Res Medica, Volume 21, Issue 1 Page 1 of 8 HISTORICAL ARTICLE Orthotopic liver transplantation in the making: key pioneers and events relevant to current practice Craig Gouldthorpe BSc (Hons) Year 4, MBBS Hull York Medical School Correspondence email: [email protected] Abstract Within the field of liver transplantation the concepts of warm liver transplants and hepatocyte transplantation are currently under investigation. Although such novel research efforts are intricate and complex, the concept of human liver transplantation posed quite a challenge itself in the not so distant past. The development of the orthotopic liver transplant relied on numerous individuals and novel approaches of the time. Success resulted following cumulative developments in early experiments when Thomas Earl Starzl performed the first human liver transplantation 50 years ago in 1963. This article highlights key developments in the lead up to such an attempt, details of the procedure itself and biographies of three key leaders; Alexis Carrel, Peter Medawar, and Thomas Starzl. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, 2013, 21(1):68-75 doi: 10.2218/resmedica.v21i1.207 Gouldthorpe, C. Orthotopic liver transplantation in the making, Res Medica 2013, 21(1), pp.68-75 doi:10.2218/resmedica.v21i1.207 Gouldthorpe C. http://journals.ed.ac.uk/resmedica Liver transplantation in the 21st Century HISTORICAL Although transplant research has an Orthotopic liver transplantation (OLT) extensive history, liver transplant (see Box 1) is currently the only curative developments span over a much shorter treatment for patients with end-stage liver period. The year 2013 signifies an important failure. Although quality and length of life landmark in liver transplantation with the can be improved, patients are committed to first human OLT taking place 50 years ago. lifelong immunosuppressant therapy. This The general principles discovered in the carries its own risks in addition to those build-up to such a success are discussed associated with the procedure. within this article and many of the basic concepts can be applied across In the UK, at the end of March 2012, 553 of transplantation medicine. Although 7,636 patients on the active transplant list significant developments have been made were in need of a new liver.1 A 25% increase over that time, problems with organ supply in liver-related deaths were reported still need to be tackled; techniques need to between 2001 and 2009, where a male be refined and new technologies researched. predominance was seen and the majority of The recent use of ‘warm liver’ transplants by cases occurred in those under 70 years old.2 the University of Oxford has proved This signifies both the increasing burden on successful, and novel approaches such as the NHS and the importance of OLT. As hepatocyte transplantations are currently 4,5 with many areas of organ transplantation, under investigation. the demand far exceeds supply. 819 patients were removed from the total active waiting The history of liver transplantation (see list during the financial year due to clinical Figure 1) is an expansive topic; the purpose deterioration and 508 died while waiting for of this article is to focus on the key a transplant.1 developments that led to the first human liver transplant. Box 1. Key terms within transplantation3 Orthotopic graft: tissue or organ transplant is placed in the same anatomical site as the original organ or tissue (e.g. heart or liver transplant) Heterotopic graft: tissue or organ transplant is placed within a different anatomical site (e.g. kidney transplant) Allograft (homograft): tissue or organ transplanted between genetically non-identical individuals of the same species (e.g. heart or liver transplants) Autograft: tissue or organ transplanted between different sites of the same individual (e.g. skin transplants) Heterograft (xenograft): tissue or organ transplanted from a different species (e.g. pig to human) Isograft (syngraft): tissue or organ transplanted between genetically identical individuals Volume 21, Issue 1 68 Res Medica Orthotopic liver transplantation in the making: key pioneers and events relevant to current practice Peter Medawar (1915-1987) Rio de Janeiro, Thomas Earl Starzl (1926-), Iowa Brazil Alexis Carrel (1873-1944) Lyon, France Post-graduate surgical training focussed on Early work focussed on regeneration of vascular, thoracic and general surgery Major in the French Army Medical Corp peripheral nerves, tissue culture and (1914-1919) where he developed new Extensive research in organ transplantation development of organisms methods to treat war wounds with over 1600 publications Investigated skin grafts following requests Key developments include methods for Performed the first human liver transplant from the Medical Research Council during blood vessel anastomoses (1902), whole (1963) the Second World War (1939-1945) organ transplantation (1908), and effective Once elected fellow of the Royal Society, cold storage of blood vessels (1910). London, he was then awarded a Royal He was the youngest Nobel Laureate age 39 Medal (1959) and Nobel Prize (1960) Figure 1. Key pioneers6-8, Nobel Prizes (1901 – 1960) relating to immunology and transplantation9, and significant developments in liver transplantation history (pre-1963). 6-MP: 6-mercaptopurine, TBI: total body irradiation. Alexis Carrel and Peter Medawar images courtesy of the Wellcome Library, London. Thomas Starzl image courtesy of the Archives Service Center, University of Pittsburgh. Volume 21, Issue 1 Res Medica 69 70 Gouldthorpe C. http://journals.ed.ac.uk/resmedica Transplant immunology mesenchymal and vascular reaction, with a thin detached band of skin now replacing 11 Transplant immunology: blood the previously well-grown tissue. Medawar HISTORICAL reactions reported the destruction of foreign tissue as 11 the result of an antigen-antibody reaction. Karl Landsteiner, an assistant within the In 1949 Burnet also showed how, when Pathological-Anatomical Institute in Vienna, exposed to foreign antigens, antibodies were was the first to discover blood groups in produced and further work developed the 12 1900 following agglutination reactions, concept of cellular immunity. The immune whereby antibodies and red blood cells, or system would target foreign body cells and corpuscles, adhere to form a mass, in normal cause destruction of tissue. Whether it was human serum.10 Originally believed to only immediate or within weeks, the occur in diseased states, the reaction was transplantation of organs between non- later found in 22 healthy individuals, which identical humans would eventually resulted categorized individuals into blood groups A, in rejection. A second culprit for the B or C.10 The possibility of successful blood rejection reaction was identified. Compatible transfusions became a reality. Identification blood groups and tissue matching, a much of these blood groups was one of the first more intricate task, were necessities for key steps in transplantation: correct transplantation. Even so, a lack of control identification and matching of individuals over the immune system was responsible for based on their blood group is a necessity in many of the earlier failures. transplantations to prevent the agglutination process that could result in transplant Transplant immunology: early findings failure. of tissue rejection Transplant immunology: the mid- The immune system needed to be 20th century suppressed after transplantation, and interest built in the use of cortisone and total body Following on from Landsteiner, Medawar irradiation in an attempt to dampen down found, while working for the Medical the immune response. Research Council in the 1940s, tissue reactions when using skin grafts.11 Skin In 1951, Billingham’s work with skin homografts from the patient’s brother were homografts and autografts in rabbits showed used in a 22 year old woman with extensive a role for cortisone in preventing transplant 13 burns. Subsequent biopsy specimens during rejection. The transplanted tissues became each dressing change allowed the swollen and hard, with a colour change to determination of local reactions within brick red and subsequently to what is the tissues.11 At day five, both sets of grafts described as “shades of dirty yellow, green 13 were similar to the naked eye and or brown”. The tissue eventually degraded. histologically.11 A subsequent polymorph Interestingly, following administration of and lymphocyte infiltration of collagen, and cortisone it was reported that the usual acute a multinucleate giant cell reaction, were progressive rejection, comprising of an seen.11 By day fifteen retrogressive changes inflammatory response, oedematous swelling had been shown, involving both a Volume 21, Issue 1 70 Res Medica HISTORICAL Orthotopic liver transplantation in the making: key pioneers and events relevant to current practice and lymphocytic infiltration, was converted experiments.12 Attention moved towards to a chronic delayed reaction with bone marrow and a form of tolerance