Discovery of cellular mechanisms for oxygen sensing earns prestigious Nobel for 2019
This year’s prize in Physiology or Medicine honors the seminal discoveries of “how cells sense and adapt to oxygen availability”. This knowledge helped our understanding of various diseases including cancer and anemia and fueled our efforts to combat them.
The Nobel Assembly at the Karolinska Institutet announced their decision to jointly award the 2019 Nobel prize to the research trio comprising of two American scientists, William G. Kaelin Jr. of the Dana-Farber Cancer Institute in Boston, and Gregg L. Semenza of John Hopkins University School of Medicine in Baltimore, and Sir Peter J. Ratcliffe of the Oxford University, United Kingdom. The award recognizes their pioneering works in identifying the molecular machinery that regulates the activity of genes in response to varying levels of oxygen. The trio were also recipients of the 2016 Albert Lasker basic medical research award.
Oxygen is an integral part of our existence and it is essential for cellular respiration, the metabolic process of converting food into energy. However, the mechanism through which cells adapt to varying levels of oxygen and how they were regulated at the level of gene expression was obscure. Researchers found that the metabolic response to varying oxygen levels could be seen at the level of transcription. Low cellular oxygen (hypoxia) increased the mRNA levels of the erythropoietin hormone (EPO). Hypoxia was also long known to increase RBC production, a condition known as erythropoiesis but the underlying mechanisms were unknown.
Researchers soon turned their focus to characterize the regulatory regions in the EPO gene which were called hypoxia-responsive element (HRE). Both Semenza and Ratcliffe studied the EPO gene and the factor responsible for regulation. Semenza and his team were the first to identify the transcription factor called hypoxia-inducible factor (HIF), a dimer composed of two members. Semenza showed that HIF-1α is the oxygen-sensitive member which gets regulated under hypoxia. HIF-1α was later shown to be responsible for the expression of several mRNAs under hypoxia and subsequent research revealed that the HIF response is crucial for cellular homeostasis, an imbalance of which is a hallmark of cancer.
However, the key question of who controls this transcription factor remained. The clue came from the research of William Kaelin, who was studying von Hippel-Lindau’s (VHL) disease. VHL is a genetic disease that increased the risk of certain cancers in families that inherited mutations in the tumor suppressor protein VHL. Kaelin found that cancer cells with VHL mutations showed increased expression of HIF-regulated genes thereby linking VHL to hypoxia. Ratcliffe and his team soon made the discovery that VHL can physically interact with HIF-1α and is required for its degradation under normoxia. These breakthroughs have aided in our improved understanding of fundamental physiological processes making this award a well-deserved recognition for excellence in science.
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