Professor Sir Philip Randle, 1926-2006
3 November 2006
Professor Sir Philip Randle founded the Department of Biochemistry at Bristol in 1964, building it up into one of the strongest in the UK both in research and teaching.
Philip Randle was born in 1926 in Nuneaton, Warwickshire. His father was a baker and his mother a music teacher. He went to the local King Edward VI Grammar School before studying Natural Sciences at Cambridge University. In his final year (1947), he obtained a first class degree in Biochemistry – a subject still in its infancy then. It was at this time that he first developed his lifelong interest in insulin and changes in metabolism that occur in diabetes. He moved to University College Hospital Medical School and completed his medical studies before returning to Cambridge as a research student of Professor Frank Young. He was awarded a PhD in 1955 for studies that focused on the metabolic actions of insulin. Immediately, he was appointed to a lectureship in the Cambridge Biochemistry Department and continued his studies into various aspects of insulin action and the control of metabolism particularly in muscle.
These studies culminated in a series of very influential papers published in 1963 and 1964 with a group of outstanding research students and fellows – Eric Newsholme, Nick Hales, Peter Garland and Hal Coore. This was at the time he was moving from Cambridge to Bristol. These papers taken together have been cited over 10,000 times and are cited frequently to this day. They set out the basic evidence both for the ‘glucose-fatty acid cycle’ of fuel selection by tissues (often referred to as the Randle Cycle) and for the ‘substrate-site hypothesis’, the means whereby increases in blood glucose cause insulin release from the beta-cells in the pancreas. Much of the research of Philip Randle in the next three decades was concerned with uncovering in detail the basic biochemical mechanisms involved in these two fundamental processes. Crucially, the ‘glucose-fatty acid cycle’ recognises that given a choice between glucose and fatty acids, muscle uses the fatty acids as the main energy source.
Philip Randle and his colleagues went on to reason that increased fatty acid use might be responsible for the insulin resistance associated with obesity and type 2 diabetes. The fundamental importance of the ‘glucose-fatty acid cycle’ in normal physiology is now fully accepted but more recent studies indicate that probably it is only partly the answer to insulin resistance. The ‘substrate-site hypothesis’ of insulin secretion came about from truly groundbreaking studies on pancreatic pieces with Hal Coore, in which insulin secretion was measured by a new radio-assay also developed within the Randle group by Nick Hales. It was generally thought at the time that glucose stimulated insulin secretion by binding to a receptor similar to a hormone receptor. In contrast, on the basis of their observations, Coore and Randle hypothesised that it was the actual metabolism of glucose by the beta-cells in the pancreas that was coupled to the release of insulin. Subsequent studies including those by Steve Ashcroft with Philip Randle have established the ‘substrate-site hypothesis’ and uncovered much about the mechanisms involved.
Philip Randle moved to Bristol in 1964 in a period of expansion in UK universities but the rapid development of the Department of Biochemistry under his leadership was quite remarkable. Bristol University had had Medical, Veterinary and Dental Schools for many years and was also strong in many areas of medical and other sciences. However, there was no biochemistry department. There were a few biochemists scattered between the Departments of Physiology, Biology and Chemistry but overall the subject at Bristol was very weak by national standards. Within seven years, the new department was one of the strongest in the UK both in research and teaching.
How did Philip Randle do this? In hindsight, it is easy to see that his most important action was a whole series of inspired academic appointments across the full range of the discipline of biochemistry. Particular research successes in the very early years of the department included groundbreaking studies on mitochondrial transporters (Professor Brian Chappell), molecular enzymology (Professor Freddie Gutfreund FRS) and protein structure (Herman Watson and Hiliary Muirhead), as well as the control of mammalian metabolism by the group headed up by Philip Randle himself, which also included Peter Garland.
Virtually all these appointments were of individuals from Cambridge, who then brought more junior colleagues and research students who in time also were to play a major role in the development of the new department. These included Tony Crofts, Dave Yates, John McGivan, Steve Ashcroft and myself. However, it was also necessary for Philip Randle to ensure that the new department had its fair share of space and investment within the University. His expansionist plans did not always get the instant support of old-established departments who naturally saw the new department as a serious threat to their own plans! Philip Randle’s physical presence (over two metres high), intellect, booming voice and strong pipe smoke undoubtedly helped in diminishing the more conservative forces that he had to overcome at that critical period in the department’s development.
During the 12 years that Philip Randle was to stay in Bristol, his personal research became focused on two areas – the control of insulin secretion (largely with Steve Ashcroft) and the regulation of an enzyme, pyruvate dehydrogenase, that plays a central role in the selection of fuels in muscle and other cells (often with myself). Despite his many responsibilities, substantial progress was made in both areas. This included the first strong evidence that glucose metabolism was essential for the initiation of increased insulin secretion and that insulin activated pyruvate dehydrogenase activity in adipose tissue (important in the increased conversion of carbohydrate into fat brought about by the hormone).
In 1975, Philip Randle moved to Oxford to found yet another new department – this time a Department of Clinical Biochemistry. This department was very different from the large department he had developed in Bristol. Instead of over 20 established academic staff members and their research groups covering the full range of modern biochemistry, it had only four academic staff members, two of whom where Philip Randle himself and Steve Ashcroft, who moved from Bristol with him. This new department focused very successfully on diabetes-related research and Philip Randle’s own major interest continued to be the regulation of pyruvate dehydrogenase, mainly in muscle. Philip Randle retired from this position in 1993. The major scientific meeting held in Oxford that year in his honour entitled ‘Metabolic fuel selection in health and disease’ was an eloquent testimony of the esteem in which he was held throughout the world.
Over the years, Philip Randle took on many other responsibilities in addition to those in his universities. These included appointments as chairman of a large number of research committees and boards for Diabetes UK, the Medical Research Council and British Heart Foundation, President of the European Association for the Study of Diabetes, Vice-President of the Royal Society and President of the Biochemical Society. In the early 1980s, Philip Randle devoted great energy to advising the government on aspects of food policy. In particular, he chaired an influential Food Policy Panel on Diet and Cardiovascular Disease. This panel came up with advice about lowering intakes of saturated fat, simple sugars and salt. This advice is still accepted today but sadly not always heeded.
Among the many honours that Philip Randle received were the Banting Lecture of Diabetes UK (1965), first recipient of the Minkowski Prize of the European Diabetes Association (1966), the Humphrey Davy Rolleston Lecture of the Royal College of Physicians (1983), election to Fellow of the Royal Society (1983), Knight Bachelor (1985) and a Founder Fellow of the Academy of Medical Sciences (1998).
He had a massive influence on the PhD students and young research fellows passing through his laboratory. To date, three of his research students have become Fellows of the Royal Society and the number now holding university chairs or comparable positions in the pharmaceutical industry is well into double figures. Although the death of Philip Randle is truly an end of an era, he has left a substantial legacy of both the department he started here in Bristol and a worldwide network of researchers whose careers were influenced in a very substantial way by the time spent under his supervision.
Philip Randle was supported in all his activities by his wife Elizabeth, whom he married in 1952 and who sadly died two years ago. He also suffered the loss of his son, Peter, who died still a teenager in 1971 and a daughter, Susan, who died in 2005. He is survived by two daughters, Sally and Rosalind, and four grandchildren.
Professor Dick Denton FRS