Sir Peter John Ratcliffe, FRS, FMedSci (born 14 May 1954) is a British physician-scientist who is trained as a nephrologist. [1] [2] [3] He was a practising clinician at the John Radcliffe Hospital, Oxford and Nuffield Professor of Clinical Medicine and head of the Nuffield Department of Clinical Medicine at the University of Oxford from 2004 to 2016. He has been a Fellow of Magdalen College, Oxford since 2004. In 2016 he became Clinical Research Director at the Francis Crick Institute, [4] retaining a position at Oxford as a member of the Ludwig Institute of Cancer Research and director of the Target Discovery Institute, University of Oxford. [5]
Ratcliffe is best known for his work on cellular reactions to hypoxia, for which he shared the 2019 Nobel Prize in Physiology or Medicine with William Kaelin Jr. and Gregg L. Semenza. [6] [7]
Ratcliffe was born in Lancashire [8] on 14 May 1954, to William Ratcliffe and Alice Margaret Ratcliffe. [9] He attended Lancaster Royal Grammar School from 1965 to 1972. [10]
He won an open scholarship to Gonville and Caius College, Cambridge in 1972 to study Medicine at the University of Cambridge [11] and then completed his MB BChir medical degree with distinction at St Bartholomew's Hospital Medical College in 1978. [12]
Ratcliffe then trained in renal medicine at Oxford University, focusing on renal oxygenation. [13] He earned a higher MD degree from University of Cambridge in 1987. [14]
In 1990, Ratcliffe received a Wellcome Trust Senior Fellowship to study cellular responses to hypoxia from low oxygen levels in the blood. [12] [15] From 1992 to 2004 he was senior research fellow in clinical medicine at Jesus College, Oxford. [16] In 2002, Ratcliffe was accepted into the Academy of Medical Sciences and was appointed the following year the Nuffield Professor and head of the Nuffield Department of Clinical Medicine at Oxford. [17]
In 1989, Ratcliffe established a laboratory in Oxford University's Nuffield Department of Medicine to explore the regulation of erythropoietin (EPO), a hormone released by the kidneys and responsible for stimulating the production of red blood cells. EPO was known to be produced by the kidneys in response to low oxygen levels, and Ratcliffe's work looked to understand the mechanisms of how the kidneys detected hypoxia (low oxygen levels in the blood) to trigger EPO production. From his studies, Ratcliffe discovered that the mRNA from kidneys that were part of the EPO production pathway that were capable of detecting hypoxia was also present in several other organs, both human and animal, including the spleen, brain, and testes. [18] His group found that cells from these organs could switch on EPO production when deprived of oxygen. [17] Further, Ratcliffe was able to modify other cells using the identified mRNA to give these cells oxygen-sensing capabilities. [18]
Building on these discoveries, the Ratcliffe group, along with joint studies with William Kaelin and Gregg Semenza, helped to uncover a detailed molecular chain of events that cells use to sense oxygen. A specific step identified was the binding of proteins expressed by the Von Hippel–Lindau tumor suppressor gene (VHL) to hypoxia-inducible factors (HIF), a transcription factor which trans-activates the EPO gene. Ratcliffe found that the VHL protein can bind a hydroxylated residues of HIF when oxygen is present at acceptable levels; the VHL protein then ubiquitylates the HIF protein which ultimately leads to the HIF protein's destruction. When oxygen levels fall, oxygen-requiring HIF hydroxylase enzymes, PHD1, 2 and 3 no longer act and VHL does not bind HIF, allowing HIF to remain and activate the EPO gene. This is a process that takes minutes to complete allowing the body to react quickly to hypoxia. [2]
This same pathway is also switched on in many cancer tumours, allowing them to create new blood vessels to sustain their growth. Much of the current understanding of hypoxia has emerged from the laboratory of Ratcliffe. [13] The understanding of the molecular pathway of EPO production from hypoxia has led to the development of drugs that block VHL from binding with HIF to help treat patients with anaemia and kidney failure. [2]
Ratcliffe married Fiona Mary MacDougall in 1983. [9]
Ratcliffe has received a number of awards, accolades, and honours for his seminal work on hypoxia.
He was knighted in the 2014 New Year Honours for services to clinical medicine. [26]
Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body. Although hypoxia is often a pathological condition, variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise.
Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease.
Blood doping is a form of doping in which the number of red blood cells in the bloodstream is boosted in order to enhance athletic performance. Because such blood cells carry oxygen from the lungs to the muscles, a higher concentration in the blood can improve an athlete's aerobic capacity (VO2 max) and endurance. Blood doping can be achieved by making the body produce more red blood cells itself using drugs, giving blood transfusions either from another person or back to the same individual, or by using blood substitutes.
Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia.
The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina. It is also associated with kidney and pancreatic lesions.
Ola Didrik Saugstad is a Norwegian pediatrician, neonatologist and neuroscientist noted for his research on resuscitation of newborn children and his contribution to reduce child mortality. He is a Research Professor at Oslo University Hospital and Professor of Neonatology at Northwestern University's Feinberg School of Medicine in Chicago. He is Professor Emeritus of Pediatrics at the University of Oslo and was Director of the Department of Pediatric Research at Oslo University Hospital from 1991 to 2017.
Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. The Nobel Prize in Physiology or Medicine 2019 was awarded for the discovery of HIF.
Egl nine homolog 2 is a protein that in humans is encoded by the EGLN2 gene. ELGN2 is an alpha-ketoglutarate-dependent hydroxylase, a superfamily of non-haem iron-containing proteins.
Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), or prolyl hydroxylase domain-containing protein 2 (PHD2), is an enzyme encoded by the EGLN1 gene. It is also known as Egl nine homolog 1. PHD2 is a α-ketoglutarate/2-oxoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. In humans, PHD2 is one of the three isoforms of hypoxia-inducible factor-proline dioxygenase, which is also known as HIF prolyl-hydroxylase.
Egl nine homolog 3 is a protein that in humans is encoded by the EGLN3 gene. ELGN3 is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylases, which are non-haem iron-containing proteins.
Hypoxia-inducible factor 1-alpha inhibitor is a protein that in humans is encoded by the HIF1AN gene.
The Wiley Prize in Biomedical Sciences is intended to recognize breakthrough research in pure or applied life science research that is distinguished by its excellence, originality and impact on our understanding of biological systems and processes. The award may recognize a specific contribution or series of contributions that demonstrate the nominee's significant leadership in the development of research concepts or their clinical application. Particular emphasis will be placed on research that champions novel approaches and challenges accepted thinking in the biomedical sciences.
Hypoxia-inducible factor-proline dioxygenase (EC 1.14.11.29, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-proline, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating). This enzyme catalyses the following chemical reaction
Hypoxia-inducible factor-asparagine dioxygenase (EC 1.14.11.30, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-asparagine, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating). This enzyme catalyses the following chemical reaction:
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
The Massry Prize was established in 1996, and until 2009 was administered by the Meira and Shaul G. Massry Foundation. The Prize, of $40,000 and the Massry Lectureship, is bestowed upon scientists who have made substantial recent contributions in the biomedical sciences. Shaul G. Massry, M.D., who established the Massry Foundation, is Professor Emeritus of Medicine and Physiology and Biophysics at the Keck School of Medicine, University of Southern California. He served as Chief of its Division of Nephrology from 1974 to 2000. In 2009 the KECK School of Medicine was asked to administer the Prize, and has done so since that time. Ten winners of the Massry Prize have gone on to be awarded a Nobel Prize.
Gregg Leonard Semenza is a pediatrician and Professor of Genetic Medicine at the Johns Hopkins School of Medicine. He serves as the director of the vascular program at the Institute for Cell Engineering. He is a 2016 recipient of the Albert Lasker Award for Basic Medical Research. He is known for his discovery of HIF-1, which allows cancer cells to adapt to oxygen-poor environments. He shared the 2019 Nobel Prize in Physiology or Medicine for "discoveries of how cells sense and adapt to oxygen availability" with William Kaelin Jr. and Peter J. Ratcliffe. Semenza has had ten research papers retracted due to falsified data.
William G. Kaelin Jr. is an American Nobel laureate physician-scientist. He is a professor of medicine at Harvard University and the Dana–Farber Cancer Institute. His laboratory studies tumor suppressor proteins. In 2016, Kaelin received the Albert Lasker Award for Basic Medical Research and the AACR Princess Takamatsu Award. He also won the Nobel Prize in Physiology or Medicine in 2019 along with Peter J. Ratcliffe and Gregg L. Semenza.
Sónia Maria Campos Soares da Rocha, usually referred to as Professor Sónia Rocha, is a Portuguese cell biologist who holds a personal chair in biochemistry at the University of Liverpool, where she is the head of the Department of Biochemistry. Rocha runs an active multidisciplinary cell signaling research group studying hypoxia, and focused around transcription factors such as Hypoxia-inducible factors and NF-κB. Her laboratory is currently based in the Institute of Integrative Biology.
The MRC Weatherall Institute of Molecular Medicine at the University of Oxford is a research institute located at the John Radcliffe Hospital in Oxford. Founded in 1989 by Sir David Weatherall, the institute focuses on furthering our understanding of clinical medicine at a molecular level. It was one of the first institutes of its kind in the world to be dedicated to research in this area.
Belzutifan, sold under the brand name Welireg, is an anti-cancer medication used for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma. It is taken by mouth. Belzutifan is an hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.
Further support for an oxygen-sensing mechanism was provided by the discovery of erythropoietin (EPO), a glycoprotein hormone that stimulates erythrocyte production [...] During the same time period in which Semenza was developing EPO-transgenic mice, Peter Ratcliffe, a physician and kidney specialist, was establishing a laboratory in Oxford University's Nuffield Department of Medicine to study the regulation of EPO