanism is functional in many different cell types. In addition, Semenza’s work helped clarify how oxygen levels relate to bodily functions. Medicine or Physiology Prize co-winners also studied aspects of cellular oxygen flow; Sir Peter Ratcliffe, Director of Clinical Research at Francis Crick Institute, London, and Director of the Target Discovery Institute in Oxford, and fellow American William Kaelin of the Dana Farber Cancer Institute in Boston. A professor of genetic medicine, pediatrics, radiation oncology, biological chemistry, medicine and oncology at Johns Hopkins University School of Medicine in Maryland in the U.S., Semenza began his studies about 30 years ago during his post-doctoral work at Johns Hopkins. According to Semenza, “Oxygen is constantly required by every cell in the body and there is a fundamental response to ensure cells get enough oxygen. This could have considerable applications for different disease states, such as heart disease and cancer.” Semenza set out to learn how oxygen regulates the control of red blood cell production. When oxygen levels in cells decrease, a condition called hypoxia, the levels of the hormone erythropoietin (EPO) increase, which leads to a greater production of red blood cells, a process called erythropoiesis. As part of his work, Semenza studied the EPO gene and how varying oxygen levels regulate it. “By using gene-modified mice, specific DNA segments located next to the EPO gene were shown to mediate the response to hypoxia,” states the Nobel Prize Committee. Both Semenza and Ratcliffe discovered the oxygen-sensing mechanism in almost all tissues, not only in kidney cells, which normally produce EPO, the Nobel Prize Committee noted. Semenza’s goal was to identify the cellular components regulating this response. In cultured liver cells he discovered a protein complex that binds to the identified DNA segment in an oxygen-dependent manner, and named it the hypoxia-inducible factor (HIF). The next step was purifying the HIF complex. Semenza was able to publish some of his most important findings by 1995, including identification of the genes encoding HIF. Two different DNA-binding proteins were found in HIF, which were found to be transcription factors, now named HIF-1 and HIF-1 . Researchers now know that the presence of oxygen leads to the destruction of HIF-1α so that the factor is only active when cells lack oxygen. “This work and Gregg’s contributions are so deserving,” says Dr. Charles Wiener, President, Johns Hopkins Medicine International and a professor of medicine at Johns Hopkins. “The HIF-1/VHL story is one of the basic mechanisms of physiology that allow life. Over the passing years since its discovery, the importance of HIF1 has been increasingly clear.” Wiener worked with Semenza in his lab during a sabbatical in 1995 and discovered other HIF-1 functions. “I was interested in hypoxia and glucose metabolism in the lung, and wanted to explore the role of HIF-1,” Wiener says. “I became even more excited about Gregg’s NORDICLIFESCIENCE.ORG 73