By Dr. Ravi Mohanka | 11-Jul-2023
Throughout history, people have always been intrigued by the possibilities of transplantation of organs and tissues from one body to another. However, clinical transplant has been successful only in the last 50 years, a very short period in any field of medicine for the successful translation of ideas and concepts into reality. The history of transplantation is the story of the persistence of a few innovative scientists, physicians and surgeons leading to spectacular advancements and Noble prizes despite opposition and hostility from peers. During this achievement not only natural and biological laws were transcended (organs were not supposed to be swapped within and between species), but cultural, social, political, legal and ethical barriers were overcome (death was redefined, new laws were made to prevent exploitation and allow fair chance to patients), new knowledge and skills in surgery, organ preservation, immunology, immunosuppression and infections were acquired. Medical disciplines competed, cooperated and converged internationally to enable the treatment of debilitated and terminally ill patients into a routine, clinically effective, life-saving and cost-effective practice.
There are many figures in Egyptian, Greek, Roman, Chinese, Persian and other European mythologies that were part animals by virtue of which they had supra-human powers. These hybrid figures technically cannot be considered as “transplants”. In Hindu mythology, Ganesha (Indian god, remover of obstacles), whose head was cut off by Shiva in rage (Supreme Indian god, destroyer of evil), underwent transplantation of an elephant’s head transplant in place of his own. In 400 to 300 BC a Chinese medicinal practitioner is said to have exchanged hearts of two soldiers, one with a strong spirit but weak will and the other with a strong will and weak spirit to restore balance in both, using wine for anesthesia, an “exchange heart transplant”. In 3rd century, a Roman white bell tower custodian, Justinian was in considerable pain due to his gangrenous leg. Saints Cosmos and Damien are reported to have transplanted the leg of a dead Ethiopian Gladiator in him. Justinian who woke up with a new black leg, without pain. Although the validity of these accounts may be questioned, they certainly provide evidence of our desire to correct organ injury, dysfunction or failure with transplantation.
Indian text from 2500 – 3000 BC describes skin grafts from the buttocks or chin used for reconstruction of the nose (rhinoplasty) for deformities (from war injuries or as a form of punishment). Around 1000 – 800 BC Sushruta, an Indian surgeon, described a rhinoplasty technique using skin from the forehead. Another rhinoplasty technique was described by Tagliacozzi, an Italian surgeon, in the 15th century. These techniques were practiced in Persia and later popularized by a British surgeon in Europe in the 17th century. The New Testament of the Bible has several mentions of instances that could be defined as auto-transplantation or re-implantation. The Christ of Nazareth restored a high priest’s servant's ear severed by Simon Peter's sword in a battle, Saint Peter re-implanted the breasts of tortured and mutilated Saint Agatha after a Roman counsel removed them with tongs because she repulsed his advances and Saint Mark re-implanted a battle-amputated hand of a soldier.
In the 17th and 18th centuries, skin and nose were transplanted for reconstruction, teeth for cosmesis and sexual organs to restore youth and delay aging from slaves or corpses into the rich. These non-visceral superficial tissues were transplanted without anesthesia, hastily (to minimize the duration of pain), unsuccessfully and often caused syphilis. In 1760 John Hunter transplanted teeth, and auto-transplanted cocks' spurs into their combs and coined the term "transplant". With the discovery of microorganisms, infection, thermal and chemical disinfection and the demonstration of anesthesia in the mid-18th century, surgeries could be done successfully. In 1900, Karl Landsteiner identified major blood groups A, B, O and antigen-antibody reactions allowing safe transfusion of blood between patients with compatible blood groups. Around 1905 Alexis Carrel introduced the technique of full-thickness blood vessel suturing. In 1928 Penicillin was discovered, significantly reducing infection-related peri-operative mortality. These developments encouraged surgeon scientists to explore experimental transplant of organs and tissues between different areas of the same individual (autograft), genetically identical individuals (twins) (isograft), between members of the same species (allograft) or other species (xenografts).
The first cornea transplant was performed in 1905 by Eduard Konrad Zirm, an Austrian ophthalmologist in the Czech Republic. Alois Glogar, a laborer from a small town who had been blinded while slaking lime. Eduard used sutures from outside without the operating microscope and restored his sight. This paved the way for transplantation of other tissues and organs. However, the success of cornea transplant did not reflect the problems others were to face with transplantation, as, unlike other organs, as cornea derives nutrition from adjoining tissue fluid (without blood supply), immune cells did not reach the cornea or reject it as a foreign tissue. Subsequent successes by Russian surgeon Vladimir Filatov in 1931 and Ramon Castroviejo, a Spanish Surgeon, in 1936 further popularized the procedure. In 1944, R Townley Paton established the world’s first eye bank in New York. Currently, an estimated 200,000 Cornea transplants are performed every year supported by about 1,000 eye banks in more than 100 countries.
Our immune system is complex, with many types of cells (tissue phagocytes, neutrophils, lymphocytes, antigen-presenting cells and others) and molecules (antigens, antibodies and others), but this knowledge was not easy to come by. In 1908 Metchnikoff and Ehrlich won the Nobel Prize for describing the role of phagocytes and antibodies in inflammation, respectively. The role of lymphocytes, the immobile cells of the immune system, was still a mystery. In the 1920s James Murphy showed that the lymphoid system destroyed skin allografts and removing lymphocytes by irradiation, splenectomy, or benzol improved their survival. In the 1930s Leo Loeb also showed that lymphocytes caused rejection (also called recipient-host versus graft disease) of skin allografts and depended on donor-recipient genetic disparity. In 1948, Gorer described tissue-type antigens and antibodies in mice and Gibson recognized the immunological basis of skin graft rejection in humans.
It was recognized that non-identical (dizygotic) twin cows could accept blood transfusion (by Owen in 1945) and skin grafts (by Anderson in 1951) from each other without any reactions (freemartin cattle), as their placenta and blood circulation were common during fetal life. This state where an animal could accept blood, skin or an organ from another animal without rejection is called as “tolerance”. Between 1950 to 1953 antibodies responsible for graft rejection were identified and reversed using anti-lymphocyte serum (antibodies against lymphocytes) or steroids in dogs. In 1953, Billingham injected donor mice’s bone marrow cells into recipient mice at the fetal stage and found that the recipient developed tolerance to skin allografts and Peter Medawar demonstrated that if donor and recipient lymphocytes could be induced to co-exist (called “chimerism”) they developed tolerance.
The success of kidney transplants between identical twins in 1954 established that transplants were feasible between genetically identical individuals. In 1957 Simonsen and Billingham demonstrated graft versus host disease (GVHD) in chick embryos and mice, respectively, where the donor’s immunologically active cells destroyed recipient tissues after transplant (more common with bone marrow transplant, uncommonly seen with other transplants too). In 1958, Jean Dausset identified Human Leukocyte Antigen (HLA), (tissue types in humans) and Rose Payne and Jon van Rood identified antibodies against them in pregnant women. In 1959, James Gowan demonstrated that lymphocytes were not immobile and recirculated between blood vessels and the lymphatic system, and were responsible for rejection, refuting previous beliefs.
After World War II studies on the harmful effects of radiation on animals and humans were undertaken leading to recognition of their role in immunosuppression. Between 1958 to 1962, Murray, Jean Hamburger and Rene Kuss performed kidney transplants after total body radiation (to suppress the recipient’s immune system) few with donor bone marrow infusion (to induce chimerism), out of which few patients survived thus overcoming the “genetic barrier”. Although immunosuppression with radiation served as a proof-of-concept, infection-related mortality was almost universal.
In 1960, Robert Schwartz and William Dameshek used 6-MP (Mercaptopurine), an anti-cancer drug with anti-proliferative properties (drugs that suppress rapidly dividing cells such as lymphocytes) to extend the survival of skin allografts in rabbits. It was shortly used with radiation for kidney allografts in dogs and patients, with occasional successes. Gertrude Elion and George Hitchings developed Azathioprine in 1962 (a derivate of 6-MP), another anti-proliferative drug, which Roy Calne found to significantly delay rejection in dogs and was used with steroids by Thomas Starzl to achieve > 70% one-year survival in dogs. In 1963, Michael Woodruff, Monaco, Levey and Medawar found a remarkable improvement in mouse skin allograft survival using an anti-lymphocyte serum.
In 1964 Paul Terasaki developed a micro-cytotoxicity test in which by mixing recipient serum and donor lymphocytes tissue type (HLA) incompatibility could be identified (“HLA crossmatch”). Using the HLA cross-match test Starzl selected donor organs against which the recipient has pre-existing antibodies for transplant, thus eliminating the phenomenon of hyperacute rejection. He also used anti-lymphocyte serum to prevent rejection in kidney and liver transplants in 1966 and 1967, respectively. In 1964 Bach and Bain independently described another test, mixed lymphocyte culture (MLC) to identify tissue type incompatibility between donors and transplant recipients. Between 1969 and 1974 T and B lymphocyte sub-types, the role of “helper” T-cells in antibody production, the roles of antigen-presenting cells, cytokines, and the involvement of MHC in T-cell recognition of viruses were appreciated.
In 1977 Jean-François Borel developed Cyclosporine, which worked by blocking antibody production from helper T-cells (these types of lymphocytes and antibodies cause rejection) without causing bone marrow suppression (such as the anti-proliferative drugs) or generalized widespread immunosuppression (such as steroids) and was successfully used clinically in 1979 and 1980 by Clane for kidney transplants and Starzl for kidney and other organ transplants, respectively, improving the results of kidney transplants to around 90% and that of liver and heart transplants to around 80%, heralding a new era in transplantation, the “Cyclosporine Era” and making them mainstream. This immunosuppressive strategy was soon adopted by others with similar successes, thus making kidney transplants the standard of care for the treatment of end-stage renal disease.
In 1961, Waksman demonstrated the efficacy of anti-lymphocyte serum (ALS) in preventing rejection of skin allograft in rats. In 1963, Woodruff showed a reduction in skin allograft rejection with thoracic duct drainage and anti-lymphocyte serum in rats. In 1981 the first monoclonal antibody directed against T lymphocytes (OKT3) was successfully used in clinical practice. Since then, many other monoclonal antibodies against different lymphocyte subsets have been developed, such as anti-thymocyte globulin (ATG) (produced in horses or rabbits), antagonists of interleukin-2 receptors (anti-CD25) on T-cells such as Dacluzimab and Basiliximab (FDA approved in 1997 and 1998, respectively), Alemtuzumab an anti-CD52 (first used in 1999 by Calne) antibody on T-cells, Rituximab an anti-CD20 antibody (FDA approved in 1997) against B-cells (and its precursors). These antibodies differ in the antigen sites (epitopes) targeted, the spectrum of cells affected and their immunosuppressive actions and effects.
In 1989 Starzl found another drug Tacrolimus that worked similarly to Cyclosporine was more potent and was successful in reversing rejection and further improving graft and patient survival. Its use improved the results of kidney transplants and enabled liver, heart, pancreas, lungs, intestine and other transplants routinely. In 1995, another anti-proliferative agent Mycophenolate was approved by FDA for use in transplant and currently is a part of standard immunosuppression. In 1999 Sirolimus, a new category of immunosuppressive drugs (mTOR inhibitors) that acts by a different mechanism was approved and clinically used to avoid immunosuppressive drug nephrotoxicity. In 2010 another drug closely resembling Sirolimus in mechanism of action, Everolimus was approved and clinically used with very encouraging results.
With increasing knowledge of transplant immunology and the availability of potent immunosuppression, it was realized that, unlike bone marrow transplants, a perfect HLA match was not required for solid organ transplants. Patients with blood group or HLA mismatch may require pre-transplant desensitization, a higher degree of post-transplant immunosuppression and may have higher rejection risk, but even ABO or HLA incompatible transplants can be performed under appropriate desensitizing protocols. With the success of transplants, short-term graft losses are fewer and long-term chronic allograft loss, infections, malignancies, and immunosuppression-related toxicities. Each drug has different mechanisms of action, efficacies and toxicities common ones being nephrotoxicity, hypertension, hyperlipidemia, diabetes, cardiovascular diseases and others.
Experimental skin transplant both in animals and humans has been responsible for most knowledge gained about the immune system, rejection and development of immunosuppressive drugs. Early attempts at skin transplant failed, until 1869 when Swiss surgeon Jacques-Louis Reverdin discovered that small, thin “pinch” skin autografts healed over burns, ulcers, or open wounds. In 1870, George Lawson proposed a deeper-thickness graft, including the epidermis and reticular dermis. In 1875, German surgeon Thiersch described partial-thickness skin allografts. In 1881, Girdner systematically used autologous skin grafts for burns and wounds. His first case was in a 10-year-old burn patient who was leaning against a metal door when lightning struck, burning the skin off his arm, which was grafted with skin from the thigh of a young German boy who had died recently. After World War I there was an increased use of skin allografts for severe burns and other battle injuries although their success was limited by rejection without immunosuppression, they could be preserved and served as ideal biological dressings in patients with inadequate donor sites for skin autografts. Modern skin banking was started by Webster and Matthew in the 1930–1940s, but it became more standardized and reproducible during World War II and the Vietnam War. Between 1950 and 1980 skin and tissue banks were established across the globe. When skin is used as a part of vascularized composite allografts (VCA) such as limbs and face, immunosuppression is vital to their success.
In 1902 Emerich Ullmann performed an auto-transplant in a dog and a dog-to-goat transplant. In 1906, Jaboulay performed pig-to-human and sheep-to-human kidney transplants. In 1909 Ernst Unger performed two monkey-to-human kidney transplants (after performing more than 100 kidney transplants in animals), all without success.
In 1933, a Soviet surgeon Voronoy performed the first human-to-human kidney transplant from a dead donor (anterior thigh placement, uretero-cutaneous drainage) and four more until 1949, all without success. In 1950, Richard Lawler performed a kidney transplant from the same blood group cadaver for a patient with polycystic kidney disease in Chicago that lasted for several months. In 1951, Charles Dubost, Marcel Servelle, Michon and Kuss performed nine kidney transplants in Paris mostly from guillotined criminals (retroperitoneal placement, using iliac vessels, bladder drained), the last being the first living related donor (patient’s mother) transplant that functioned well for 3 weeks. Concurrently, David Hume performed nine kidney transplants (anterior thigh placement, uretero-cutaneous drainage) in Boston from donors who had died during surgery or hydrocephalus patients who had undergone nephrectomy for ventriculo-ureteric shunt using ACTH, cortisone and testosterone with a single functioning transplanted kidney at 5.5 months before rejection and graft loss. Although these kidney transplants were “technical successes”, most grafts functioned well for a short period followed by rapid destruction by then poorly understood host factors (“immunological failures”) often resulting in recipient’s death with few survivors.
The first technically and immunologically successful kidney transplant was performed on 23rd December 1954 between identical twins Ronald and Richard Herrick, by Joseph Murray, David Hume and others that generated widespread publicity for the procedure. Subsequently, kidney transplants between identical twins were performed across the globe, limited only by the rare availability of identical twins for donors. It was also realized that organ transplants between genetically diverse individuals needed further development of allied fields of immunosuppression, tissue typing and matching.
William Dempster used radiation and cortisone for kidney transplants in London, without much benefit. In 1958, Murray performed 12 kidney transplants after total body radiation, 2 of whom received donor bone marrow infusion (to induce chimerism), out of which one patient (between non-identical brothers) survived for 20 years, thus overcoming the “genetic barrier”. In Paris, one transplant between fraternal twins using total body radiation led to long-term (26 years) survival. Between 1960 to 1962, Jean Hamburger and Rene Kuss performed 4 successful kidney transplants with total body radiation alone, without donor bone marrow infusion, one with 18-month survival. These occasional successes offered a ray of hope and were the principal justification to continue kidney transplant trials. Although immunosuppression with radiation served as a “proof-of-concept”, infection-related mortality was almost universal.
In 1960 to 1962 Roy Calne and Charles Zukoski found fewer rejections in dog kidney transplants and David Hume in 27 human kidney transplants and Murray had one patient (out of 13) surviving more than one year using 6-MP and Azathioprine. In 1963, at a national conference of all active transplant centers in Washington, most surgeons had few patients surviving a year, except Thomas Starzl, who achieved 67% 1-year survival using Azathioprine and prednisone for reversal of rejection. In 1967 Starzl conducted the first clinical trial with anti-lymphocyte globulin (ALG), azathioprine and prednisone for kidney transplantation. Over the next 15 years, although the results of kidney transplants only improved marginally, several allied developments expanded its scope:
Kidney became the pathfinder organ for the field of transplantation as with chronic dialysis (became available in 1940 – 1950s) and arteriovenous shunts (1960) end-stage kidney disease patients could be kept stable (unlike other organs where end-stage organ failure was often fatal) not only increasing the pool of potential kidney transplant recipients but also, serving as a “bridge to transplantation” and an alternative to death if the transplant failed. Kidney being a paired organ, living donation provided an additional organ source, increasing overall organ availability and the graft function was easy to monitor. Currently, about 90,000 kidney transplants are estimated to be performed globally, about a third each in America, Europe and others, about 40% of which are from living donors.
The first heart transplant was performed heterotopically in the neck of a dog by Carrel and Charles Guthrie in 1905 at the University of Chicago followed up by similar attempts by Mann in 1933 with an average survival of 4 days. Mann’s technique was very physiological and was further modified by Marcus in 1953 to obtain similar results. In 1962 Demikhov described twenty-four variants of heterotopic heart transplants, including inguinal and intra-thoracic with the highest survival of 32 days. He even transplanted an additional head in a dog with an intrathoracic heart-lung before the availability of cardiopulmonary bypass. In 1957, Webb and Howard reported successful preservation and heterotopic transplantation of the heart in dogs by flushing the organ with cold potassium citrate and in 1959 with hypothermic preservation. In 1959, Goldberg performed the first orthotopic heart transplantation in dog using the technique of left atrial cuff anastomosis with a cuff of the orifices of the four pulmonary veins with cardiopulmonary bypass, the conventional technique of cardiac transplantation. In the same year, Cass and Brock improvised with an additional right atrial anastomosis instead of caval anastomosis to describe the standard technique of orthotopic heart transplantation in dogs. Lower and Shumway had 6-21 days survival without immunosuppression, diagnosed rejection with changes in electrocardiography (ECG) voltage and reversed it with azathioprine and methylprednisolone achieving a survival of 250 days in 1965.
In 1964 Hardy performed the first human heart xenotransplant from a chimpanzee. The heart was too small to support circulation and failed in 2 hours. In 1967, Christian Bernard performed the first successful heart first heart transplant at Cape Town, South Africa on Louis Washkansky who was a 53-year-old Lithuanian immigrant who was diagnosed with myocardial infarction leading to cardiomyopathy. He received the heart of a girl, Denise Darvall hit by a drunk driver which worked well for 18 days. It generated such widespread interest, that by 1968, 102 transplants were done in 17 countries and 52 centers. In 1969, Denton Cooley implanted the first total artificial heart as a bridge to transplant, after which the patient died. The introduction of Cyclosporine in 1979 made heart transplants routine. Currently, an estimated 8,000 heart transplants are performed every year globally in 60 countries.
In 1946 Demikhov unsuccessfully attempted single-lung transplantation in a dog complicated by bronchial anastomotic dehiscence. Henri Metras in 1950 and Haglin in 1963 reported first successes in a dog and a non-human primate, respectively. The first lung transplant successful in a patient was performed by James Hardy in 1963 at the University of Mississippi, Jackson, USA on a 58-year-old man serving a life sentence in prison with lung cancer causing obstruction, collapse and recurrent pneumonia, with 18-day survival. Fritz Derom’s lung transplant in 1971 in Belgium had a 10-month survival. The first successful combined heart–lung transplant was performed by Shumway and Reitz in 1981 with cyclosporine, which allowed steroid reduction and better healing of bronchial anastomosis. In 1983, Joel Cooper at the Toronto Lung Transplant Group performed a successful lung transplant with 7-year survival, which was followed by the first double lung transplant in 1987, on Tom Hall who was suffering from pulmonary fibrosis and lived for 6 years after the transplant, their technique remains the current standard. Currently, about 5,500 lung transplants are performed in 45 countries worldwide with good success.
Liver TransplantIn 1955 Welch performed auxiliary (additional) liver transplantation in dogs and by 1960, it was performed orthotopically (at its original location) independently in Boston and Chicago in dogs. In 1963, Thomas Starzl performed the first human liver transplant in a 3-year-old child suffering from biliary atresia, and subsequent two more, were unsuccessful, primarily because of technical difficulties and excessive bleeding. Experiments between 1964 – 1966 revealed that mesenteric blood supply was essential for the liver and reconstruction of both hepatic artery and portal veins and the use of antilymphocyte serum and Azathioprine achieved more than one-year survival in dogs. Clinical liver transplants were also performed unsuccessfully at Boston and Paris. In 1966 Cordier and others observed a lack of rejection in livers transplanted in pigs and Starzl performed a chimpanzee-to-human liver transplant, unsuccessfully. The first successful liver transplant was performed by Starzl on a child with hepatoblastoma in 1967, who succumbed to recurrent metastatic disease 18 months later. Subsequently, four out of seven patients survived although rejection posed a significant problem in the long-term. Similar success was achieved by Calne in Cambridge. Availability of livers from brain-dead donors and cyclosporine improved the results significantly over the next 15 years. It was recognized as a standard of care for treatment of end-stage liver disease and many centers were established successfully globally. In 1988, Rudolf Pichlmayr first performed a split-liver transplantation enabling two transplants from one liver. A living donor liver transplant was first attempted by Raia and the first success was achieved by Strong in 1989. In 1994 the first success with living donor liver transplants was reported by Hashikura using a left lobe and by Yamaoka using a right lobe. Currently, about 30,000 liver transplants are performed annually globally, out of which about 20% are living donor transplants.
In 1966 William Kelly and Richard Lillehei first successfully transplanted a duct-ligated segmental pancreas simultaneously with a kidney from a cadaver donor into a 28-year-old uremic type 1 diabetic woman at the University of Minnesota followed by a whole pancreas later that year with enteric drainage of duodenum. In 1983 Hans Sollinger at the University of Wisconsin described the technique of bladder drainage for pancreatic transplants, which became a standard technique as rejection was easy to monitor. Since the 1990s, enteric drainage, which is more physiological, regained popularity. Currently, about 2,500 pancreas transplants are performed annually globally.
In 1959 Lillehei reported successful transplantation of the small intestine in dogs. In 1964 Ralph Deterling in Boston attempted the first human intestinal transplant unsuccessfully. In 1988, the first successful intestinal transplant was performed in Germany by Deltz followed shortly by teams in France and Canada and in the same year simultaneously with a liver transplant at the London Health Sciences Center. Currently, about 225 small bowel transplants are performed worldwide.
The history of transplantation is an epic journey of the medical community’s quest to understand how the human body and organs work, its most daring efforts to defy illness and death, the supreme generosity of organ and tissue donors, unparalleled courage of transplant recipients resulting in extraordinary and hitherto unimaginable progress for human race. The progress will only accelerate to yield newer avenues in the future.
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