History of organ transplantation

The history of organ transplantation traces the development of transplantation from an experimental, almost uniformly fatal procedure in the first half of the twentieth century into a routine, life-saving therapy. Its central milestones are the first successful human kidney transplant between identical twins by Joseph Murray in 1954; the first human-to-human heart transplant by Christiaan Barnard in 1967; the development of liver and multi-organ transplantation by Thomas Starzl; and the introduction of the immunosuppressant ciclosporin in clinical use around 1978-1983, which transformed transplantation between non-identical individuals from rarely successful to routinely viable.[1][2][3] The central scientific obstacle throughout this history was immunological rejection, the recipient's immune destruction of genetically foreign tissue, and the modern era of transplantation is defined by progressively better means of controlling it.[3][4]

Early experiments and the rejection problem

Surgical techniques for joining blood vessels, a prerequisite for organ transplantation, were developed in the early 1900s by the French surgeon Alexis Carrel, who was awarded the 1912 Nobel Prize in Physiology or Medicine for his work on vascular suture and the transplantation of blood vessels and organs.[5] Carrel's techniques made it technically possible to implant an organ, but early attempts at kidney transplantation in humans and animals failed within days as the grafts were rejected, and the immunological basis of this failure was not understood.[1][4]

The understanding of rejection as an immune phenomenon emerged in the 1940s and 1950s, chiefly through the work of Sir Peter Medawar and colleagues, who showed that the destruction of skin grafts was an active, acquired, and specific immune response, and who, with Frank Macfarlane Burnet, developed the concept of acquired immunological tolerance, for which the two shared the 1960 Nobel Prize in Physiology or Medicine.[6] This established the conceptual framework: a successful transplant required either genetic identity between donor and recipient, or suppression of the recipient's immune response.[4][6]

The first successful transplants (1954-1967)

The decisive breakthrough came on 23 December 1954, when a surgical team led by Joseph Murray at the Peter Bent Brigham Hospital in Boston transplanted a kidney from Ronald Herrick into his identical twin brother Richard Herrick.[7][8] Because the twins were genetically identical, there was no immunological barrier, and the recipient survived for years, the first unequivocally successful human organ transplant.[7][8] This proof of principle was followed by efforts to overcome the rejection barrier between non-identical individuals, first using total-body irradiation and later using chemical immunosuppression with azathioprine and corticosteroids, a combination developed in the early 1960s that made cadaveric kidney transplantation possible, if hazardous.[1][3]

Other organs followed. Thomas Starzl performed the first human liver transplant in 1963 and the first prolonged-survival liver transplant in 1967.[9] The first human lung transplant was performed by James Hardy in 1963, and the first human-to-human heart transplant by Christiaan Barnard at Groote Schuur Hospital in Cape Town on 3 December 1967; the recipient, Louis Washkansky, survived 18 days.[10][11] Pancreas transplantation was first performed at the University of Minnesota in 1966.[3]

The immunosuppression revolution (1978-1983)

Despite these surgical achievements, the 1960s and 1970s were marked by poor survival, because available immunosuppression was crude and the price of preventing rejection was often fatal infection.[2][3] Many programs, including heart transplantation at most centers, were curtailed.[10] The turning point was the introduction of ciclosporin (cyclosporine), a fungal metabolite with a selective effect on T-lymphocytes discovered at Sandoz in Switzerland; its immunosuppressive activity was identified in 1972, it was first used in human transplantation around 1978 in the work of Roy Calne in Cambridge and Starzl in the United States, and it was approved for clinical use in 1983.[12][13] Ciclosporin dramatically improved graft and patient survival and is widely credited with converting transplantation from an experimental procedure into a standard therapy, triggering a rapid expansion of transplant programs worldwide in the 1980s.[2][12][13] It was later joined and partly superseded by tacrolimus, developed clinically in the late 1980s.[3][9]

Building national systems

As transplantation became clinically successful, the limiting resource shifted from surgical capability to the supply of donated organs, and countries built systems to procure and allocate them equitably. In the United States, the National Organ Transplant Act of 1984 created the Organ Procurement and Transplantation Network and prohibited the sale of organs.[14] In Europe, Eurotransplant (founded 1967) and later national bodies such as the United Kingdom's NHS Blood and Transplant and Spain's Organización Nacional de Trasplantes (founded 1989) coordinated donation and allocation.[15][16] In 2010 the World Health Assembly endorsed the WHO Guiding Principles on human cell, tissue and organ transplantation, codifying an international consensus that donation be voluntary and unpaid.[17]

Continuing developments

Subsequent decades saw the maturation of donation after circulatory death, machine perfusion for organ preservation, the first successful hand (1998) and face (2005) transplants under the umbrella of vascularized composite allotransplantation, and renewed work on xenotransplantation using gene-edited animal organs.[3] Throughout, the defining tension of the field has remained the gap between the number of people who need transplants and the number of organs available. See organ donation gap.

See also

• Joseph Murray · Christiaan Barnard · Thomas Starzl
• Ciclosporin and the immunosuppression era
• Organ transplantation · Transplant immunology
• Heart transplantation · Kidney transplantation · Liver transplantation

References

• Barker CF, Markmann JF. Historical overview of transplantation. Cold Spring Harb Perspect Med. 2013;3(4):a014977. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683917/ ; doi:10.1101/cshperspect.a014977
• Calne R. The history and development of organ transplantation: biology and rejection. Baillieres Clin Gastroenterol. 1994. PMID 7949454. https://pubmed.ncbi.nlm.nih.gov/7949454/
• Watson CJE, Dark JH. Organ transplantation: historical perspective and current practice. Br J Anaesth. 2012;108(suppl 1):i29-i42. https://www.bjanaesthesia.org/article/S0007-0912(17)33476-X/fulltext ; doi:10.1093/bja/aer384
• Murray JE. Organ transplantation (skin, kidney, heart) and the plastic surgeon. Nobel context / transplant immunology overview, NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1990/murray/facts/
• The Nobel Prize in Physiology or Medicine 1912 (Alexis Carrel). NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1912/summary/
• The Nobel Prize in Physiology or Medicine 1960 (Burnet and Medawar). NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1960/summary/
• Murray JE, Merrill JP, Harrison JH. Renal homotransplantation in identical twins. Surg Forum. 1956;6:432-436 (the 1954 Herrick twin transplant). Reprinted J Am Soc Nephrol 2001;12(1):201-204. https://journals.lww.com/jasn/fulltext/2001/01000/renal_homotransplantation_in_identical_twins.31.aspx
• Tilney NL. Renal transplantation between identical twins: a review. World J Surg. 1986. See also Joseph E. Murray - Facts, NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1990/murray/facts/
• Starzl TE. The long reach of liver transplantation. Nat Med. 2012;18:1489-1492. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549009/ (Zarrinpar/Busuttil profile, PMC5549009)
• Barnard CN. The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. S Afr Med J. 1967;41(48):1271-1274. PMID 4170370. https://pubmed.ncbi.nlm.nih.gov/4170370/
• Cooper DKC. Christiaan Barnard, The surgeon who dared: the story of the first human-to-human heart transplant. Glob Cardiol Sci Pract. 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062759/
• Borel JF, Kis ZL, Beveridge T. The history of the discovery and development of cyclosporine. In: The Search for Anti-Inflammatory Drugs. 1995. https://link.springer.com/chapter/10.1007/978-1-4615-9846-6_2
• Tedesco D, Haragsim L. Cyclosporine: a review. J Transplant. 2012;2012:230386. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503279/
• National Organ Transplant Act of 1984, Pub. L. 98-507. https://www.congress.gov/bill/98th-congress/senate-bill/2048
• Eurotransplant. History and timeline. https://www.eurotransplant.org/about-eurotransplant/history-and-timeline/
• Matesanz R, Domínguez-Gil B, Coll E, et al. How Spain reached 40 deceased organ donors per million population. Am J Transplant. 2017;17(6):1447-1454. https://onlinelibrary.wiley.com/doi/full/10.1111/ajt.14104
• World Health Organization. WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation (WHA63.22, 2010). https://www.who.int/publications/i/item/WHO-HTP-EHT-CPR-2010.01