Organ Transplantation - History

History

Successful human allotransplants have a relatively long history of operative skills that were present long before the necessities for post-operative survival were discovered. Rejection and the side effects of preventing rejection (especially infection and nephropathy) were, are, and may always be the key problem.

Several apocryphal accounts of transplants exist well prior to the scientific understanding and advancements that would be necessary for them to have actually occurred. The Chinese physician Pien Chi'ao reportedly exchanged hearts between a man of strong spirit but weak will with one of a man of weak spirit but strong will in an attempt to achieve balance in each man. Roman Catholic accounts report the 3rd-century saints Damian and Cosmas as replacing the gangrenous leg of the Roman deacon Justinian with the leg of a recently deceased Ethiopian. Most accounts have the saints performing the transplant in the 4th century, decades after their deaths; some accounts have them only instructing living surgeons who performed the procedure.

The more likely accounts of early transplants deal with skin transplantation. The first reasonable account is of the Indian surgeon Sushruta in the 2nd century BC, who used autografted skin transplantation in nose reconstruction rhinoplasty. Success or failure of these procedures is not well documented. Centuries later, the Italian surgeon Gasparo Tagliacozzi performed successful skin autografts; he also failed consistently with allografts, offering the first suggestion of rejection centuries before that mechanism could possibly be understood. He attributed it to the "force and power of individuality" in his 1596 work De Curtorum Chirurgia per Insitionem.

The first successful corneal allograft transplant was performed in 1837 in a gazelle model; the first successful human corneal transplant, a keratoplastic operation, was performed by Eduard Zirm at Olomouc Eye Clinic, now Czech Republic, in 1905. Thyroid gland tissue was transplanted in 1882 by Theodor Kocher. Pioneering work in the surgical technique of transplantation was made in the early 1900s by the French surgeon Alexis Carrel, with Charles Guthrie, with the transplantation of arteries or veins. Their skilful anastomosis operations, the new suturing techniques, laid the groundwork for later transplant surgery and won Carrel the 1912 Nobel Prize in Physiology or Medicine. From 1902 Carrel performed transplant experiments on dogs. Surgically successful in moving kidneys, hearts and spleens, he was one of the first to identify the problem of rejection, which remained insurmountable for decades.

Major steps in skin transplantation occurred during the First World War, notably in the work of Harold Gillies at Aldershot. Among his advances was the tubed pedicle graft, maintaining a flesh connection from the donor site until the graft established its own blood flow. Gillies' assistant, Archibald McIndoe, carried on the work into the Second World War as reconstructive surgery. In 1962 the first successful replantation surgery was performed – re-attaching a severed limb and restoring (limited) function and feeling.

The first attempted human deceased-donor transplant was performed by the Ukrainian surgeon Yu Yu Voronoy in the 1930s; rejection resulted in failure. Joseph Murray and J. Hartwell Harrison performed the first successful transplant, a kidney transplant between identical twins, in 1954, successful because no immunosuppression was necessary in genetically identical twins.

In the late 1940s Peter Medawar, working for the National Institute for Medical Research, improved the understanding of rejection. Identifying the immune reactions in 1951 Medawar suggested that immunosuppressive drugs could be used. Cortisone had been recently discovered and the more effective azathioprine was identified in 1959, but it was not until the discovery of cyclosporine in 1970 that transplant surgery found a sufficiently powerful immunosuppressive.

Dr. Murray's success with the kidney led to attempts with other organs. There was a successful deceased-donor lung transplant into a lung cancer sufferer in June 1963 by James Hardy in Jackson, Mississippi. The patient survived for eighteen days before dying of kidney failure. Thomas Starzl of Denver attempted a liver transplant in the same year but was not successful until 1967.

The heart was a major prize for transplant surgeons. But over and above rejection issues, the heart deteriorates within minutes of death, so any operation would have to be performed at great speed. The development of the heart-lung machine was also needed. Lung pioneer James Hardy attempted a human heart transplant in 1964, but when a premature failure of the recipient's heart caught Hardy with no human donor, he used a chimpanzee heart, which failed very quickly. The first success was achieved on December 3, 1967, by Christiaan Barnard in Cape Town, South Africa. Louis Washkansky, the recipient, survived for eighteen days amid what many saw as a distasteful publicity circus. The media interest prompted a spate of heart transplants. Over a hundred were performed in 1968–69, but almost all the patients died within sixty days. Barnard's second patient, Philip Blaiberg, lived for 19 months.

It was the advent of cyclosporine that altered transplants from research surgery to life-saving treatment. In 1968 surgical pioneer Denton Cooley performed seventeen transplants, including the first heart-lung transplant. Fourteen of his patients were dead within six months. By 1984 two-thirds of all heart transplant patients survived for five years or more. With organ transplants becoming commonplace, limited only by donors, surgeons moved on to riskier fields, including multiple-organ transplants on humans and whole-body transplant research on animals. On March 9, 1981, the first successful heart-lung transplant took place at Stanford University Hospital. The head surgeon, Bruce Reitz, credited the patient's recovery to cyclosporine-A.

As the rising success rate of transplants and modern immunosuppression make transplants more common, the need for more organs has become critical. Transplants from living donors, especially relatives, have become increasingly common. Additionally, there is substantive research into xenotransplantation, or transgenic organs; although these forms of transplant are not yet being used in humans, clinical trials involving the use of specific cell types have been conducted with promising results, such as using porcine islets of Langerhans to treat type 1 diabetes. However, there are still many problems that would need to be solved before they would be feasible options in patients requiring transplants.

Recently, researchers have been looking into means of reducing the general burden of immunosuppression. Common approaches include avoidance of steroids, reduced exposure to calcineurin inhibitors, and other means of weaning drugs based on patient outcome and function. While short-term outcomes appear promising, long-term outcomes are still unknown, and in general, reduced immunosuppression increases the risk of rejection and decreases the risk of infection.

Many other new drugs are under development for transplantation.

The emerging field of regenerative medicine promises to solve the problem of organ transplant rejection by regrowing organs in the lab, using the patients' own cells (stem cells or healthy cells extracted from the donor site.)