Late in the summer of 1954, Richard Herrick was referred by his doctor to the Peter Bent Brigham Hospital in Boston, Massachusetts. Richard was 24 years old, and had been suffering for some time from high blood pressure and puffiness around the face and eyes. His doctor suspected a kidney problem, and the Brigham is where you went if your kidneys were malfunctioning. The medical staff at the Brigham ran a battery of tests that initially might have indicated any number of problems. But they noticed that in addition to high blood pressure Richard had a bit more protein than normal in his urine, as well as traces of blood. Together with other findings, this confirmed the diagnosis of a kidney dysfunction. Richard was transfused with several units of blood, which improved his condition considerably, and he was sent home. Only time would tell how serious the problem with his kidneys was.

Five months later, Richard Herrick was back, and this time it was clear he had a very serious problem indeed. His blood pressure was now dangerously high, and he was beginning to experience problems with his vision, a not uncommon by-product of high blood pressure. Protein levels in his urine were double what they had been before, and he was showing signs of congestive heart failure. Several days after this second admission Richard began to exhibit bizarre behavioral changes; he occasionally became drowsy and disoriented; at other times he was irritable or even aggressive toward the staff. He went into convulsions several times. It was a set of symptoms the doctors at the Brigham were all too familiar with, and about which they knew they could do precious little. Their young patient was experiencing the beginning stages of massive and terminal kidney failure.

Dr. John P. Merrill took a special interest in this particular patient. Merrill had been working with a medical equipment company on the refinement of an "artificial kidney," what we would today call a renal dialysis machine. This machine, first developed in Holland during the World War II, was showing great promise in being able to substitute for one of the most vital kidney functions - removing from the blood toxic substances that could cause precisely the symptoms this young man was experiencing. In fact, on this second visit to the hospital Richard was treated with one of the artificial kidneys and, as the doctors expected, showed great improvement.

But another chance to demonstrate the usefulness of his new machines was not what attracted Merrill to this case. Merrill knew that the kidney machine could never be more than a stopgap measure, able to keep a patient alive for a period of time but never able to offer a cure. What he was really interested in was the possibility of kidney transplantation. He had recently completed a series of nine kidney transplants, taking healthy kidneys immediately after death from patients who died of causes unrelated to their kidneys, and transplanting them into patients with terminal kidney failure. In several cases, the transplanted kidney had seemed to take hold for awhile, bringing almost immediate improvement in the recipient's condition. But in a fairly short time all nine transplants had failed, and the recipients all ultimately died of terminal kidney failure. This was incredibly frustrating, because Merrill's team was considered to be one of the most skilled in the world at this procedure.

Like other experts in his field, Merrill was convinced the transplants were failing not because of problems with the surgery, or because an organ from one person simply could not function in another, but because the transplanted organ was being attacked and rejected by the recipient's immune system. Among the various lines of evidence in support of this notion, he had been particularly struck by the experiments of Ray Owen, who had shown that twin cows that shared a single placenta during fetal life could exchange grafts as adults. Merrill had argued for some time that human identical twins should be able to exchange organs and tissues without any fear of immunological rejection. And that was what interested him about this young man. According to the doctor who had referred Richard Herrick to the Brigham for treatment, Richard had an identical twin, Ronald. After reassurances that he could survive with a single kidney, Ronald agreed to give the new procedure a try. Dr. Merrill and the Herrick boys were about to make medical history.

As a preliminary test of his hypothesis, Merrill's team carried out an exchange of skin grafts between Richard and his twin brother. After a rather anxious month in which his doctors had to struggle to keep Richard alive, it was confirmed by microscopic examination that he had completely accepted his Ronald's skin. Without waiting any further, the two brothers were prepped and wheeled into adjacent operating rooms. Ronald’s left kidney was removed and taken in a stainless steel pan to the surgeons waiting in the adjoining operating room. While the first twin was being closed, the surgeons opening Richard saw a sight usually only seen at autopsy - two shriveled, shrunken kidneys wasted away to a tenth their normal size. Although the healthy twin's kidney had grown pale and cold during the eighty-odd minutes between operations, as soon as it was connected to Richard's blood system it swelled ever so slightly and turned pink and warm to the touch. After the surgeons checked meticulously for leakage, this young man, who only days before had been within a stone's throw of death, was carefully sewn back together. Recovery from the surgery was uneventful for both brothers, and the transplanted kidney began to function beautifully in its new surroundings. All of Richard's previous symptoms disappeared in a matter of days. He was discharged after two weeks, and over the course of the next few months regained his former physical vigor, as well as twenty-five pounds of lost weight. Ronald’s remaining kidney underwent a gradual enlargement as it took on the sole task of cleaning out his blood, but he suffered no ill effects whatsoever. Both brothers lived for many years.

Thus began the age of human organ transplantation. Of all the miracles wrought by modern medicine, none has moved us quite the way organ transplantation has. That an organ can be severed of all its connections with one human being, implanted into another, and recover the full function it needs to sustain life in the recipient, was and remains simply awe-inspiring. When, as in the case of bone marrow or a kidney, both the donor and the recipient may be alive and well after the transplant has been accomplished, a bond is established between them that is unique in the human experience. On the other hand, to see a transplanted heart still beating and sustaining life in a human being a quarter century after its original owner has returned to the elements he or she came from, puts us in very close touch with some of the deepest mysteries of life, and stretches our conception of the meaning of mortality and immortality. How did we come to be able to do such a miraculous thing?

Our fascination with the possibility of using transplantation to restore broken or worn-out body parts seems to have been around for a very long time. Ancient medical texts describe attempts to replace at least the external parts of the body. As early as several hundred years BCE Hindu surgeons described a technique for reconstructing noses from tissue obtained elsewhere in the body. This was necessitated by a fairly common punishment for a number of crimes in ancient India: cutting off the nose. One of the earliest accounts of transplantation in Western culture although certainly apocryphal, suggests that such experiments may at least have been thought about. Cosmas and Damian were two third-century Roman physician-brothers who had the strange practice of not charging for their services. They were eventually beheaded for their erratic behavior, which also included conversion to Christianity. They are alleged to have returned some two hundred years after their execution to a church in Rome dedicated to their martyrdom, where the caretaker of the church had apparently developed gangrene in one of his legs. According to legend the brothers removed the bad leg and transplanted a good one from a recently deceased Moor. We are left to believe that this worked, and that the caretaker went about ever after with one black leg and one white leg.

Gasparo Tagliacozzi, a sixteenth-century Italian surgeon, described a method for using tissue taken from the arm to rebuild a nose. The arm is brought up and fixed into position next to the nose; an appropriately shaped slice of muscle with its overlying skin is gradually carved away from the arm and allowed to implant on the face. After the tissue has been finally severed from the arm and is settled into its new location, the arm is lowered and allowed to heal. With only minor variations, this technique is still used today, and is called the Tagliacozzi flap procedure. The use of tissues taken from one part of the body to reconstruct or repair another part of the same body, called autografting, is strictly a surgical problem. With proper technique, any part of the body should be transplantable to any other part of the body; whatever barriers may exist are clearly not immunological in nature. The exchange of body parts between two genetically different individuals (allografting) is, the Miracle of the Black Leg excepted, quite another matter.

Of all the surgical techniques associated with organ transplantation, the most critical is vascular anastomosis, or the suturing together of blood vessels between the donor tissue and the recipient's blood system. Every organ in the body is intricately connected with the body's circulatory system. Each organ is served by arteries, which bring fresh blood to it, and by veins, which take used blood away from it. If this circulation is interrupted for more than a few minutes, the organ will suffer irreversible damage and die. It is very easy to disconnect the arteries and veins when removing an organ; a surgeon can just snip them with a scissors or slice them with a scalpel. Damage to the organ owing to removal from its oxygen supply can be minimized by cooling. But reconnecting an organ to the recipient's circulatory system is very demanding, almost an art as much as a science. The intricate methods for achieving this were not developed until the turn of the twentieth century, by a surgeon named Alexis Carrel. The techniques he developed at that time, specifically for the purpose of transplanting organs, were used by John Merrill almost exactly as he first described them. Dr. Carrel thus made two new fields possible: vascular surgery and, indirectly, organ transplantation.

Carrel and other surgeons in fact spent the next thirty years exploring the surgical aspects of organ transplantation in animals, and they made great progress. Moving organs from one place to another in the same individual, and getting them to function, proved with practice to be fairly easy. But in terms of their ultimate objective - transplanting organs from one animal to an unrelated animal and achieving long term-survival and function of the organ - they, no less than Dr. Merrill after them, were completely without success. What Merrill's very important experiment with human identical twins showed was that the surgical skills necessary to accomplish successful organ transplantation were well in hand, indeed probably already had been in hand in Carrel's day. What remained was to remove, or at least to manage, the immunological barriers.

It seems intuitively obvious that human beings are all very different from each other, and that the immune system could possibly spot these differences and respond to them. But what exactly are the differences between people that the immune system responds to? These differences are clearly absent in identical twins, and present in everyone else. But are all differences the same? Might some people be closer in terms these differences than others? And if so, is it easier to exchange grafts between them?

One of the most important steps toward understanding the immunological basis of organ transplant rejection was the gradual unraveling of a concept that came to be referred to as histocompatibility. Histos is a Greek word referring to a weaving, or a web, and immunologists co-opted this term in combinatorial form to refer to the compatibility of living tissues or organs from people or animals who are genetically different. Our understanding of histocompatibility stems from an interesting intersection between the fields of organ transplantation and cancer research. At the beginning of this century, researchers wanted very much to be able to pass tumors from one animal to another in order to study the process of tumor growth and development. The animal most often used in such studies was the mouse, which is small, relatively inexpensive, and easy to maintain in the laboratory. The problem with studying tumors in mice (or any other animal) is that although tumors may start out small, they keep on growing and eventually kill the animal carrying them. So as the tumor got larger, and the poor mouse carrying it might seem to be nearing the end, researchers would try to pass a small piece of the tumor to another mouse to keep the study going. Usually this would fail. The tumor would seem to grow for a day or two or three, and then shrink and disappear. But on rare occasions the tumor would "take" and could even survive passages through several consecutive mice. There was great speculation about the reason for this occasional success. The failure to "take" was assumed by many scientists to be due to some special property of tumors. But no one could discover what this property was, or why it worked in some cases and not in others.

At some point an alert lab worker apparently noticed that the more closely related two mice were genetically, the more likely it was that a tumor could be passed successfully between them. In a study carried out in Germany in the early 1900s, it was observed that a tumor arising in wild mice captured in a particular house could be passed with a substantial number of positive takes to other mice captured in the same house; with less success to mice captured in nearby houses; and not at all to mice captured in distant neighborhoods. The explanation of this lies in the sociobiology of mice. Mice living in any given household tend to be closely related, forming what is known as a deme. This is largely due to the murine equivalent of incest, which results in a substantial degree of genetic homogeneity. Occasionally, disgruntled males may leave one deme and bully their way into a neighboring house, establishing a distinct but genetically related deme just next door.

Around the same time, it had become fashionable to keep so-called "fancy mice" as pets for children. These were mice specifically bred, using techniques known to farmers for centuries, to bring out some property thought to be cute, or at least commercially profitable. This sort of inbreeding produced albino strains with white fur and pink eyes, for example - a real oddity at the time, although fairly commonplace now. Selective breeding also produced the famous "Japanese waltzing mouse", a poor creature with an inner ear defect that led it to stagger ("waltz") in circles in its cage. (This apparently was an example of cute.) But like mice living together in the same house, these partially inbred strains of mice showed a high degree of acceptance of each other's tumors.

And so one day, as happens from time to time in immunology, a light went on. The more closely related two individuals are, the more likely it is that they will be able to exchange tumors - or, for that matter, any tissue. And this led ultimately to the discovery of histocompatibility antigens. This is perhaps one of the most important discoveries in all of immunology, from both a practical and a theoretical point of view. We now know that histocompatibility antigens are special proteins found on the surface of each cell in the body. Every cell in the body of the same individual (whether mouse or human) will have exactly the same histocompatibility ("tissue compatibility") antigens on its surface, marking those cells as belonging to that individual. However, two different individuals (unless they are identical twins) will have different histocompatibility antigens.

In humans, the likelihood that two randomly selected individuals could have the same set of histocompatibility antigens (called HLA antigens in humans) is less than one in twenty million. These are thus truly "markers of individuality", and are the main reason human beings cannot exchange tissue grafts: The immune system is exquisitely sensitive to differences in histocompatibility antigens and will mount a vigorous and effective rejection response against any HLA antigens that are not self. So the inability to pass tumors from one animal to another turns out to be simply a variation of the general theme that tissue grafts cannot be passed between individuals. In both cases, it is the difference in histocompatibility antigens between donor and recipient that triggers rejection.

Although the odds of two randomly selected individuals being completely HLA identical are extremely low, it still helps to try to match them up as best we can. This is done by a process called tissue typing, in which the HLA antigens of prospective donors and recipients are identified, and the best possible match is made. There is a reasonably good correlation between the degree of HLA matching and success of the transplant. Especially when the donor and recipient are unrelated, every effort is made to achieve the closest possible HLA match between them.

The basis for graft rejection between non-identical individuals was hotly debated throughout the first half of the twentieth century. As early as 1912 there were suggestions that it might be immunological in nature, but this was not immediately obvious to many people. Most early transplant experiments in animals involved the exchange of skin grafts, which are technically easy to perform. These studies demonstrated that graft-specific antibodies, although indeed produced during skin transplant rejection, had little or no effect on graft survival. Because antibodies were at the time the only known immune effector mechanism, it was quite reasonable to conclude from these results that skin graft rejection could not be immunological in nature.

The fact that graft rejection is indeed immunological in nature was finally demonstrated to everyone's satisfaction by the British physician-scientist Peter Medawar during the World War II. Medawar (later Sir Peter) was working at a burn hospital in London, treating civilians injured in bombing raids in England, as well as British soldiers and airmen returned from more distant fronts for advanced care. It had been known for some time that the most effective treatment for severe burns is to get the burned area covered as quickly and as completely as possible with fresh skin to prevent infection and loss of body fluids. Skin taken from another part of the patient's own body was obviously the best solution, but this was not always possible. Using skin from other donors could sometimes offer temporary relief, but the transplanted skin would always be rejected in the end. Nevertheless, foreign skin could sometimes last long enough to allow the scarring process in the patient's own underlying tissues to get under way.

In particularly bad cases, it would sometimes be necessary to apply a second transplant of skin to keep patients alive until their own healing processes could take over. Medawar noticed that a second application of skin taken from the same donor, after the first graft had been rejected, would last only a few days, whereas the first graft may have lasted up to two weeks. However, a skin graft from a completely different donor applied to a previously grafted patient would again last up to two weeks. So it had become common practice never to use skin from the same source twice on the same patient. Upon reflection, Medawar concluded that the skin graft recipient must have been mounting an immune reaction to the original transplant of skin. If skin from the same donor was transplanted a second time, then immunological memory came into play, and the graft was vigorously and rapidly rejected in the same way as a secondary infection with any standard pathogen would be. Medawar followed up his clinical observations, published in 1943, with a series of incisive skin-grafting experiments in rabbits that convinced everyone working in the field that graft rejection was indeed immunological in nature. The combination of his clinical and experimental studies on transplantation and tolerance resulted in a Nobel Prize (shared with Sir MacFarlane Burnet) in 1960.

Several years after Medawar's experiments, it was finally shown that skin transplant immunity was caused by white blood cells rather than antibodies, thus providing a rational immunological basis for transplant rejection. We now know that skin graft rejection is caused almost exclusively by T cells that recognize foreign histocompatibility antigens on the incoming graft cells. These T cells belong to a different subset than the ones we have seen previously. The cells that help B cells and macrophages, and that are attacked by HIV, are CD4 helper cells. The T cells that cause graft rejection are CD8 "killer" T cells, also called cytotoxic T lymphocytes, or CTLs. The result of CTL attack is swift and violent: The graft drops away, withered and dried, less than two weeks after transplantation.

By the end of the 1960s, physicians and scientists could add organ transplantation to the list of clinical situations in which the immune system was part of the problem, and not part of the solution. Organ transplants that could demonstrably save a patient's life are thrown out of the body as rabidly and as rapidly as any disease-bearing pathogen. True, the immune system is not doing anything wrong. Evolution had never prepared it to make decisions about spare body parts that are not part of self. The question became, would it be possible to somehow selectively disconnect the immune system with respect to a newly transplanted organ without, at the same time, crippling it with respect to its ability to fight infections?

The very first transplants in humans - the kidney transplants using identical twins as donor and recipient - were carried out without the need for suppression of the immune response of the recipient. Because both recipient and donor always had exactly the same histocompatibility (HLA) antigens, there was nothing to provoke an immune response. On the other hand, as every transplanter up through Dr. Merrill had found out the hard way, all transplants attempted with other than an identical twin donor - even if donor and recipient were closely related - involved HLA differences, and they failed because of immunological rejection. It seemed at first that transplantation might be limited to that small handful of cases in which an identical twin donor was available. Only a dozen or so such transplants had been carried out in the United States in the years immediately following 1954. It began to look as though transplantation would simply take its place on the shelf of medical and immunological oddities, of little use to society at large.

Few attempts at immunosuppression were made in those earliest days of transplantation. The only known way to suppress the immune system at the time was with radiation. High energy radiation from sources like radioactive isotopes or X-ray generators was known to inhibit immune function, and in fact several transplants were attempted in the late 1950s and early 1960s using whole-body X-irradiation to prevent rejection. The level of radiation that had to be used to see any effect, however, was simply too toxic, especially toward bone marrow, to be tolerated, and this approach was soon abandoned.

And then one of those completely unforeseen breakthroughs occurred that virtually revolutionized organ transplantation overnight. Like the discovery of histocompatibility, it too was tied to cancer research. The new field of cancer chemotherapy had begun in the early 1950s with a deliberate attempt to synthesize drugs that would interfere with known metabolic pathways crucial to cancer cells in the hope of selectively halting their growth without affecting normal cells. For example, cancer cells divide very rapidly, and thus they synthesize DNA on average much more frequently than do normal cells. In the early 1950s, chemists began to synthesize drugs that might interfere selectively with DNA synthesis in cancer cells. One such drug was 6-mercaptopurine (6-MP). Like AZT, the drug used to treat AIDS patients, 6-MP is an analog of one of the building blocks of DNA, and it too can deregulate the normal synthesis of DNA. The development of 6-MP was a result of the process of rational drug design discussed earlier in connection with AIDS.

It was hoped that cancer cells, because of their high rate of DNA synthesis, might prove to be especially sensitive to 6-MP. Although 6-MP did prove to be modestly successful in that regard, its most important biological effect would be found to lie elsewhere. In 1959 it was reported that, unexpectedly, 6-MP could also profoundly inhibit the ability of animals to clear foreign proteins that had been injected into their systems. It was rightly suspected that this was due to an impairment of antibody synthesis. This was the first documented instance of chemical suppression of the immune response. The possibility that human beings could reach inside the body and manipulate the immune response with drugs opened the door on an entirely new era in immunology.

Tremendous excitement surged through both the medical and scientific communities as the implications of these findings for organ transplantation became apparent. Within a year 6-MP was used successfully in an attempt to prevent rejection of kidneys transplanted between unrelated dogs. The results were so impressive that barely a year later 6-MP was brought to the clinic for its first use in human transplantation. Although the first patient treated with 6-MP, a twenty-two-year-old male with end-stage renal disease who received a kidney from an unrelated cadaveric donor, lived only twenty seven days, a medical record was set. Moreover, the patient died of a heart attack, not kidney failure, and his transplanted kidney showed no sign of immunological rejection at autopsy. Within a very short time, patients were surviving for several months, and then several years, as medical personnel became more skilled in administering 6-MP and managing its side effects.

These results, achieved in a remarkably short time, truly ushered in the modern era of organ transplantation. As we said earlier, organ transplantation was first made possible technically by the development of vascular surgery. But it was rescued from being a mere medical curiosity limited to identical twins by the advent of chemical immunosuppression.

Immediately after the introduction of 6-MP to the clinic, the number of centers venturing into this new area of medical razzle-dazzle blossomed overnight. Chemists were set to work to make derivatives of 6-MP that would be less toxic. One such derivative, azathioprine (also known as Imuran), became the standard of the transplant clinic for twenty years. Pharmaceutical companies everywhere began screening a wide range of drugs in animals to see if other acceptable immunosuppressants might be out there. Among the more effective were various corticosteroids that, when used in combination with Imuran, gave quite impressive results.

But this medical miracle would not be without its costs. The immunosuppression accompanying transplantation can have serious side effects, and in the early days of transplantation these were often severe. The drugs used are almost all deadly poisons, originally developed in many cases to kill tumor cells. They are introduced into the body with the aim of selectively suppressing cells of the immune system involved in graft rejection, but there is absolutely no way to limit their effects just to cells of the immune system. Thus one notable limitation to the use of these drugs is the serious damage, unrelated to immunosuppression, they may do to any of a number of organs or tissues in the body, including the transplant itself.

The second problem with these drugs, and perhaps the more profound one, is that although the intent may be just to suppress those immune cells involved in rejection of the transplanted organ, they in fact suppress the immune system as a whole. The result, not surprisingly, is a secondary or acquired immune deficiency condition not unlike that seen in AIDS. It is characterized by infections with a wide range of external and opportunistic pathogens, and by abnormally high rates of cancer. The opportunistic pathogens causing problems in transplant patients are basically the same as those seen in AIDS: the fungi C. albicans and P. carinii, and various viral infections. P. carinii pneumonia was for many years the most common cause of death in transplant recipients and is still a major problem. A disturbingly high proportion of patients died from infection with their transplanted organ looking robust and healthy at autopsy.

In the early years of transplantation the major cancers seen were cancers of white blood cells. As these were the cells targeted by the immunosuppressive drugs used, it was thought that the cancers seen might be a direct effect of the drugs on the white cells, rather than a result of immunosuppression per se. But as patients started to live longer with their transplants, a much wider range of cancers began to be seen, suggesting that the immune suppression needed to prevent transplant rejection was indeed allowing cancers normally controlled by the immune system to break free and cause disease. Ironically, one of the cancers now seen most commonly in long-term transplant survivors is Kaposi's sarcoma.

Thus by the late 1960s, transplantation across genetic differences was a reality, but reality with a stiff price. In the early 1970s, that price would go down dramatically. A team of scientists at Sandoz Laboratories, a Swiss pharmaceutical company, had been screening various soil funguses in search of drugs that could be used to treat fungal infections in humans. This is the process of "shotgunning" referred to earlier in connection with the search for new AIDS drugs. Drug companies are constantly scrutinizing nature's own pharmacy, looking for new medicines, in addition to using the kind of rational drug design that led to the development of 6-MP. The Sandoz scientists were working on the idea that one strain of fungus might produce a substance - an antibiotic - that it used to kill off other strains of fungus competing for the same environmental niche. They were not having much luck. A few compounds did seem to have some antifungal activity, but these did not look promising clinically because they were ineffective against those funguses that are serious pathogens for humans.

One of these compounds, which eventually came to be known as cyclosporin A (CsA), had been isolated from a fungus growing in the soil in southern Norway. It seemed interesting because it had very low toxicity; it could be used in animals at quite high concentrations without apparent side effects. One of the Sandoz team members, Jean Borel, decided to carry out a wider examination of the pharmacological properties of CsA in other situations of potential clinical interest. What Borel found surprised him, and put broad smiles on the faces of the directors of Sandoz that would last for years. Cyclosporin A turned out to be an incredibly potent immunosuppressant, equal to anything known at the time. But more importantly from a clinical point of view, it had a profound inhibitory effect on organ transplant rejection, with far fewer side effects and much less toxicity than the drugs currently in use.

When CsA was brought to clinical trial in 1983, the results were beyond Borel's wildest expectations. Prior to 1983, some fifty percent of kidneys transplanted from cadaver donors failed after one year. Almost immediately after the introduction of CsA, this number fell to fifteen percent! The impact on heart transplantation was equally remarkable: not only did the success rate nearly double, but the average hospitalization time fell from 70 to 40 days, greatly easing the financial burden on the overall health care system.

Unlike 6-MP and Imuran, which allow transplants to survive by suppressing essentially the entire immune system, CsA acts specifically to block the activation of T cells. If it is present during the period when a T cell is encountering a particular antigen for the first time, it will prevent that particular T cell from becoming activated and carrying out its immune function. But it does not affect in any way T cells that are not involved in the transplant rejection, leaving them alive and healthy to participate in other immune reactions.

While this exquisite specificity greatly decreases the complications from generalized immune suppression (the AIDS-like consequences), CsA is not without its own toxic side effects. Some are relatively minor, like nausea and the growth of excessive body hair. Of more concern clinically is the nephrotoxicity of CsA - its toxicity to kidneys. No one understands completely how this happens, but nephrotoxicity remains to this day a major limitation to the use of CsA.

The discovery of CsA, and its tremendous clinical (and commercial) success, sent drug companies all over the world scurrying to find similar compounds. Remarkably, about six or seven years later another one was found, and even more remarkably, again in a soil fungus - this time in a field right outside the back door of a pharmaceutical company in Japan. This new compound, called FK-506, was first brought to clinical trial in 1989. It turns out to be every bit as effective as CsA, and it is even less toxic to humans. It too works by selectively suppressing the activation of new T cells. And in just the past few years, yet another immunosuppressant, called rapamycin (again, discovered in a soil microbe), has been cleared for clinical trials. The exciting thing about rapamycin is that it seems to block T-cell activation in a manner completely different from CsA and FK-506, so it may be possible to use these various drugs in combination, at lower strengths for each, reducing the toxic side effects of each.

Thus basic research into immunosuppression has taken us in a few short years from a time when we could transplant only between identical twins, to a point where a wide range of worn-out organs critical to human survival can be transplanted almost at will. Current statistics for some of the more commonly transplanted organs are shown in the Table below:

____________________________________________

Organ Total number Longest living

of transplants recipient (U.S.)

worldwide (as

. of 1992). .

Kidney 295, 000 30 years

Bone Marrow 45,000 24 years

Liver 27,000 22 years

Heart 26,000 22 years

_____________________________________________

Virtually every U.S. city of more than a few hundred thousand residents now has at least one hospital where transplants can be performed. Not only has organ transplantation received the full backing of the medical establishment, it has - perhaps more importantly - received the approval of insurance companies and Medicare, both of whom are willing to pay for it. Yet this has in turn created a new dilemma. The number of critically ill patients whose lives could be saved by an organ transplant, and medicine's readiness, willingness, and ability to provide one, has now far outstripped the supply of donor organs. This was a possibility not readily appreciated in the heady early days of transplantation, following the introduction of chemical immunosuppression. But it is now the single most important remaining barrier to expansion of organ transplantation worldwide.

The magnitude of this problem can be appreciated by taking a closer look at kidney transplantation. In the United States alone, there are over 150,000 people with end-stage renal disease; about 30,000 of these are currently on the waiting list for a donor kidney. Another 12,000 or so are added to the waiting list each year. These patients have no kidney function, and cannot clear the poisons produced by their own bodies. They suffer from the same maladies Richard Herrick suffered from, and they will die if untreated. While they wait for a suitable kidney to become available, they are kept alive by kidney dialysis. Although greatly refined since the days when John Merrill introduced it at the Brigham Hospital, dialysis still involves being connected to a machine for at least three half-days each week. The physical and psychological demands placed on such patients are enormous. Their treatments are frequently accompanied by nausea and cramps; patients often develop a negative attitude toward their bodies; there may be transient or even permanent loss of sexual function. Clinical depression and even suicides are common. The vast majority of these individuals do not have a suitable first degree relative as a potential donor, and thus must wait for a reasonably well HLA-matched cadaveric organ.

Just under ten thousand kidney transplants are performed each year in the United States, from both living related and cadaveric unrelated donors. This number, which has remained relatively constant for the past several years, is limited entirely by the availability of donor organs. As a result, more than twenty-five hundred patients, meeting all the criteria for suitability as a kidney transplant recipient, die from their disease each year while on the waiting list of approved recipients. The average waiting time on this list is now close to one year. Given the tremendous backlog of people kept alive by dialysis, and the stalled rate of kidney transplantation, both the waiting list and the number of candidates on the list who die awaiting a transplant are expected to grow rapidly in the coming years.

For organs other than kidney, the outlook is even more bleak, because the possibility of a living donor does not exist. Moreover, there is no equivalent of kidney dialysis for, say, patients with end-stage heart disease. As a result, although the number of people who need heart transplants is about the same as the number who need a kidney, the waiting list is much shorter for hearts, because people die much sooner after getting on the list. Yet the success rate for heart transplants, when they can be done, is about as good as that for cadaveric kidney transplants. The bottom line is that now, at a time when organ transplantation is more successful than it has ever been before, the number of patients dying for lack of a donor organ is larger than it has ever been, and growing each year.

The solution to this dilemma is clear: increase the supply of donor organs. Few would disagree with that. The question is how to go about increasing the supply. And that question is at the heart of one of the most important debates in medical ethics in the latter half of the twentieth century.

That debate is still in full force today. Any professional meeting of transplant specialists involving more than a few hundred participants invariably has one or more full sessions dedicated to the ethics of transplantation. Initially, the discussions tended to focus on whether the procedure itself was appropriate. As can be imagined, in the early years of transplantation success rates varied wildly. Both the surgeons and the various postoperative management specialists were engaged in essentially a "learn-as-you-go" enterprise. Many patients suffered considerably, some with little or no benefit. To a person, of course, these were all patients desperately ill - in fact, terminally ill - because of a diseased organ, and so in that sense they had little to lose. But this very element of desperation on the part of the potential recipient itself became a prominent topic in these debates. Can a patient in this situation, or his or her immediate family, rationally analyze the pros and cons of such a new and complex procedure? Medical specialists dedicated to making transplantation succeed in those early days clearly had an agenda of their own, and to pursue their aims they needed patients who required transplants. Were these specialists able to give dispassionate and disinterested advice to potential recipients?

Few would argue any longer that organ transplantation per se crosses any ethical boundaries. Its benefits, balanced against an almost certain fatal outcome in its absence, are simply too compelling. The discussion now centers around what society can or should do to increase the supply of donor organs. For kidney and bone marrow, the donor may be either living, or very recently deceased. For all other human organs, recently deceased donors (cadavers) are the only source. Concerning cadaveric donation, some seventy percent of Americans, when queried, indicate that they are in favor of voluntary donation of organs for transplantation. But fewer than twenty percent actually make arrangements before death to do so. How can this gap be closed?

Living donors. In the case of kidneys, living donors in most Western countries are almost always first-degree blood relatives of the recipient, and these account for roughly twenty percent of all transplants. By more or less common consent, first-degree relatives are considered to have a sufficient personal interest in the survival of the recipient that the slight (but real) risk involved in donating a kidney is acceptable. On the other hand, most transplant centers in the U.S. will not even consider an unrelated living kidney donor (with the exception of spouses) under all but the most special circumstances. In particular, the notion that a living, healthy person could be paid to donate a kidney needed for transplantation has generally been anathema in the United States and most Western European countries. Various regional and international transplantation societies founded in the West, and led largely by American and European scientists and doctors, have repeatedly passed resolutions to the effect that the human body and its component parts cannot be the objects of commercial transactions. Participation in such transactions may be grounds for expulsion from these societies, which also urge governments to make such commerce illegal.

In many developing countries, however, the question of living unrelated donors is approached differently. In India, for example, there are very few kidney dialysis machines, which are expensive to purchase and operate, and there is no organized program for the recovery and distribution of kidneys from cadavers. Yet there are quite a few surgical centers with the requisite trained personnel to perform kidney transplants. Thus the only hope for most patients with end-stage renal disease in India is a transplant. At present, however, the government health system does not pay for organ transplants, and most people do not have private insurance that covers catastrophic illness. Hence transplants are available only to individuals wealthy enough to have appropriate insurance or to pay for the procedure themselves. In the absence of an organized system for retrieving cadaveric organs, those without an appropriate first-degree relative who can afford it usually resort to the practice of paying an unrelated living donor to part with a kidney. Inasmuch as the price paid may represent several years' wages to many Indians, there is no shortage of donors. Several thousand such transplants are carried out each year.

Despite expressions of deep concern and even outrage from the industrialized nations of the West, many countries in the same circumstances as India have developed and refined the concept of "rewarded gifting" to get around the injunction against paying living unrelated donors for organs. Most international medical societies that condemn the buying and selling of organs have recognized that living donors are likely to undergo a great deal of personal loss - aside from the organ or tissue donated - in connection with the donation procedure. There may be up to two weeks of costly hospitalization, for example, as well as follow-up treatment and loss of income. Transplant societies generally agree that donors can be compensated for such losses as long as the cost of the organ or tissue itself is not part of any resulting financial transaction. A number of countries have found that by making the terms of such "collateral compensation" sufficiently generous, a monetary value does not have to be put on the organ itself, and the exchange technically does not violate any existing guidelines.

But in fact some developing countries such as India, Iraq, and Egypt have actually gone on the offensive and are working within regional and international transplantation societies to have some form of rewarded gifting officially sanctioned. Some of their points are rather convincing. Listen to Dr. K. C. Reddy, a transplant specialist from Madras, India:

While statements such as this once provoked a great deal of anger among many Western specialists, in fact the richest one-sixth of the world is coming to realize that the other five-sixths may have a very different point of view about organ transplantation, based not only on economic differences, but also on different philosophical and ethical systems. In countries as disparate as Iran and Japan, for example, there is nonetheless a similar cultural attitude of reverence toward the body of the deceased that makes retrieval of organs from cadavers difficult in the extreme. In Japan, a very wealthy nation, only a very few transplanted kidneys come from cadavers. Patients with end-stage renal disease who do not have a suitable living donor are kept on dialysis essentially until they die. As a result many transplant professionals are beginning to accept the possibility that with suitable government control to prevent abuse, it may be appropriate for some countries to approach organ donation by living donors differently from what is done in the West.

Unquestionably, if money is involved, the flow of organs will always be from poor individuals to wealthy ones. We in the West find this repugnant. Why? The necessity of asking ourselves such a question was highlighted dramatically by a case several years ago in which a poor Turkish workingman was flown to England and paid $3,300 to donate one of his kidneys. He used the money to pay for an operation needed by his two-year-old daughter, without which she would likely have died. What would the overwhelming majority of us in the West, who would ban organ sales outright, tell this father? That it's okay to donate a kidney to his daughter to save her life, but he cannot sell the same kidney to someone else for the same purpose? By doing what he did he saved two lives - his daughter's and that of the recipient of his kidney, who happened to be wealthier than he was. By forbidding his action, and allowing two people to die, would our moral indignation be assuaged?

J. Radcliffe Richards, in a brilliant essay on this topic that touched on the dilemma posed by the case of the Turkish father, had this to say about moral indignation:

While there may be some willingness to accommodate countries that sponsor and properly supervise paid organ donation from living donors within their own borders, there is still universal repugnance concerning the rapidly increasing and largely unregulated international trade in such organs, which is handled by private brokers on a strictly for-profit basis. According to a recent report of the International Commission of Health Professionals, more than one thousand kidneys from living donors were sold from India in 1988 to various wealthy individuals around the world, mostly in the oil-rich countries of the Middle East, but also in the U.S. and Europe. Such transactions are not overseen by any official health agency, and they raise a great many concerns. Given that the donor was almost certainly poor and undernourished, what was the state of his or her health at the time of donation? Could the donor really have stood the rigors of surgery in such a condition? How well are such individuals followed after donation to ensure an event-free recovery? Could consent in such a situation be truly informed? Was the donor screened thoroughly for infectious diseases? The latter has proved to be a major problem in situations where the purveyors of organs recognize no obligation to be involved beyond the procurement itself. In a recent study of wealthy individuals in Oman and the United Arab Emirates who purchased kidneys from India in the mid-1980s, a high proportion were found to have contracted a variety of diseases, including AIDS, through their transplants.

Cadaver donors. After all the emotion-charged arguments and dramatic anecdotes surrounding the buying and selling of body parts from living donors, discussions of ways to increase the yield of organs from cadaveric donors could be expected to be pretty tame. But in fact the debate on this subject, particularly in the U.S. and Europe, where living related donors are not even part of the discussion, is every bit as intense as that over live donors. Before we get into the various arguments about ways to increase recovery of cadaveric organs for transplantation, let's look at the sources of such organs.

There are two categories of cadaveric donors in the United States. Many people arrange while they are still alive to make their organs available for transplantation as needed when they die. They do this simply by signing and carrying a Uniform Anatomical Gift Act card, usually pasted to the back of a driver's license. In such cases, no further consent is needed. The family of the deceased may object strongly to the donation, and physicians and medical centers may respect the family's wishes, but they are not obliged to.

The second category of cadaveric donor includes those who did not make their position on organ donation known while they were alive. In such cases family members of the deceased must give their consent before organs can be removed for transplantation. That is the law of the land in the U.S., and it is called required consent. In some European countries, on the other hand, a deceased person is presumed to have agreed to make his or her organs available for purposes of transplantation after death unless he or she specifically indicated opposition to donation prior to death. This is called presumed consent, or sometimes "opting out." However, in practice if relatives of the deceased express opposition to removal of organs from their loved one, this wish is almost always honored.

The controversy over the use of cadaveric donor organs is thus taking place largely in the United States, and in those European countries where required consent governs organ recovery from cadavers. The debate is not about buying and selling organs per se, but rather about how to increase the recovery of transplantable organs after death. Within the context of required consent, this means increasing the number of people who express a willingness while they are alive to make their organs available for transplantation after death. The traditional approach has been to encourage voluntary donations through public education programs. This worked well in the early years of transplantation, but the percentage of the public who carry Uniform Anatomical Gift Act cards has stabilized at about 15 to 20 percent for at least the past decade. How do we get this number closer to the 70 percent or so who say they generally favor organ donation after death but never seem to do anything about it?

One school of thought (for ease of reference we will call them the altruists) maintains that better and more effective public education is the only permissible approach to increasing recovery of cadaveric organs. Let's listen to Dr. Renee Fox, a bioethicist at the University of Pennsylvania:

There is, from this point of view, something very special about the transfer of an organ from one human being to another, even if the donor is deceased. Above all there is an element of altruism in this act, which ennobles both the donor and the act itself, and the altruists insist that this aspect of donation must be preserved. In fact, studies have shown that in the case of living donors, the donor almost invariably does feel very positive about the act of donation, and often experiences an increased sense of self-worth that is long- lasting, even if the transplant fails. Family members who give consent for transplantation of the organs of a recently deceased loved one have similar experiences, often feeling that they have somehow extended the positive impact of the deceased on the world he or she lived in.

While not arguing that transplantation should not be performed, the altruists often do contend that the eagerness to transplant may create pressures to supply organs that could lead society onto treacherous ethical ground. There is a sense in these arguments that perhaps we need to rethink the desire simply to use, without question, whatever technologies science can create to prolong human life. At bottom, these proponents would favor an attempt to educate and encourage the public to participate in voluntary, altruistic organ donation, but no more.

This argument seems to strike a chord in most Americans and Western Europeans, probably the same chord that makes us want instinctively to prohibit persons from selling their own organs. But as with the latter question, there is also another viewpoint emerging and demanding to be heard concerning cadaveric organ procurement. It is based on the inherent value of the life of the potential transplant recipient. Confronted with the death of any human being who could be saved by an organ transplant, proponents of this viewpoint (whom we will call the pragmatists) find that "...poetic statements about the dignity of human life being degraded by commercialism [are] revealed as the empty moral pieties of armchair philosophers incapable of a reasonable balancing of human needs." Strong words, indeed. But these individuals find the ultimate moral repugnance to be the burial or burning of perfectly healthy organs that, if transplanted, could extend another human being's life for ten, twenty, or even thirty years. They greatly resent the implication on the part of healthy, comfortable "armchair philosophers" that someone in the throes of terminal organ failure should simply let go rather than scratch and claw for a chance at a transplant. Let the philosopher speak when he or his child is lying at death's door, they say; then we will listen.

At present only about twenty-five hundred or so cadavers per year are "harvested" for transplantable organs in the United States, less than 20 percent of the number of suitable cadavers potentially available. While not at all against intensifying efforts to encourage altruistic donation, the pragmatists urge going a step further. They suggest that the reason the number of people who indicate a willingness to donate organs after death does not increase is quite simple: There is no incentive for it to increase. Altruism is apparently a sufficient motivating factor for about one in six of us to donate our organs. Another fifty percent or so seem willing to do it in principle, but never seem to get around to filling out a donor card. Any market analyst would immediately suggest that the appropriate corrective would be to provide incentives - modest at first, gradually increasing until the desired level of donation is achieved. Various incentive plans have been proposed, and are currently being discussed. For purposes of future reference, we can refer to proponents of this approach as "marketeers."

Nearly everyone favoring this approach agrees that some responsible, not-for-profit intermediary must act as an "honest broker" in any market system for the procurement of cadaveric organs if the system is to gain everyone's trust. This could be the federal government, or one of the numerous professional transplantation societies or agencies already in existence. The basic idea would be to establish a price for various major or minor organs that could be harvested upon death from a suitable donor. In the most optimistic form of this idea, the so-called "futures market" approach, individuals would be attracted by these incentives to indicate before death their willingness to participate. They could designate the recipient of the financial consideration involved, or specify that it be applied to inheritance taxes, or to pay for funeral or burial costs.

Beyond a doubt, this argument also strikes a deep chord in a number of Americans, and among many Europeans. We use free-market principles to solve problems in virtually every segment of our culture; why should organ donation be any different? We pay people to donate blood or sperm while they are alive; what is wrong with paying their estates for donation of their organs after death? The majority of people who now arrange ahead of time to donate organs at death are financially comfortable and well educated. It is thus unlikely that such a system, if extended, would take unfair advantage of the poor and illiterate. Through an "honest broker" system for distribution, the possibility that the rich would be the primary recipients of the increased influx of organs would be avoided.

Do the altruists buy these arguments? Not for a minute! Again, Dr. Renee Fox:

There are also serious concerns that any gains made in a market system for organ procurement would be offset by a decrease in altruistic donations. Some people may not want to participate in a scheme so distasteful as the buying and selling of organs. Others may ask why they should give away something that can be sold, and then never get around to selling it, which is bound to be much more complicated than filling out a donor card on the back of their driver's license.

And are the marketeers convinced? Larry Cohen, an economist and foremost proponent of the "futures market" concept for increasing cadaveric organ donations, has this to say:

Who would have thought that reaching inside the body and tinkering with the immune system could have created such a storm of human emotion? It is impossible at present to see how these two points of view, so fundamentally different, can ever be reconciled. They represent a basic dichotomy in the human personality that is seen in many, many segments of our culture. The contradiction, as someone pointed out, is not just between altruists and market theorists; it also lies partly in the conflict between our scientific and our cultural conception of our bodies. There is a vague feeling that we cross some invisible yet real line when we mutilate human bodies even for the noblest of reasons, let alone profit. And yet, as the marketeers say, in the midst of the antiphony and cacophony, people whose lives could be saved by an organ transplant are dying, and dying in ever-increasing numbers each year.

It's not easy being human.

While the debate over how to increase the supply of human organs for transplantation continues to roll in and out of bounds, physicians and scientists are busy exploring other means of replacing worn-out body parts. Particularly in cases where the use of living related donors is not possible (almost all transplants except bone marrow and kidney), human organs may never be able to satisfy the need even if everyone signed a universal donor card. There may never be enough healthy, transplantable hearts, for example: too many are defective when a potential donor dies. Lungs are tricky to transplant unless the donor and recipient have chest cavities that are reasonably close in size. Pancreases are notoriously difficult to keep from decomposing in the time it takes to remove them from donors and implant them in recipients. In the sections that follow we will examine some of the alternatives being explored to deal with the inadequate supply of human organs for potentially life-saving organ transplants.

Xenotransplantation. Almost as soon as immunosuppressive drugs made the transplantation of organs between unrelated humans possible, some of the early leaders in this new field began to explore an approach called xenotransplantation, the exchange of organs between different species. Perhaps anticipating an eventual shortage of human organs for transplantation, several transplant teams in the early 1960s explored the use of chimpanzee and baboon hearts and kidneys for transplant into humans. They were playing on the hunch that, because these species are so close evolutionarily to humans, there might be a chance for successful transplantation with proper immunosuppression. Moreover, the planned use of a specific animal as a donor would allow thorough advance tissue typing and harvest of the organ at exactly the right moment for the recipient. These were reasonable assumptions, but early trials were extremely discouraging. Immunological rejection seemed more vigorous than with even the most poorly matched human organs, although one patient transplanted with a baboon kidney did manage to survive ten months. After a few early trials this approach was largely abandoned; fewer than a dozen xenotransplants were performed in the United States through the early 1990s. However, the advent of more potent and specific immunosuppressants such as CsA and FK-506, and the rapidly escalating crisis in the supply of transplantable human organ, has since led to a reexamination of the possibilities of xenotransplantation.

One case that riveted the attention of scientists, doctors and the public on xenotransplantation was that of "Baby Fae", a female infant born three weeks prematurely with a condition known as hypoplastic left heart syndrome.This is a uniformly fatal congenital abnormality in which the left side of the heart is almost completely missing. It affects about one newborn in 12,000, and most of these infants die within a few weeks of birth. Surgery to correct the underlying heart defect is not well developed. Prior to Baby Fae there had been only one organ transplant involving such an infant, using a human infant heart that became available shortly after the unexpected death of a healthy infant. The transplanted infant lived three weeks.

The decision that resulted in Baby Fae becoming the first human infant ever to be transplanted with an animal heart was not taken lightly. Her condition was diagnosed within 48 hours of birth by an alert and competent team of neonatal specialists at the hospital of her birth. Both the situation and its inevitable outcome were described clearly and compassionately to the child's parents, who elected to take her home to wait for her to die. On Baby Fae's sixth day of life the hospital contacted the parents - would they consider the possibility of a somewhat radical surgical approach to dealing with their daughter's problem? A medical team at this same hospital had been planning for some time to try xenotransplantation in exactly such a case, and institutional approval had been granted just one week earlier for these trials to begin. After a thorough discussion of all the pros and cons of this approach, the parents approved. The surgeon in charge of the procedure flew back immediately from vacation. Baby Fae was readmitted to the hospital and placed on mechanical life-support while the necessary surgical and follow-up teams were assembled.

The donor was a seven and one-half month old female baboon. Baboon hearts are remarkably similar to human hearts, and a baboon of the age selected has a heart similar in size to a newborn human being. The transplant took place in a five-hour operation on October 26, 1984, when Baby Fae was twelve days old. This is brutal surgery, but, amazingly, infants are able to absorb far more of this kind of punishment, pound for pound, than adults. Baby Fae came through just fine and was able to feed normally within a few days. As soon as it was clear that she would survive the surgery, and not immediately reject her heart, the hospital notified their regional organ procurement agency to begin searching for a human donor organ. As part of their initial experimental protocol, they viewed implantation of the baboon heart largely as a holding action, what has come to be called a "bridge to transplantation", while waiting for an appropriate human organ.

But Baby Fae would not live to see that fortunate event take place. By the end of the second post-transplant week, her doctors began to detect signs that her heart was weakening. The following week her kidneys began to fail, and finally her heart stopped. After a futile attempt to massage her heart back into life, she died during the evening of November 15, 1984, twenty days after her transplant. At autopsy, Baby Fae’s heart showed signs of heavy immune attack, with complications spreading to her lungs and kidneys.

What went wrong? It was clear that immunological rejection had severely damaged the infant’s heart. But she had been maintained on levels of CsA that should have prevented T cells from being activated. Like the other higher primates (apes, chimpanzees, orangutans), baboons have histocompatibility antigens virtually indistinguishable from human HLA antigens. The principal mode of immune attack thus should have been by T cells, principally CTLs, with which CsA specifically interferes. In fact, microscopic examination of Baby Fae's heart tissues showed little evidence of T cell attack. The culprit turned out to be antibodies. Through a bizarre oversight, her surgeons had failed to type both donor and recipient for ordinary blood antigens. Again like humans, the higher primates have standard ABO blood types. Baby Fae was type O, making her a universal donor but unable to accept other blood types. The baboon, as it turned out, was type AB - a universal recipient whose blood would be rejected by just about anyone else. There could not have been a worse combination. Enough blood cell antigens were carried over with the baboon heart to trigger an antibody-mediated rejection reaction by Baby Fae. The Cyclosporin A was of no help in this case, because the antibodies needed to reject an AB blood type (baboon or human) were already there. Baby Fae never had a chance; experts wondered afterward how she managed to live as long as she did.

The twenty days of life she experienced with the baboon heart were not much more than the time she might have been expected to live without a transplant. On the other hand, they were days of much better quality than would otherwise be expected. Instead of fighting for every heartbeat and every breath, she was, for a couple of weeks at least, pretty much like any other baby - crying, feeding, and very alert. And she was the longest living human being with an animal heart transplant. The previous record was three-and-a half days for an adult male human transplanted with a chimpanzee heart in 1977. Although more transplants of this type had been approved by the hospital that treated Baby Fae, the trauma associated with this failure led to their immediate discontinuance.

Recently, a more fortunate outcome has been obtained in the first xenotransplantation to take place since Baby Fae - that of a baboon liver to an adult human patient. It may well be the harbinger of a revolution in organ transplantation. The transplant was performed by Dr. Thomas Starzl, one of the first surgeons to carry out a xenotransplant in the 1960s. He never truly lost interest in it. Over the past two decades Dr. Starzl has established the world's foremost liver transplant center in Pittsburgh, which heretofore had relied exclusively on human cadaver donor organs. As with patients needing heart transplants, a large percentage of people waiting for livers die before one can be found. The recipient in this case was a thirty-five-year-old male whose liver was in an advanced state of failure because of hepatitis B infection. The donor was a fifteen-year-old male baboon who had the same blood type as the recipient. The use of a baboon liver seemed particularly appropriate because baboon livers are not capable of being infected by the hepatitis B virus. Previous attempts to save patients like this man with transplantation of a human cadaveric liver had failed, because residual virus in the body would always infect the new donor liver and ultimately destroy it. Thus a major category of patients who could benefit from liver transplantation had been excluded in the past.

The transplant was performed in June 1992, and the recipient lived for seventy days with excellent liver function. He had been in a coma due to liver failure just before the transplant, but was awake and alert within hours after the operation. Five days later he was up and walking. The baboon liver was able to process and store food (one of its major functions) and to make critical blood products like clotting factors. At the time of his death, the patient had high levels of baboon proteins in his blood, and as far as could be determined they were all functioning as well as their human counterparts. Moreover, although the baboon liver was only about a third the size of the patient's own liver at the time of transplantation, by the time the patient died it had grown to nearly normal size for a human.

One of the most promising aspects of this otherwise tragic outcome is that at the time of death the patient showed little or no sign of immunological rejection of his liver. He had been maintained on FK-506 in combination with other immunosuppressants throughout the postoperative period, and this regimen clearly worked. The cause of death was a brain hemorrhage triggered by a fungal infection. The infection was facilitated by a surgical complication that is now understood, and should be avoidable in the future. The patient may also have been maintained on a higher level of immunosuppression than was necessary, which could have contributed to his problems. Although it was a bit premature to draw definitive conclusions, it did not look as though there was any evidence of hepatitis B virus in the baboon liver.

Finally, this case was also rare in that the patient was HIV-positive, although not yet showing signs of AIDS per se. Liver transplantation is major surgery, lasting many hours and with many instruments involved. The risk to the surgical team was considerable. The Pittsburgh team had transplanted a few HIV-positive patients previously, although with normal cadaveric human organs. The possibility of successful transplantation of baboon tissues into human beings raises an extremely interesting possibility for people who are HIV-infected. Just as the hepatitis B virus does not infect baboon liver cells, so too the AIDS virus does not infect baboon T cells. What would happen if an HIV-infected individual were to receive a transplant of baboon bone marrow? Would the T cells that derived from the bone marrow be resistant to HIV infection? Could the baboon T cells, B cells and macrophages work together to provide immune protection for a human being? Rest assured this is a possibility that will be studied very closely, indeed.

Before leaving this story, we should note that a second transplant of a baboon liver, into a 62 year-old man whose own liver had also been destroyed by the hepatitis B virus, was carried out by the Pittsburgh team in January of 1993. The technical adjustments suggested by the first transplant were applied to this second procedure. For reasons that are not clear, the patient never regained consciousness after surgery. He lived in a coma for a total of twenty-five days. As with the first transplant, the baboon liver had increased in size until it just filled the space left by the patient's own liver, which had been removed, and it showed no signs of immunological rejection. More transplants are currently planned; whether this latest problem will lead to a delay or cancellation of these procedures is uncertain at present.

Modern moral dilemmas, Part II. Whatever clinical problems xenotransplantation may help resolve, it is not going to provide us with an end run around discussions of medical ethics related to transplantation. The participants in these discussions may be different, but the discussions themselves will certainly be no less acrimonious. During the years when no one was doing xenotransplants, all was quiet. The Baby Fae incident almost brought the ethicists up out of their chairs, and it almost stirred the medical community to man the ramparts. But after Baby Fae it seemed that xenotransplantation would go on the back burner again, and no action would be needed. Besides, even the most committed animal rights groups were probably reluctant to argue against saving the life of a human newborn. Part of the strategy for any battle is knowing how to select your targets.

But the years between Baby Fae and the Pittsburgh liver transplant were crammed with experiments carried out in many laboratories and medical centers, published openly in the scientific literature, and clearly aimed at exploring to the fullest the eventual use of animal organs in human transplantation. The relative success of the Pittsburgh experiments will certainly drive this program forward, and we can expect to see more xenotransplants in the near future. We can also expect the debate about the moral propriety of these experiments to go up several decibels.

The key buzzword in the new debate is "speciesism" - an awkward word at best, but one the public may as well get used to. If xenotransplantation goes forward, we will hear a great deal more about it. The concept it defines is the following: Does one species - Homo sapiens - have the moral right to systematically exploit other species for its own gain? Can the lives of the members of one species be claimed to have an inherently greater moral worth than the lives of other species? The context in which this concept has developed has been stated eloquently by Peter Singer, a bioethicist from Melbourne, Australia:

What does the other side of the debate have to say about all this? In a phrase, "Stuff and nonsense!" For the past ten thousand years at least, they argue, human beings have systematically reared animals for the sole purpose of slaughtering them and eating them. By that act alone, we have already answered the question of whether a human life has greater moral significance than an animal life. How is the proposed use of animal organs for transplantation to save human lives more repugnant morally than using them for food? True, some cultures and a few individuals have opted out of eating animals, but it is clear that human beings evolved as meat-eaters. The acquired cultural preferences of the few cannot be allowed to suppress the will of the majority.

But a major ethical complication does in fact arise when we contemplate the use of higher primates as involuntary donors in xenotransplantation. ("Higher primates" includes animals such as gorillas, chimpanzees, orangutans, and baboons. Of these, only chimpanzees and baboons have been seriously considered for xenotransplantation.) Numerous studies have shown quite convincingly that these animals are uncomfortably close to humans in more ways than just blood types and HLA antigens. In fact, it is widely accepted that many of these animals in their native state have intellectual and cultural traits as adults that equal or exceed human beings in certain states - any human in the first three months of life, for example, or infants born with severe brain defects. No one would propose using a healthy newborn as a forced organ donor, because that infant is an individual with unlimited potential for development into a sentient human being. But what about an infant born without a brain? Even though human, this is a higher primate with less mental capacity than any animal primate, and with zero hope for future intellectual or cutural development. If we would not consider ending the life of such an infant for purposes of harvesting its organs for transplantation, can we in good conscience kill a baboon or a chimpanzee for its organs?

This is not entirely a rhetorical question. About one thousand infants are born each year in the United States with a condition known as anencephaly, in which most of the brain is missing. Various portions of the head and skull may or may not be present. In cases where a portion of the brain stem is present, allowing the infant to breathe, it may live for a week or two, but such infants always die. They never experience pain, thought, or feeling of any kind. To the extent they have eyes, ears, a nose, or a mouth, they are not connected to anything neurologically. Anencephalics have no knowledge that they are in the world, or even that they are alive.

In a well-known and intensely studied case that occurred in 1992, a Florida couple was told in advance by their doctor that the child they were expecting was almost certainly anencephalic. They decided to carry the pregnancy through to completion anyway, with the plan of offering their child's organs for transplantation into infants like Baby Fae. When it was clear after birth that their infant was extensively anencephalic, they asked the Florida courts to declare the infant brain dead, the current legal standard by which organs may be harvested before removing all life-support systems. The court demurred, arguing that brain- stem function is part of the definition of brain life. The parents pressed their case through several additional levels of the legal system, arguing that waiting for brain-stem function to cease would result in deterioration of the infant’s other organs. But the lower court ruling was upheld. Thei couple’s daughter died a week later of lung failure; her other vital organs were unusable for transplantation.

We are faced with a complicated question, indeed. We have declared ourselves unwilling to take the organs from an anencephalic infant to save other human lives; can we then take organs from higher primates? We do not rear higher primates as a food source. If we were to rear them for xenotransplantation, we would be doing so for the express purpose of killing them and removing their organs for transplantation to save a human life. We may well decide to do that, but the ethicists have made a point. If we are not willing to end the life of a human being with no mental capacity at all to get organs for transplantation, what is the moral basis on which we believe we have a right to kill a partially sentient higher primate for the same purpose?

The debate over the sale of human organs, and various means to increase recovery of cadaveric organs, has been a bitter one. But it has remained largely cerebral, confined to trading shots through published scientific papers, enlivened by the occasional personal exchange at professional meetings. If the past ten years are any guide, the debate over the use of animals to provide organs for human transplantation will be much more visceral, even physical. More than one university, including my own, has been the target for disruption, vandalism, and personal threats against scientific and medical staff. Clearly, if we are going to go forward with xenotransplantation, we will need the public's support. A case for doing it needs to be made, not assumed, and the public needs to be informed at each step, both about its successes and its failures. We need to answer questions posed by ethicists fully and openly. It is the failure to be completely open and honest about the limitations of animal experimentation, and the ethics of it, that lends its opponents the most effective ammunition.

Bioethicists are not completely united in their opposition to the use of higher primates for xenotransplantation, although most ethicists (and, frankly, many physicians and scientists) are uncomfortable about it. If we could use organs from animals that are already used for food, most serious opposition would drop away rather quickly. The animal most suitable for organ transplantation into humans, after the primates, is the pig. Fully grown pigs are roughly the size of human beings, and their organs are thus capable of supporting the load imposed by human metabolic functions. Hundreds of thousands of pigs raised solely for food are slaughtered annually in the United States, and the vast majority of their major organs end up in sausage or pet food. A few transplants of pig tissues have been tried in humans, but rejection has been immediate and violent - a phenomenon termed hyperacute rejection. Hyperacute rejection is caused largely by something called complement. Complement is used by antibodies to help them destroy invading microbial cells that can cause disease. Most healthy adult humans have antibodies in their bloodstreams that will also attach to the cells of an incoming animal transplant. These antibodies then bind and activate complement, leading to rapid destruction of the targeted tissue.

Complement can be a dangerous substance. In patients with autoimmune disease, for example, or chronic infections that generate antigen-antibody complexes, complement can cause serious problems such as vasculitis (blood-vessel inflammation) or glomerulonephritis (kidney inflammation. These conditions result from physical destruction of cells by complement. Because all of us have a lot of complement running around in our bodies all the time, and because a lot of it gets activated in the ordinary course of fighting bacterial and other infections, our cells are equipped with a variety of devices to protect them against complement damage. An example is a molecule called DAF (decay accelerating factor), which promotes the rapid breakdown or decay of any complement molecules that accidentally settle onto normal healthy cells, thus preventing damage. (Complement damage in situations like vasculitis occurs because protective molecules like DAF simply get swamped out by excessive amounts of complement. But under normal conditions, DAF and other protective molecules work just fine.)

Because complement-mediated hyperacute rejection is a principal barrier to transplantation of pig organs into human beings, molecular biologists decided to "build" a pig that was equipped with human DAF. If the heart of such a pig were transplanted into a human being, it would be protected from human complement in the same way normal, healthy human cells are. The technique for making such an animal is one that molecular biologists have used for the past decade to build transgenic mice, which have become a routine tool for laboratory research. A fertilized ovum is removed from a recently mated female, and the desired gene is microinjected into it. The altered egg is then implanted into a pregnant female's reproductive tract, and in a reasonable number of cases an offspring is born that expresses the transgene. The first pigs bearing a human DAF transgene were born in England in early 1993. A number of studies will need to be carried out before the animals are ready to use clinically, and of course they need to be bred into larger numbers if they are to provide a stock for future xenotransplantation. We probably will not see the first transplants of their organs until at least the late 1990s. But if everything goes as planned, the pigs would then be used for the same food purposes for which we currently use pigs, and their organs will be available for transplantation.

Artificial organs. Another option that has been explored for the past several decades is the production of completely mechanical replacement parts for defunct human organs, in a sort of "bionic man" scenario. Serious efforts to design and make such organs started in the 1960s, when the National Institutes of Health, foreseeing a time when human organs might not be able to meet the need for transplantation, began supporting university and private industry research into artificial organ systems. Work on an artificial kidney had begun during World War II, and was by the 1960s fairly advanced. It was already clear by 1970 that an implantable kidney, or even a relatively portable artificial kidney, was not likely to be developed. Biomedical engineers have never figured out a way to reproduce the efficiency of the human kidney on the scale that nature has designed it. Today, of course, kidney transplantation is so successful, especially with living related donors, that work on miniaturization of dialysis machines has virtually stopped.

But an implantable mechanical heart is another story. There are currently almost three thousand patients on the waiting list for a heart transplant. Although some two thousand cadaveric hearts are transplanted annually in the United States, with an average waiting time of about four months, approximately a quarter of the people on the waiting list die before receiving a transplant. University, government, and private research teams have worked for the past several decades to overcome the problems associated with creating a mechanical device that could replace the human heart. It is a daunting task. Doctors, scientists, hydraulics experts, naval control systems engineers, oil field drillers and materials experts have collaborated on electric, nuclear, and air-driven models of this four-chambered marvel. After untold person-hours of effort, and hundreds of millions of dollars of research investment, we are still probably a decade away from the goal of a totally implantable mechanical heart.

That does not mean that progress has not been made. There are very impressive heart assistance machines designed to take the load off a failing heart and allow it time to recuperate. These are most often so-called "extra-corporeal" bedside machines to which a patient is connected by tubes. The pump itself is outside the body. These devices were developed by Dr. Denton Cooley, and were used as early as 1969. Depending on the underlying problem, a period of time on such a cardiac assistance device may be sufficient to allow the heart to regain a significant portion of its normal function. If not, and if other factors permit, the patient is removed from the assistance device and placed on the waiting list for a heart transplant. Often a patient may be hooked up to such a machine for a short period after transplantation, to allow the new heart time to settle in before it assumes the full burden of supporting blood circulation in its new home.

Perhaps the best known artificial heart recipient was Barney Clark, a 61-year-old dentist from Washington State. Dr. Clark had been suffering for several years from chronic end-stage heart disease and the associated emphysema. As 1982 drew to a close, his cardiologist told him candidly that he had very little time left to live. He had already been referred to a Seattle hospital for a human heart transplant. Seattle has for many years been in the forefront of American cities developing organ transplant programs; some of the very best surgeons and immunologists in the field practice there. But Barney Clark was turned down because of his age - he was over fifty. Experience at that time had shown that older patients with advanced heart disease simply did not do well with a transplant. The precious few donor organs available were targeted to recipients more likely to receive long term benefit from transplantation.

However, Dr. Clark had also been in touch with the artificial heart team at the University of Utah headed by Dr. William DeVries. The medical center at the University of Utah was the home of Dr. Willem Kolff, a pioneering Dutch surgeon who had moved to the United States after World War II. Dr. Kolff developed the first artificial kidney to be used in the United States, and in fact had worked with Dr. John Merrill at the Brigham Hospital in the early 1950s. Dr. Kolff had been pushing development of an artificial heart for many years, but unlike those who had gone before, he and his followers were interested in a totally implantable heart, one that would allow the patient to be fully mobile. Research on an air-driven version of the human heart designed by Dr. Robert Jarvik had been intensively pursued at the Utah center. The plan was for the diseased heart to be removed and the entire pump implanted in the chest cavity. The Jarvik heart was not wholly self-contained; the air pumps driving the heart still remained outside the body, connected to the implanted heart by tubes that had to pass through the body wall. Nevertheless, it was designed to allow a fair degree of mobility to the patient. Most of the problems that could be anticipated on paper had been solved using animals into whom the Jarvik heart had been implanted. But it had never been placed in a human before, and the human body puts different demands on a pump of this type than do the animals on which it had previously been tested. These differences needed to be studied, and they could only be studied meaningfully in a human patient. By late 1982 the Utah team was ready for the first human trial, and Barney Clark was selected as the team’s first patient. He received his implant on December 1, 1982.

Barney Clark lived with his Jarvik heart for 116 days - difficult days both for the patient and for the team managing him. There were mechanical problems with the heart itself. Parts of the pump did not function as expected. The left ventricle had to be replaced twice. Dr. Clark had to undergo surgical procedures three times to clear up problems associated with his new heart. Only once was he able to get up and move about, and then only with great difficulty. Complicating the purely mechanical adjustments that had to be made was the fact that he had been extremely ill - probably within days of death - at the time of the implant. Many of his physiological and metabolic systems were already seriously compromised.

Dr. Clark's case revealed a poignant but unavoidable side of every bargain underlying medical experimentation: Whenever a completely new technique is tried on a human being - a technique that could, if something went wrong, bring grievous harm to the patient - it can only be tested on someone so ill that there is no other hope for survival. Depending on how it works in essentially terminal patients, the technique may be gradually approved for use in patients less ill.

Even before Barney Clark died, controversy developed over whether the experiment was justified. The medical research community seemed about evenly split on the issue. Those close to the subject knew that at some point the only way to find out if an artificial heart would work or not in humans was to try it. The Jarvik heart in various modified forms was subsequently used on a number of other patients, some living for almost two years, and in fact a great deal was learned. Bioengineers discovered how to coat the surfaces of the pump so that clots would not form, and bacteria would not attach to it. They gained a good deal of information about balancing pressure and flow once such a pump was placed in a human, and about the design of valves that do not rupture red blood cells.

However, in 1990 the Food and Drug Administration decided to suspend use of the Jarvik heart, and the company that manufactured it has gone out of business. The primary reason for its discontinuance was a problem that did not show up in Barney Clark but that did show up in a disturbing number of patients after him: stroke. The cause of these strokes has never been entirely clear. But it was also clear that the Jarvik heart had little appeal to patients and their families because of the limited mobility it afforded. Even in its most advanced version, it still involved a unit about the size of a TV console that had to remain outside the body and be pulled around from place to place. It seems likely now that the air-driven Jarvik heart pump will eventually be replaced by a fully implantable electric heart powered by batteries. Such a heart has shown great promise in calves, and should be ready for clinical trial by the turn of the century.

There is no question that Barney Clark deserves to be remembered for what he did just as much as the doctors and scientists who made his transplant possible. The hundred-plus-days during which he ventured into the unknown were at times filled with intense stress, pain, and physical discomfort. But part of the reason he was selected was that he was enough of a medical scientist himself to know exactly what his condition was from the start, and exactly what he could expect as a result. He also reserved the right to discontinue the experiment at any time should the experience become too stressful. Throughout his ordeal, he showed tremendous courage in facing inordinate pain and suffering. But he also knew that every breath he took, every beat of his artificial heart, provided researchers with information that would make it easier for the next patient, whatever happened to him. Shortly before he died, he smiled weakly and said, "All in all, it's been a pleasure to be able to help people."

Finally, there is one issue that has not yet been squarely faced by those working to develop artificial organs, but which is clearly understood by almost everyone involved. If we are to view artificial organs, or even xenotransplants for that matter, as temporary implants, as a "bridge to transplantation," then we may contribute to human misery as much as we relieve it. For this approach is still dependent for its success on the ultimate availability of human organs. By keeping people alive on an interim basis, we simply increase the size of the waiting lists for the scant number of human organs available. The suffering undergone by these people, most of whom will likely die before a transplant is found, will be for nought. We must truly ask ourselves the question posed by Dr. Denton Cooley, when he was asked to comment on Barney Clark's operation: Are we prolonging life, or are we simply prolonging death?