First Nobel Prize for Oxford Clinical School
22 November 2019
Awards and appointments
Sir Peter Ratcliffe FRCP FRS was awarded the 2019 Nobel Prize for Physiology or Medicine, sharing it with Dr Gregg Semenza of Johns Hopkins University and Dr William Kaelin of the Dana-Farber Cancer Centre in Boston.
This achievement has caused celebrations in all the institutions with which Sir Peter is and was associated. He is different from many Nobel laureates in that he was first a physician and nephrologist caring for patients in Oxford’s Kidney and Transplant Units at the Churchill Hospital. Before embarking on his search for the mechanism by which the kidney sensed hypoxia and regulated erythropoietin production he was involved in a number of studies in renal transplantation in the Nuffield Department of Surgery, which was later renamed as the Nuffield Department of Surgical Sciences (NDS). There were eight papers published between 1989 and 1996. These included: a trial of an analogue of atrial natriuretic factor on early renal allograft function; a trial of complete steroid withdrawal after transplantation; and descriptive work of hyperlipidaemia and hyperparathyroidism after renal transplantation. As well, he developed a model of perfusion of the isolated rat kidney in the NDS microsurgery laboratory, together with Brian Ross and Vernon Marshall.
The kidney has a special relationship with oxygen; it has a mechanism to “measure” its oxygen supply and adjust the production of the hormone erythropoietin which determines the rate of production of red cells which are the deliverers of oxygen to the tissues. Patients with advanced renal disease are anaemic because they fail to produce appropriate amounts of erythropoietin and therefore normal numbers of red cells. In 1985, the gene for the hormone was cloned allowing in vitro production for therapeutic use. It’s administration, tested in the Oxford Kidney Unit, reversed the anaemia. Peter was more interested in how the kidney sensed the hypoxia caused by anaemia and why this feedback loop failed in renal failure patients. His group, which included several nephrology trainees, including Christopher Pugh, Patrick Maxwell, Chorh Chuan Tan, Jonathan Gleadle, Morwenna Wood, Emma Vaux and David Mole, identified the elements of the gene complex which controlled synthesis and the cells within the kidney that synthesise the hormone. Importantly, they were also able to show that the control element could operate in all cell types and that similar control elements existed in many other genes, including those controlling metabolic processes such as glycolysis. Dr Gregg Semenza discovered the protein complex which acts on these control elements and called it, HIF, for Hypoxia Inducible Factor and showed that it was present in all cell types. In the steady state HIF is produced and then broken down by binding to another protein complex called VHL. William Kaelin found that mutations of VHL (common in kidney cancer) caused over-activity of hypoxia-regulated genes. Peter’s group showed that HIF and VHL proteins interact directly and that HIF proteins are stabilised by lack of oxygen when the VHL protein is normal, but are stable, regardless of oxygen levels when the VHL protein is mutated. Both groups linked these findings and the role of oxygen directly by showing that HIF had to be hydroxylated to allow it to bind to VHL. Peter’s group had already identified that the HIF system existed in other species including fruit flies and nematode worms. Genetic studies on the worms allowed identification of a prolyl hydroxylase enzyme responsible for this oxygen-dependent hydroxylation, and thus the three human enzymes responsible for the same function. This meant that in relative hypoxia the rate of HIF degradation was reduced allowing it to act for longer on the control elements of the genes controlled by HIF.
The discovery of this system means that it is now possible to treat the anaemia of renal failure by administering an inhibitor of the HIF prolyl hydroxylase which leads to increased endogenous erythropoietin production avoiding the need for injection of the recombinant hormone. These findings are highly relevant to cancer biology because as malignant cells grow they often outgrow their oxygen supply. As oxygen levels fall the tumour cells adapt and survive by co-opting the HIF pathway. In these circumstances HIF has many actions including the production of tissue factors which encourage new blood vessels to grow and changes in the metabolism of the tumour cells which make them less dependent on oxygen. Given the wide operation of the HIF pathways other therapeutic possibilities may emerge.
This story which has taken thirty years to evolve is the result of a number of supportive mentors, opportunities and choices. Peter speaks of the enthusiasm of his science teachers at his grammar school in Lancashire, the preclinical years at Cambridge, clinical training at St Bartholomew’s Hospital and then coming to specialise in medicine and nephrology in the Nuffield Department of Medicine where he was inspired by Professor Sir David Weatherall FRS and Professor John Ledingham. In the Transplant and Kidney Units he worked for Sir Peter Morris FRS and Dr Desmond Oliver, a dialysis expert. He initially worked in Professor Sir John Bell’s laboratory where he had to teach himself the techniques of molecular biology and biochemistry. He attracted a cadre of bright young clinicians to share his ambition to unravel the oxygen sensing system. In parallel to the research work, he was sharing clinical duties with his NHS colleagues and teaching medical students. Jesus College recognised his talent and made him an SRF in 1992. The students were in awe of him and disappointed for themselves when in 2004 he was appointed to the Nuffield Chair of Medicine and moved to Magdalen. He fulfilled the huge administrative burden including chairing the weekly “Medical Grand Rounds” and still carried on being a doctor and teacher. He continued his clinics in the Oxford Transplant Centre, particularly his annual review clinic of all transplant patients, which he had established some years before. In 2014, he left the Chair of Medicine to pursue his scientific career in his Oxford laboratory and at the Crick Institute in London. Without doubt he is the true clinician scientist and the NDS and the Renal Unit can certainly vouch for that!
Christopher Winearls and Peter Morris*
*Christopher Winearls, a Rhodes Scholar in the NDS, and later Clinical Director of the Renal Unit; Peter Morris, Emeritus Nuffield Professor of Surgery and Director of the Oxford Transplant Centre.