Cellular oxygen sensing and the anesthesiologist: the Nobel-worthy discovery of hypoxia inducible factor and its implica
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Cellular oxygen sensing and the anesthesiologist: the Nobelworthy discovery of hypoxia inducible factor and its implications in clinical practice Gregory M. T. Hare, MD, PhD Received: 25 October 2019 / Revised: 28 October 2019 / Accepted: 29 October 2019 Ó Canadian Anesthesiologists’ Society 2019
On October 7 2019, the Nobel committee awarded the prize in physiology or medicine to Drs Gregg Semenza (Johns Hopkins University), Peter Radcliffe (Oxford University), and William Kaelin Jr. (Harvard University) for their discovery of hypoxia inducible factor (HIF) and associated mechanisms of oxygen sensing and biological regulation.1,2 The committee noted that the prize was awarded for ‘‘establishing the basis of our understanding of how oxygen levels affect cellular metabolism and physiological function’’.1 The importance of their discovery has been long understood by many across both basic science and medical fields, and was acknowledged by the Canadian Gairdner Institute in 2010.3 In many senses, this is also a definition of one of the central roles of practicing anesthesiologists—i.e., to preserve optimal perfusion and oxygen delivery to the body’s tissues.
The history of oxygen discovery and its importance to physiology The current level of oxygen in the atmosphere has evolved over the past billion years allowing complex (metazoan) organisms including humans to develop.4 From the earliest days, populations have been able to adapt to life at lower oxygen levels at altitude as exemplified by the Himalayan and Andean cultures. From a Western scientific perspective, the collaborative research of Carl Wilhelm Scheele (1742–1786), who first published on the nature of oxygen; Antoine Lavoisier (1743–1794), who coined the term ‘‘oxygen’’ as the acidic portion of the atmosphere that
G. M. T. Hare, MD, PhD (&) Department of Anesthesia, St. Michael’s Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada e-mail: [email protected]
supported combustion; and Joseph Priestly (1733–1804), who most clearly showed evidence that oxygen production by plants was necessary for animal survival, we have continued to focus on the importance of oxygen to support our survival.5 Of interest, one of the scientific discoveries linking hypoxia at altitude with changes in hemoglobin (Hb), initiated via HIF-dependent erythropoietin (EPO) expression, was achieved by Mabel Purefoy FitzGerald (honorary Master of Arts, Oxford University). As a member of Haldane’s Pike’s Peak Expedition, she independently provided one of the first observations of the relationship between reduced partial pressure of oxygen exposure at increased altitude and increased Hb concentration in men and women.6
The discovery of HIF The discovery of HIF and its biological significance was derived from collaborative research performed over many years. The known relationship between EPO expression and hypoxia led Gregg Semenza to ask ‘‘what is the element that promotes EPO transcription under hypoxic conditions?’’7 Ingenious investigat
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