We kick off the 2027 Crick Lectures with a talk from Principal Group Leader and former Crick Clinical Director Peter Ratcliffe.
Peter Ratcliffe is a physician scientist who trained in medicine at Gonville and Caius College, Cambridge and St. Bartholomew's Hospital, London, before moving to Oxford to specialise in renal medicine.
After studying the physiology of renal circulation, he became interested in the regulation of the haematopoietic growth factor erythropoietin, which is produced by the kidneys in response to reduced blood oxygen availability.
In 1990, with funding as a Wellcome Trust Senior Fellow, he set up the Hypoxia Biology laboratory in the Weatherall Institute of Molecular Medicine, Oxford. In 2004, he was appointed Nuffield Professor of Clinical Medicine at the University of Oxford and served as Head of the Nuffield Department of Clinical Medicine from 2004-2016. In May 2016 he was appointed Director of Clinical Research at the Francis Crick Institute, retaining a position at Oxford as member of the Ludwig Institute of Cancer Research and Director of Oxford's Target Discovery Institute.
This work led to the unexpected discovery that the oxygen sensing process underlying the regulation of erythropoietin production in the kidneys and liver operates across essentially all animal cells, irrespective of the production of erythropoietin, and that it directs a broad range of other cellular and systemic responses to hypoxia. These include altered energy metabolism, angiogenesis and cell survival/differentiation decisions. The laboratory went on to elucidate the mechanism of 'oxygen sensing', an unprecedented mode of signal transduction mediated by oxygen-dependent catalysis of prolyl and asparaginyl hydroxylation at specific sites within the key transcription factor, HIF (hypoxia inducible factor). Prolyl hydroxylation marks HIF-alpha polypeptides for destruction by the von Hippel-Lindau ubiquitin E3 ligase, whist asparaginyl hydroxylation blocks the recruitment of co-activators. In hypoxia these processes are suppressed, allowing HIF-alpha to escape destruction and assemble an active transcriptional complex with its dimerization partner HIF-beta.
Peter was elected to the Fellowship of the Royal Society and to the Academy of Medical Sciences in 2002. He is a member of EMBO and a foreign honorary member of the American Academy of Arts and Sciences. His work on oxygen sensing has won numerous awards including the Louis-Jeantet Prize in Medicine, the Canada Gairdner International Award, and the Lasker Award for Basic Biomedical Research. He was knighted for services to medicine in the New Year's Honours, 2014. In 2019, Peter was awarded the Nobel Prize in Physiology or Medicine alongside William Kaelin and Gregg Semenza for their work examining how cells sense and adapt to oxygen availability.
Peter's current research aims to understand the biological roles of signalling through protein hydroxylation and related oxidations. The work is focused both on the operation of the HIF hydroxylases themselves and on related enzymes that catalyse hydroxylations on other proteins. It aims to link these biochemical pathways to physiological control and to the pathophysiology of human diseases including cancer and ischaemic vascular disease.
