Professor Peter J. RATCLIFFE
Winner of the 2009 Louis-Jeantet Prize for medicine

The information below refers to the time of the award.

Peter J. Ratcliffe was born in 1954 in Lancashire (Great Britain), and studied medicine. Having specialised in renal medicine, he then turned towards cell and molecular biology, while at the same time maintaining close links with the clinic. He currently holds the Nuffield Chair of Clinical Medicine and heads the Department of Medicine at the University of Oxford. He also runs the Hypoxia Biology Laboratory of the Centre for Cell and Molecular Physiology at this university. He is a fellow of the Royal Society and of the European Molecular Biology Organization (EMBO). In 2007, he was elected a foreign honorary member of the American Academy of Arts and Sciences.

The consequences of hypoxia on cells

Oxygen is indispensible for the life of our cells. Cells are capable of detecting the lack of oxygen (hypoxia), to which they respond by producing a protein known as HIF (hypoxia inducible factor).

Peter J. Ratcliffe discovered the widespread operation of these pathways in cells and the processes that connect HIF to oxygen, including the enzyme HIF prolyl hydroxylase – the key oxygen sensor that controls oxygen-dependent degradation of HIF. Active when normal amounts of oxygen are available (normoxia), HIF prolyl hydroxylase becomes inactive if there is a lack of oxygen (hypoxia), leading to a rapid increase in HIF concentration in the cell, where HIF then reprograms the genetic transcription affecting notably energy metabolism, angiogenesis (creation of new blood vessels) and cell proliferation. These hypoxia signalling pathways thus play an important part in the development of numerous diseases, such as cancer and cardiovascular or pulmonary disorders.

Peter J. Ratcliffe’s research has thus helped to better understand these diseases. It has aroused interest among numerous pharmaceutical groups seeking to use it in the development of new treatments.

Oxygen sensing

Maintaining oxygen homeostasis is a central physiological challenge. Insufficient oxygen (hypoxia) is a key component of many diseases of the lungs, heart and vascular systems, and also of cancer, where tumour growth often outstrips its blood supply.

Peter Ratcliffe’s laboratory has discovered fundamental regulatory processes by which oxygen availability is ‘sensed’ by cells and directs biological outputs. Working initially on the feedback regulation of erythropoietin (a haematopoietic growth factor that regulates red blood cell production in response to low blood oxygen delivery), the Ratcliffe laboratory unexpectedly demonstrated that the underlying ‘oxygen sensing’ process was widespread, had other functions, and was conserved in primitive invertebrate species without red cell or vascular systems.

Together with the discovery by G.L. Semenza of the key transcription factor, hypoxia inducible factor (HIF), Peter J. Ratcliffe’s work led to the definition of hypoxia signalling pathways that are conserved throughout the animal kingdom, and direct a very wide range of responses to hypoxia, including reprogramming of energy metabolism, angiogenesis, and cell proliferation/survival decisions.

The Ratcliffe laboratory went on to define upstream pathways that connect the regulation of HIF to the availability of oxygen itself (see figure). This work identified the von Hippel-Lindau protein (pVHL) as a ubiquitin ligase that targets HIF for oxygen-dependent degradation; hydroxylation of specific prolyl residues in HIF as the key oxygen-dependent modification targeting HIF to pVHL (work published simultaneously with similar findings from W.G. Kaelin); and the ‘oxygen sensing’ enzymes catalyzing HIF prolyl hydroxylation as a set of Fe(II) and 2-oxoglutarate dependent dioxygenases whose activity is highly sensitive to hypoxia (collaborative work with C.J. Schofield).

The Ratcliffe laboratory is currently working to understand whether these (hitherto unprecedented) signal pathways involving enzymatic protein hydroxylation operate even more widely in biology, and whether pharmaceutical manipulation of the HIF prolyl hydroxylases might be harnessed for therapeutic benefit, for instance in ischaemic vascular disease.

Schematic illustrating of HIF hydroxylase pathways

HIF, hypoxia inducible factor;
pVHL, the von Hippel-Lindau protein.
Reduction of HIF prolyl hydroxylation in hypoxia allows HIF to escape destruction and activate genes encoding molecules with a wide range of functions in cellular and systemic adaptations to hypoxia.

Dr. Peter J. RATCLIFFE, F.R.S.
Nuffield Professor of Medicine
Nuffield Department of Clinical Medicine
University of Oxford
Richard Doll Building
Old Road Campus

Tél.: +44 1865 287 990 (Secrétariat)
Fax: +44 1865 287 992