Sir Roy Calne FRCS FRS                                                              (1930-2024)

Following a period of research in Boston, USA Calne became a transplant surgeon at Westminster Hospital & Royal Free Hospital, before becoming Professor of Surgery in Cambridge. His notable achievements include playing a pivotal role in the introduction into clinical practice of both azathioprine and cyclosporin, the two  immunosuppressive agents which were most effective in transforming the outcome of kidney transplant from the 1960s into the 1990s. These two drugs are still used today for routine immunosuppression in many parts of the world.

 

Roy Calne and the development of immunosuppressant drugs for transplantation

 By Chris Winearls

(The story is told by Calne himself in: Organ Transplantation from the Laboratory to the Clinic.  Journal of Medical Sciences (2009);2(2):39-42)

Azathioprine

Sir Roy Caine was responsible for translating the creation in 1961 of azathioprine by Elion and Hitchings of Burroughs Wellcome, into a standard immunosuppressive drug for organ transplantation in the 1960s. “Aza and pred” became the usual  combination regimen for two decades delivering ~ 60% one-year kidney graft survival rate for cadaver (now called deceased donor) transplants.

The drug was a successor to 6-mercaptopurine which unlike many therapeutics was not a discovery but a designed molecule intended to interfere with DNA synthesis by getting in the way of purine. 6-MP was intended as a treatment for leukaemia and worked, albeit transiently. It had been shown in 1958 by Dameshek to have immunosuppressive properties in rabbits and in 1960, Calne, working with Joseph Murray at the Massachusetts General Hospital in Boston showed that would prevent organ rejection too.  6-MP was  used in three kidney transplant cases at the Royal Free Hospital reported in the BMJ by Hopewell, Calne and Beswick . Calne was then offered azathioprine that was designed to be a better deliverer of 6-MP than the original. It worked and was claimed to be more effective and less myelotoxic. Readers can judge whether the experiments justify this claim by reading pages 743 onwards in in the 1962 paper written Calne, Alexandre & Murray in Volume  99 of the Annals of the New York Academy Sciences. I did in 1975 when preparing my first research paper, and was not convinced as the drug doses were different. What I was not to know was that three of the authors of these seminal papers were to be awarded  Nobel Prizes – George Hitchings and Gertrude Elion for Physiology or Medicine in 1988 along with Sir James Black for “their discoveries of important principles for drug treatment,” and then in 1990, Joseph Murray also for Physiology or Medicine in 1990 with E. Donnall-Thomas  for “their discoveries concerning organ and cell transplantation in the treatment of human disease.” It is unlikely that my work on passive enhancement of rat kidney transplants with azathioprine performed in the Nuffield Department of Surgery under Professor Peter Morris had much influence on the Nobel Prize Committee.

Calne reprised this feat of translation in 1980 with Cyclosporine A.

Cyclosporin A

Jean-Francois Borel was an immunogeneticist  working in the Sandoz laboratories in Basel in the 1970’s. The company had a screening programme for substances with antibiotic and other effects. Someone in the lab had brought back a sample of a fungus (Tolypocladium inflatum) collected while on holiday in Norway. The molecule had T-cell immunosuppressive properties as shown in mouse model of haemagglutinin response to sheep red cells and skin grafts Borel presented the data to a meeting of the British Society of Immunology in ~1976. At that meeting was a Cambridge research fellow AK Kostakis who obtained some of the drug and used it in a rat heart transplant model. It worked but he was apparently told to repeat the experiments to convince his boss. Convinced he was,  and the agent was tested in larger mammals and then in humans. I was playing in a tennis match for Oxford Dept Surgery vs Cambridge Dept Surgery in Cambridge in 1978 after which we were invited, not for a beer, but a presentation of the first results. Graft rejection was indeed prevented but there was troublesome nephrotoxicity and one patient developed a lymphoma. The initial dose used was about three times the dose later established to be therapeutic. Curiously Sandoz was not excited and decided not to develop the drug. Roy Calne and David White flew to Basel to beg them to reconsider (there is a film of this) and they did. It was licensed and became one of their best selling drugs after being licensed in 1983, just 7 years after discover. The one-year graft survival increased to 80% which made transplantation altogether a more attractive option and helped save over-stretched haemodialysis units.

 

 

 

Borel JF et al  Biological effect of cyclosporine A:  A new lymphocytic agent. Agents Actions 1976;6:468-75

 

Kostakis AJ, White DJG, Calne RY. Prolongation of rat heart allograft survival by cyclosporin A. Int Red Commun Syst Med Sci 1977; 5: 280. 13.

 

Calne RY, Rolles K, White DJ, et al . Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978;2;1323-7

Last Updated on January 7, 2024 by John Feehally