transplantation Routine success with transplantation of human organs was not obtained until the mid 1960s, in spite of its ancient appeal. Prior to this,
skin and
endocrine gland grafting had often been attempted from one human to another, but the reports on the outcome were confusing and the observations uncritical.
The groundwork for the new science of
transplantation immunology was laid by Medawar and other British biologists in the 1940s. They showed that rejection of tissue transferred from one person or animal to another was invariable, except for grafts between identical
twins, or a few special cases (e.g. cornea). In the 1950s they further showed that this tissue rejection was a response of the
immune system, rather than a biochemical or physiological ‘misfit’. But since an antibody could not be identified, a new form of immunity was sought and found. Suspicion fell on the small lymphocytes. These, with their relatively huge nucleus and minimal cytoplasm, had always been suspected of some important role in the body, but since they had shown no capability to multiply nor to act as
phagocytes, they had not been taken seriously. Soon, however, these lymphocytes were found in fact to be capable of division and enlargement when suitably provoked by foreign cells or particular proteins. So this previously neglected cell type became recognized as the key player in the exquisite differentiation of foreign material from the ‘self’, particularly of cells only slightly different from the body's own cells. The recognition of this mechanism explained the rejection of grafts. Although understandably seen as existing to frustrate transplant surgeons, this ‘cell-mediated’ immune mechanism clearly had a wider, fundamental role, as yet not fully understood.
Human grafts
In the 1950s, surgeons in Boston, led by Joseph Murray, established that a
kidney graft, from one healthy human twin to the other who had terminal chronic kidney failure, could reverse all the features of the disease, even though the donor kidney had no nerve supply and was placed in an unnatural position in the patient's pelvis. About this time, Medawar showed that the immune response in adult mice to experimental grafts could be abolished by prior injection of the donor cells at birth — tolerance had been induced.
The first attempts at reducing the human immune response to kidney grafts employed crude total body irradiation to depress the bone marrow and lymphocyte activity. These attempts largely failed. By 1960 the strategy was to use the newer anti-cancer drugs (notably 6-mercaptopurine and related substances, derived from the military poison gas nitrogen mustard). In cancer patients such drugs were known to suppress the immune response. One such agent,
azathioprine, was shown by the British surgeon Roy Calne to have a promising effect on cell-mediated immunity against grafts, without serious side-effects of general toxicity or liability to infection. In Paris and Boston, the first medium-term kidney graft survivals were obtained using this drug alone. A major advance followed when Starzl in Denver found that
steroid hormones, previously shown to have no effect on graft survival if given alone, combined with azathioprine to give powerful immunosuppression.
Rapid progress
This unpredicted innovation led to a drug regimen which was to be the core treatment for the next 20 years, establishing kidney transplantation as an acceptable form of treatment. Indeed, from 1963 onwards there was a period of optimism that routine organ grafting of all kinds would soon follow. This was encouraged by the concurrent rapid progress in immunology. The key role of circulating lymphocytes was now known, but the similar cells in the
thymus gland were apparently inactive; the absence of any demonstrated effect of removing the adult thymus seemed to relegate it to the status of an evolutionary vestige, in spite of its size and prominence in early life. The puzzle was solved in the UK in 1960 by Jacques Miller's serendipitous discovery that immediate removal of the thymus in new-born mice caused profound and lasting absence of cell-mediated immunity, allowing permanent acceptance of a skin graft — but also liability to some types of infection. Clearly the thymus was vital in the maturation of some circulating lymphocytes. Soon, markers were developed for lymphocytes that neatly classified them into
T-cells (thymus-derived), responsible for cell-mediated immunity, and
B-cells (bone marrow-derived), responsible (after maturation into plasma cells) for antibody production.
Around this time also, tissue typing methods emerged for identification of antigens on body cells, similar to red blood cell grouping but more complex. This gave the hope that any human organs donated could be matched closely to a potential recipient. Better methods for organ storage and the construction of perfusion machines allowed preservation and even long-distance transport of kidneys to patients with a good match. In this growth period of human transplantation, with the hopes that a final solution was at hand, even monkey kidneys were transplanted to human patients — and some of them were not rejected immediately.
Kidney failure
Meanwhile, from 1960 onwards, patients with renal failure were successfully treated with long-term
dialysis on the artificial kidney. This back-up was crucial before and after transplantation. At this time kidneys were taken a little while after the donor's heart had stopped and death had been pronounced. These kidneys were slightly damaged by the intervening lack of oxygen and did not usually work immediately, but since kidney tissue shows powers of revival and can pick up later, the artificial kidney could be used during this shut-down time. However, when the first human
liver transplants were attempted in the optimistic mid 1960s, the result was disastrous, not only because of the formidable new surgical challenge, but also because the liver was more sensitive to lack of oxygen after the death of the donor. Since there was no artificial liver or heart equivalent to the artificial kidney, if these transplanted organs did not function immediately, death was inevitable. This created pressure for donor organs to be as fresh as possible, and some cautious initiatives were taken, notably cooling the donor at the time of death, to reduce the oxygen requirement of the organs.
Coincidentally with this need within the service of transplantation, the success of resuscitation and
artificial ventilation for critically-ill patients in intensive care had thrown up the problem of patients who survived with irreparable brain damage, who had otherwise good physiological function but could no longer breathe for themselves. In these circumstances it was pointless to continue artificial ventilation. The first formal discussion of possible criteria for diagnosis of irreversible coma was by the Harvard Committee of 1968, and the pioneer Boston transplant surgeons unwisely involved themselves in their discussions. Shortly afterwards in that same year, Christian Barnard carried out the first human
heart transplant. He was praised at first for his daring innovation, but others, experienced in transplantation or otherwise, followed his lead with poor results, which were publicly revealed. There was professional criticism of such adventures worldwide, and increasing hostility from the public and media over many aspects, notably the tasteless publicity attaching to the patient and donor. The public were also uneasy when, for the first time, the details of the diagnosis of
brain death and ‘heart-beating’
organ donation were revealed. It seemed to some that these reasonable criteria for death had been introduced to help transplant surgeons, whereas they were required primarily in order to avoid pointless persistence with artificial ventilation.
Hesitant times
The consequences of that ‘year of the heart’ were a loss of confidence inside and outside the small world of organ transplantation, a virtual moratorium on human organ grafting apart from kidneys, and a rise in ethical debates on biomedical matters, with the emergence of a cadre of biomedical ethicists. Worthy government committees embargoed the transport of donors, and declared that death should be decided by ‘traditional means’, but they did encourage kidney transplantation with supportive publicity and donor card drives, attempting to incorporate organ donation into a respectable routine. This was not unconnected with the emergence of kidney transplantation as a more cost-effective treatment for chronic renal failure than regular dialysis.
In the late 1960s, one new agent,
anti-lymphocyte serum (ALS), was prepared and had spectacular success in experimental grafting. This encouraged the restart of human liver transplantation by two pioneers, Starzl in Denver and Calne in Cambridge, and evaluation of heart transplantation was funded at a centre under Shumway in Stanford. Such transplants were widely regarded as experiments without hope — a last resort for the most hopeless of patients — but the results of all organ grafting improved slowly, with or without the new ALS and its successors playing a supporting role in immunosuppression. The 1970s were a time of numerous small improvements in the surgical detail of kidney transplantation and post-operative management. The still rapidly-increasing understanding of immunology made little impact on clinical transplantation at this time. Better tissue typing methods appeared, but they did not fulfil the earlier promise (except in bone marrow transplantation).
Innovation resumes
By 1976 it was thought appropriate to formalize the criteria for brain death. These were duly agreed, and issued by medical bodies and governments, separating the matter carefully from the needs of transplantation. In Britain, fully ten years after Barnard, one heart transplant unit was cautiously approved, funded and controlled. Other nations took similar steps. Though there were critics, their objections centred largely on the cost of high technology medicine in a world of simple need. With tasteless publicity avoided, the new heart transplant units soon reported good results.
After the cautious growth of the mid 1970s, organ transplantation moved forward rapidly again with the introduction, in 1978, of a new immunosuppressive agent. This innovation came neither from basic immunology, nor from cancer chemotherapy, but from the routine mass-testing of soil samples in the search for microorganisms producing antibiotics or substances with anti-cancer or immunosuppressive effects. A Norwegian fungus was found to make, in its struggle for survival, a useful product later called
cyclosporine A (CsA), which had a powerful, safe, inhibitory action on lymphocytes, and which showed promise in animal transplantation. Reluctantly the company concerned prepared CsA for sale, but only as a prestige product, since the transplantation market was judged too small at that time for profitable investment. CsA proved to be a tricky agent to use, and animal testing had failed to reveal its toxicity for human kidneys, but once the art — rather than the science — of its use was mastered, it changed the history of transplantation. Steroids were still necessary as a partner for the new drug, and the new regimen was so powerful that it overrode the need for precise tissue typing. Results of kidney transplantation improved with its use, and rejection crises were rarer and less dramatic. But the main effect was to make liver and heart transplantation possible and widely accepted, and these became routine medical practice world-wide. In America, liver grafting became the single most expensive standard procedure in the world of surgery. Other pharmaceutical companies noticed the new, expanding potential market, and in the 1990s a steady stream of new products emerged; again they were obtained by synthetic chemists' changes to anti-cancer drugs, and rivals to cyclosporine came from other fungi from Easter Island and Japan. This success in countering rejection, as well as further experience in day-to-day management, meant better graft survival with fewer complications and deaths. Those patients considered eligible for organ transplants increased, and the upper and lower age limits moved steadily apart. Patients with major additional abnormalities, notably diabetes or serious vascular disease, were no longer automatically excluded.
But this success carried with it a crisis in the supply of organs in the 1990s. While candidates for kidney transplant could survive and grow older on dialysis while waiting for an organ, suitable liver and heart patients soon died. This shortage also led to concerns from professionals and patients' organizations about the traditional allocation of scarce organs based on tissue typing matching alone, since this now had only a minor role in the cyclosporine age. New ethical questions were aired. Were those with rare blood and tissue types now unfairly excluded? Was it fair to let older or sicker patients wait as long as younger, fitter ones? Should organs be given to those known to be feckless and likely to default from their medication and follow-up? Was it acceptable to offer cadaver organs to those from ethnic minorities and religious groups opposed to becoming cadaveric donors themselves, but who nevertheless would accept organs if living in countries with well-developed donation and sharing schemes?
As the service of transplantation also expanded out from its origins in the Western, developed nations, it moved from a base in Western academic medicine to become a service available in countries with different cultural assumptions. A remarkable variety of patterns of development was seen. In well-off nations, transplantation and dialysis spread quickly as a routine, but even there divergent views on organ donation were seen — some, such as Norway, used large numbers of living, related donors, and some, such as Eire, used none. Some countries, like Japan, had deep cultural hostility to interfering with the body after death, and no cadaveric donations occurred. Previously poor nations, such as those with new wealth from oil, at first sent even their poor citizens abroad in the 1970s, with their families, for living donor transplantation; then in the 1980s their governments set up transplant units at home, usually with expatriate surgical staff who often trained local professionals and handed over to them in the 1990s. Lastly, in very poor nations with limited facilities and no cadaveric donation, the vast majority of patients with chronic renal failure remained untreated and died, usually unaware of the diagnosis, and certainly having no expectation of cure. In these nations the wealthy or the élite could purchase treatment in private clinics and could easily induce poor people to part with a kidney, for money.
New shortages
In spite of every effort, the attempts to increase cadaveric donors in the developed world were not successful and new initiatives to deal with this shortage were numerous. These included the acceptance of less-than-perfect organs, the increasing use of living, related kidney donors, and even the surgical removal of parts of the liver and pancreas or a lobe of the lung from living donors, with encouragement of emotionally-involved genetically unrelated donors, such as spouses, to come forward. Whilst payment for kidneys from unrelated donors in other lands was officially deplored in the countries in which the science and surgery of transplantation had developed, this practice occurred; if the greed of intermediary brokers could be dealt with, the arrangement was locally accepted as reasonable.
The organ shortage meant a new look at the use of
xenograft organs — from other species. It had always been assumed that monkeys, with their closeness to man, would be the first source of such organs, but by the 1990s monkeys had powerful human friends, their use in medical research was stringently controlled, and many species were declared to be protected. Pursuit of this ‘concordant’ source seemed less necessary when another scientific discipline began to impinge on transplantation and even began to supplant immunology from its traditional role as the tissue grafter's essential laboratory partner. Genetic engineering began to provide a range of new techniques which could alter the nature of donor tissue and reduce the violent antibody and cell-mediated attack on xenograft tissue. Selected genes could be inactivated in the donor; gene insertion could add new proteins that would neutralize the reaction to antibody; cloned animals could be raised by transfer of cell nuclei from adult animals to embryos, after suitably engineering the nuclei. All this meant that the use of species ‘discordant’ with man could be contemplated. The animal turned to was the easily bred, non-violent pig, an animal possessing conveniently human-sized organs, and one already used for food and lacking unpleasant diseases — except one possible retrovirus. After studies had shown no passage of this organism to humans, regulatory bodies gave a careful blessing to the development of xenotransplantation.
Organ transplantation has come far in one generation and those involved continue as before to travel hopefully, with the usual mix of help from both basic science and industry, as well as good luck and serendipity.
David Hamilton
Bibliography
Ginns, L. C.,, Cosimi, A. B.,, and and Morris, P. J. (1999). Transplantation. Blackwell, Oxford.
Starzl, T. E. (1992). The puzzle people. University of Pittsburgh Press.
See also
brain death;
dialysis;
immune system;
life support;
organ donation;
phagocytes;
stem cells;
thymus.
