Practical implications of the 2019 Nobel Prize in Physiology or Medicine: from molecular adaptation to hypoxia to novel
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Practical implications of the 2019 Nobel Prize in Physiology or Medicine: from molecular adaptation to hypoxia to novel anti‑anemic drugs in the clinic Fabiana Busti1 · Giacomo Marchi1 · Alice Vianello1 · Domenico Girelli1 Received: 24 April 2020 / Accepted: 22 June 2020 © Società Italiana di Medicina Interna (SIMI) 2020
Abstract The 2019 Nobel Prize for Medicine or Physiology was assigned to three prestigious physician-scientists, Gregg L. Semenza, William G. Kaelin, and Peter J. Ratcliffe, who clarified the molecular mechanisms of hypoxia adaptation. This viewpoint traces their fundamental findings, which have paved the way for the development of innovative drugs for a wide range of common diseases, including cancer and anemia. Keywords Hypoxia · HIF · Erythropoiesis · Iron homeostasis · PHD inhibitors · Nobel Prize In 2019, the Nobel Prize in Medicine or Physiology was jointly awarded to three physician-scientists, Gregg L. Semenza (Johns Hopkins University, Baltimore, MD, USA; pediatric geneticist), William G. Kaelin Jr. (Harvard University, Cambridge, MA, USA; internist and oncologist) and Peter J. Ratcliffe (University of Oxford, Oxford, United Kingdom; nephrologist) for their elegant studies that independently contributed to understand “how cells sense and adapt to oxygen availability”. Of note, in 2016, they had already received the Albert Lasker Medical Research Award, sometimes referred to as the “America’s Nobel”. Oxygen (O2) serves as a key substrate in many essential cellular functions, particularly ATP generation in mitochondria. Humans have developed multiple hypoxia-response strategies [1], including increased red blood cell (RBCs) production, angiogenesis (both improving O 2 delivery), and metabolic reprogramming of cells (optimizing O2 consumption and utilization). The ability to maintain O2 homeostasis has allowed humans to survive in strongly inhospitable habitat, such as high altitudes (e.g., Tibetan populations), where O2 levels are extremely low. In 1938, the Nobel Assembly at Karolinska Institutet had already awarded another researcher * Fabiana Busti [email protected] 1
Department of Medicine, Section of Internal Medicine, EuroBloodNet Referral Center for Iron Metabolism Disorders, Azienda Ospedaliera Universitaria Integrata Verona, University of Verona, 37134 Verona, Italy
interested in adaptation to O 2 changes, Corneille Heymans, who first described the “carotid bodies” as the sensory organs able to rapidly modulate breathing and blood pressure according to arterial O2 levels. Semenza, Kaelin, and Ratcliffe have elucidated the molecular mechanisms underlying cell adaptation to hypoxia, a phenomenon that had remained elusive for a long time. It is involved in several physiological conditions, such as embryonic development, response to exercise, ventilatory acclimatization to high altitude, and even immune defenses. On the other hand, its dysregulation may be associated with common diseases, such as anemia, cancer, ischemic disorders, retinal neovas
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