Acardiac Surgeon's Efforts to Develop Xenotransplantation
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In: Recollections of Pioneers in Xenotransplantation … ISBN: 978-1-53613-945-7 Editor: David K. C. Cooper © 2018 Nova Science Publishers, Inc. No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Chapter 3 THE NEXT GREAT MEDICAL REVOLUTION: A CARDIAC SURGEON’S EFFORTS TO DEVELOP XENOTRANSPLANTATION David K. C. Cooper* Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, US Keywords: Boston, Cape Town, history, medical, islets, Oklahoma City, organs, pig, genetically-engineered, Pittsburgh, xenotransplantation ABBREVIATIONS Gal galactose-α1,3-galactose; GTKO α1,3-galactosyltransferase gene-knockout; IBMIR instant blood-mediated inflammatory reaction; MSC mesenchymal stromal cell; NHH National Heart Hospital, London, UK; NHP nonhuman primate * Corresponding Author Email: [email protected]. 28 David K. C. Cooper “Success is the ability to go from one failure to another . with no loss of enthusiasm.” Winston Churchill INTRODUCTION As a medical student in the early 1960s I determined that I wished to follow a career in the relatively new field of cardiac surgery. I had been heavily influenced in this respect by the fact that at my medical school in London, Guy’s Hospital Medical School, two of the greatest hearts surgeons of that era were on the staff at the time - Sir Russell Brock (later Lord Brock) and Donald Ross. After graduation in 1963, I was fortunate to hold three internships at Guy’s - in general medicine, general surgery, and cardiothoracic surgery. Immediately following these appointments (in mid-1965), I took a temporary position as a ship’s surgeon in order to get some rest and recreation after what proved to be a period of sustained very hard work. I fulfilled this role in 1965 on a short cruise and on a six-week voyage on a scheduled liner to South Africa and back. While in Cape Town, at the suggestion of Donald Ross, a South African who had been an exact contemporary of Christiaan Barnard as a medical student at the University of Cape Town, I called on Professor Barnard, the senior cardiac surgeon there, and spent a few hours with him one afternoon. He took me on a ward round with his team, and I well remember seeing a patient with severe heart failure. When we moved away from the bedside, Barnard turned to me and said, “Of course, what this patient needs is a new heart.” At the time, I did not take this suggestion too seriously because I was aware that the results of kidney transplantation left much to be desired and I felt that it was unlikely anybody would perform a heart transplant in the near future. After a year teaching anatomy at Harvard Medical School (where I also gained my first experience of surgical research at the Peter Bent Brigham Hospital in the department headed by the legendary surgeon-scientist, Francis Moore), I spent a year in accident and emergency surgery in Cambridge in the UK. I then decided to pursue a PhD in surgical research at the University of London. LONDON AND CAMBRIDGE By this time (the summer of 1967), I firmly believed that transplantation was the next major development in cardiac surgery, and so my research at the Institute of Cardiology (attached to the National Heart Hospital [NHH]), supervised by Donald Ross, primarily involved methods of resuscitating and storing the heart for purposes of transplantation. I was also involved with some very early work in heart-lung transplantation in dogs directed by Donald Longmore, who was in charge of the cardiopulmonary bypass services at the NHH. The Next Great Medical Revolution 29 Not long after I had embarked on my research, Christiaan Barnard surprised everybody by carrying out the world’s first human-to-human heart transplant on December 3rd, 1967. Some 5 months later, I was privileged to watch the first heart transplant carried out in the UK (by Donald Ross at the NHH) on May 3rd, 1968. Having completed most of my experimental studies for the PhD, I spent three months in India as a volunteer at a hospital in the Punjab, and then returned to clinical surgery for two years in the UK to fulfill my general surgical requirements before sitting the examination for the Fellowship of the Royal College of Surgeons of England. I was fortunate to obtain an appointment at Addenbrooke’s Hospital in Cambridge where I came under the influence of Roy Calne (later Sir Roy Calne, FRS), one of the foremost pioneers in organ transplantation. Kidney transplantation was steadily being established (though the results remained poor), but liver transplantation was in its infancy at the time (1970-1971). I made a particular effort to participate in some of these operations and learn something of the immunosuppressive regimens that were being used. I was greatly impressed by Roy’s energy and drive. Following this surgical experience, I spent a year completing my PhD dissertation, and then moved into my chosen field of cardiothoracic surgery. Having completed my formal training, I was offered a temporary appointment at Papworth Hospital, where the designated senior registrar (equivalent to chief resident) was planning to spend a year in the United States. This one year extended to two years, and I was extremely fortunate to be a member of the team (led by Terence English, later Sir Terence) that carried out the first four heart transplants at Papworth in 1979, which gave me insight into the clinical management of these patients. At the end of my two years at Papworth, I was very keen to obtain an academic appointment in cardiothoracic surgery (where I would have the opportunity to combine clinical surgery with research), but this proved very difficult in the UK at that time, where there were only three academic appointments in the entire country. I therefore wrote to Christiaan Barnard, asking him whether I could join his team in a research capacity for a year. He generously offered me a position and, in the event, I remained in Cape Town for seven years, gradually being promoted to Associate Professor. CAPE TOWN When I arrived in Cape Town at the beginning of 1980 (where I was to spend some of the happiest years of my life), as well as working in the laboratory, Barnard asked me to take responsibility for the patients undergoing heart transplantation, which I was pleased to do. This proved immensely interesting, but challenging and stressful because about 50% of the patients died within a year of the transplant (as they were doing worldwide). I found Barnard a breath of fresh air as he allowed me considerable 30 David K. C. Cooper independence and also, although he demanded that the patients should be cared for conscientiously, he had a sense of humor that made working with him enjoyable. It was also in Cape Town that I had the great good fortune and pleasure of working with Winston Wicomb, PhD and Dimitri Novitzky, MD, PhD, two of the most innovative people I have ever met. While at the NHH I had written a short article in which I had stated that I thought the future of heart transplantation might lie in xenotransplantation, with the use of nonhuman primates (NHPs), such as chimpanzees, as potential sources of organs. I was probably influenced by the pioneering work of Keith Reemtsma and others in the 1960s [1]. In Cape Town, I was able to explore the possibility of xenotransplantation personally. When I arrived, I suggested this as an area of research to Barnard, but he was unenthusiastic. His opinion was that “we have enough problems in preventing rejection of a human heart without taking on the added burden of a xenograft.” Nevertheless, as NHPs were so readily available to us in Cape Town – where a baboon cost me $25 (whereas today, in 2018, in the U.S. the cost is in the region of $8,500) – I embarked on some experiments in the laboratory, transplanting African green (vervet) monkey hearts into baboons to immunologically mimic the baboon-to-human situation [2-4] (Figure 3.1). I also carried out heart allotransplantation in baboons across the ABO barrier, which had some similarities to xenotransplantation [5]. Figure 3.1. Research colleagues at the University of Cape Town in the early 1980s. (Left-to-right) Stuart Boyd, Frederick ’Boots’ Snyders, Prescott Madlingozi, Winston Wicomb, Sharon Smit, and Ferdinand Barends. Not photographed, but also valuable members of the team were Dimitri Novitzky, Joanna Martin, and John Roussouw. Although I gave thought to the potential of NHPs as ‘donors’ for humans [6], it soon became obvious to me that, for various reasons, they would not be ideal. I therefore switched my attention to the pig as a potential source of organs for humans. To my The Next Great Medical Revolution 31 knowledge, although John Najarian’s group had investigated transplants between pigs and dogs (reviewed in [7], there had been no previous studies in the pig-to-NHP model except Roy Calne’s handful of pig liver transplants in baboons and chimpanzees in the late 1960s [8-10]. In the pig-to-baboon heart transplantation model, I soon found that hyperacute rejection occurred in every case [11].