Organ transplantation came to our department—or rather, patients in our department came to transplantation—on March 31, 1951. On that day David Hume transplanted a perfectly healthy normal kidney (which had to be removed from its host because of nearby cancer) into a 37-year-old man suffering from chronic kidney infection with severe high blood pressure and advanced renal failure. His demise was imminent. The donor kidney was sutured into place in the left renal fossa (the normal position of a left kidney). Its blood vessels were joined directly to the blood vessels of one of the patient’s nonfunctioning kidneys, both of which were removed. After the transplant he was treated with adrenocorticotropic hormone (ACTH) to stimulate his adrenal glands and with heparin to prevent clotting, as well as the male hormone testosterone and antibiotics. Even so, the operative incision became infected. The kidney never functioned satisfactorily, and the patient died of renal failure on the 37th postoperative day. In present-day parlance, this would be referred to as a “random, unmatched, living-donor kidney, in the orthotopic position without immunosuppression, rejected.” Immunosuppressive drugs to prevent rejection were still unheard of (but in fact were only 8 years away). None was used here.

The significance of this operation lay in the fact that it was the first ever to be performed for kidney transplantation according to a carefully planned research design, in which a surgical department committed to this study was joined to a medical department that included some of the world’s experts in kidney disease and, again for the first time, with the availability of an artificial kidney. All this in a university teaching hospital equipped with top-flight consultants and a superb pathology department under Gustave J. Dammin, who was destined to become the world leader in the pathology and microscopic appearances of organ transplantation.

This particular operation had another unique feature. It was one of the few kidney transplants in which the organ was placed in the normal position of the kidney, alongside the aorta and the vena cava. Such a position for a transplanted kidney is anatomically difficult and surgically almost inaccessible. Only someone with the determination of David Hume could and—encouraged by me as his chief—would undertake such a procedure. The lesson was learned. No more kidneys were put there, even though that was where they ordinarily lived and seemed to belong.

Only 23 days later the second patient of this group was operated upon. Again, the patient had no significant kidney function. The donor, however, had suffered from high blood pressure. This time the new kidney was placed on the patient’s right thigh, its artery joined to a branch of femoral artery (the main artery to the leg) and its vein joined to a vein of the leg. The ureter (draining conduit for the urine) was brought out through the skin. This same technique, developed by Dr. Hume, was used in the remaining patients of this series.

The third patient was a woman of 43, operated upon on April 24, 1951. The donor had died during operation for advanced heart failure due to mitral stenosis (a narrowing of the mitral valve of the heart). Although the donor’s kidney function was subnormal because of her heart failure, her kidneys were judged to be in reasonably good shape. The kidney was placed in the thigh. ACTH was given in abundant doses as well as heparin to prevent clots, and, again, testosterone, with penicillin as a shield against infection. For the first time, the transplanted kidney functioned well. It continued to put out urine for 53 days. Even as late as

the 70th day, with some real but diminishing urine output, the kidney looked almost normal on biopsy. The patient was dialyzed three times on the artificial kidney and lived until the 99th day, not bad for those primitive times and a harbinger of better times ahead. She was up and about, doing well, for that blessed but short time. In retrospect, and based on a guess that could not be corroborated in those early days, this was a happenstance close match.

George Thorn and I had planned this series of procedures (dialysis and transplants) together and had asked David Hume to carry out the operations because of his experience with experimental kidney transplantation in the dog and his enthusiasm, surgical ability, and remarkable determination. The ethical basis for such a human experiment lay in only two components: first, the patients selected were going to die shortly unless they could get a new kidney, and second, this experiment was being undertaken under the most ideal and favorable circumstances, with conscientious recording of every detail and the availability of the artificial kidney as standby.

Whatever the merit of this series of patients might be, whatever criticism we have endured regarding the ethics of these early efforts as viewed in terms of present-day mores 40 years later, whatever the troubles, difficulties, and expense we encountered, the fact is that if nothing is ventured, nothing is won. As it turned out, lots was ventured, and, finally, something remarkable was won. Late in this series of operations occurred an event the effects of which are still to be seen in every country where organ transplantation is being carried out.

The big break came in the case of a 26-year-old South American doctor who was dying of chronic glomerulonephritis (generally known as Bright’s disease) and its lethal complication: extremely high blood pressure (210/120). The donor kidney came from a woman who had died on the operating table during surgery for a narrowed aortic valve. Her kidney function was quite good despite late-stage congestive heart failure. Dwight Harken, the operating heart surgeon, asked the family to donate the patient’s kidney. The transplant operation was done on February 11,

1953. As in the previous case, the kidney was placed in the thigh. No ACTH, cortisone, or heparin was administered, but some testosterone and antibiotics were given. David Hume had suggested that the kidney might be enclosed in a small plastic envelope to keep the patient’s white blood cells away from the outer part of the kidney. It seemed to me this was a good idea, though none of us knew enough about it to make a sage judgment. So we watched and waited. Somehow we were filled with optimism about this patient.

On the 19th day (March 2, 1953), nature smiled on kidney transplantation—and, as it turned out, on all organ transplantation—when the patient began to have a massive output of urine, a diuresis that persisted for almost 20 days. He required large amounts of intravenous fluids to compensate for the unregulated loss of fluid through the recovering transplanted kidney. After that outpouring of urine, the kidney resumed normal function that persisted almost 6 months, and he recovered from uremia (the bloodstream disorder seen in kidney failure). His blood pressure remained elevated; his own kidneys had not been removed. The patient returned home to South America. Five months later he returned, his kidney now failing. He knew that he was going to die, but like so many patients who have had some but not complete success with surgery at the frontier of knowledge, he was grateful for the 6 months of life he had been given. The magnificent human spirit of such patients cannot fail to impress everybody who sees them. He had a sort of calm assurance that the experience in his case would help others. Little did he (or we) know how right he was and how soon his prediction would be borne out.

He died on the 175th postoperative day, 5 months and 25 days after his operation. He had received a random, unmatched, fresh cadaver kidney. Under the microscope there was little evidence of rejection— another happenstance close match.

Our experience with this patient as much as any other single factor led to the successful initiation of kidney transplantation a little more than a year after his death, when Joseph Murray (David Hume’s successor in the lab) transplanted a kidney from one identical twin into his brother. Clinical transplantation was born. Because of Hume’s work, Joe Murray, George Thorn, Gus Dammin, John Merrill, and I felt assured that the identical twin experiment would be successful and should be undertaken.

In addition, we suspected—as Thorn had so often emphasized—that to control blood pressure, both diseased kidneys should be removed. In retrospect, it is possible that our failure to follow this course was responsible for the ultimate loss of this patient.

While kidney transplantation had a beginning at the Brigham and the Harvard Medical School, it soon spread widely and eventually led to the transplantation of other organs and tissues. This came to pass because of the work of many people, but especially because of the interest of George Widmer Thorn in kidney disease as well as his remarkable ability to foster innovation. George Thorn was born in 1905 and was appointed Hersey Professor of the Theory and Practice of Physic at Harvard on July 1, 1942, taking over the medical department of the Brigham Hospital following the death of Soma Weiss, the Hungarian physician who had been so inspiring to our class. George Thorn had a remarkable career, fostering new knowledge about the use of adrenal hormones, new approaches to high blood pressure, and perfection of the artificial kidney— a necessary prelude to kidney transplantation.

When the Dutch physician Willem Kolff visited the Brigham in 1947, he brought with him the design for his invention, the artificial kidney. He thought that of all American physicians, George Thorn might be the one best able to make good use of his new device. In that thought Kolff had one of the great insights of his brilliant career.

Not only was Thorn a physician steeped in knowledge about kidney disease and about the kidney’s next-door neighbors, the adrenal glands, he was also a surgically minded physician. It has been my good fortune to work with several other surgically minded physicians, notably James Howard Means and Fuller Albright at the Massachusetts General and later John Merrill at the Brigham. Though an internist, Thorn was always thinking of things in surgical terms, that is, how can it be done, what will be its effect, and when can we get started? Some years earlier he had demonstrated this approach in his development of the treatment of adrenal failure by surgical implantation of adrenal hormone pellets. Later, it was evident in his surgical approach to the adrenal glands themselves in

certain cases of high blood pressure. But in kidney transplantation, his idea was clear-cut. He wished to remove both kidneys in some instances of hypertension in which his studies showed that kidney disease was the cause. Clearly you could not remove the kidneys without putting a new one back in. The artificial kidney made it possible to think along these lines and, indeed, to temporize in acute kidney failure, sometimes long enough for the kidney to heal itself.

George Thorn and John Merrill, a young man appointed by Thorn to help in this project, supervised the use of the artificial kidney for dialysis (washing harmful waste products out of the blood) in patients with acute, reversible kidney failure, thus keeping them alive long enough for their own recovery processes to heal the kidneys. Back in 1948, the patients who recovered completely after dialysis (in the treatment of renal shutdown) were truly medical miracles and proof of the effectiveness of modern biological science.

Based on the ability of the kidneys to heal in 14 to 16 days in certain types of acute renal failure, a remarkable operation had taken place a year or two before. The artificial kidney was not yet available, and this operation was an attempt to keep a patient going those few extra days so her kidneys could heal and open up. It was a temporary transplant, the case of the “arm kidney.”

To place the arm kidney episode in its historical context, it was possible because of a British physician-scientist named Bywaters, who had clearly described the temporary nature of acute renal failure in casualties of the bombing of London in World War II. Patients crushed under collapsed buildings often developed shock and renal failure (the crush syndrome). Bywaters had shown that if, by miraculous good luck, they lived 14 to 20 days, their kidneys would open up and they could survive. The arm kidney was also in a sense the parent of the Hume series and all that followed. I like to tell the story because it demonstrates George Thorn’s unique innovative gift and his surgical imagination.

The patient who received the arm kidney was a 29-year-old housewife who was admitted to the hospital in 1946 with acute renal failure. About a week before, in her fourth or fifth month of pregnancy, she had undergone an illegal abortion without sterile precautions (as usual). Sometimes these procedures included the administration of large amounts

of quinine or the instillation of tap water into the female reproductive tract, with leakage into the circulation. Either or both of these events will result in massive destruction of red blood cells (known as hemolysis) followed by renal failure. This was the case here. Hemolyzed blood is toxic to the kidney, and her kidneys promptly shut down.

Two or 3 days after admission, with conservative treatment, she began to look a bit better but was still not making any urine and had a dangerously high level of free hemoglobin in her blood. The artificial kidney, although on the drawing boards, had not yet become available. All the doctors who saw this patient knew that if they could keep her alive a few more days she might make it. Why not use a real kidney instead of an artificial one?

Encouraged by George Thorn, a young surgeon named Charles Hufnagel (then a surgical assistant resident) and David Hume, with the help of the urologic resident Ernest Landsteiner, offered to obtain a fresh kidney from a recently deceased accident victim and attach it to the arm vessels of this patient. Hufnagel had been a research fellow in vascular surgery and was expert in blood-vessel surgery. Both Hufnagel and Hume had already demonstrated their skill in research. They were able to suture the blood vessels successfully, giving the kidney its blood supply from the major vessel of the arm without endangering the hand.

The new kidney thus received its blood supply from the artery in the arm and drained its venous blood into the corresponding vein. The kidney was kept outside the body, lying on the arm, covered with moist gauze and secured to the arm with tape. The ureter—the duct that carries the urine to the bladder—was allowed to drain freely into a laboratory flask while the kidney was kept warm by the heat from a gooseneck lamp. The whole procedure was done on the ward under local anesthesia and did not involve taking the patient to the operating room. As I later found out, somewhat to my chagrin, this fact was not even mentioned in the subsequent abstract of the case; possibly a few conservative senior surgeons were opposed to such a bold and unprecedented step.

Subsequent events led to a happy outcome. The kidney certainly put out some yellow liquid, shown on analysis to be reasonably good urine. Maybe it did not make a great deal of urine. Maybe the urine was not very concentrated. Those figures are lost in history. But a few days

later the patient’s own kidneys began to open up, of that we are certain. She recovered completely. Here, a real kidney was being used to do the job later done by the artificial kidney. After about 48 hours the arm kidney was removed, as had been the plan in the first place. The patient recovered and went home. This was a temporary transplant to tide her over. A “bridge transplant,” as it would now be called. Was it responsible for her recovery? Well, it was done and she recovered. Can we always identify cause and effect?

This patient was fated to receive two terrible strokes of fortune. First from an illegal abortionist (which led to her kidney failure) and then from the primitive knowledge of blood banking and plasma pool transfusion in 1946. During her acute illness she had been given plasma from a plasma pool that was later shown to carry the hepatitis virus. She developed a severe case of hepatitis and died about 3 months after the arm kidney episode. At autopsy examination both her kidneys were almost normal. The patient’s case was reported in the literature as an example of the potential for complete healing of the kidney after total renal failure.

Surgery has been defined as “organized optimism” and research as “organized play for grownups.” For those many members of our medical and surgical departments who knew about this patient, this procedure and its interpretation had certainly been optimistic: the arm kidney appeared to help her recover. It was one of those background events that strengthened our resolve 5 years later when George Thorn and I planned to treat a few cases of kidney failure by implantation of a new kidney, the operation carried out by David Hume. And as for organized play... well, yes, I accept that definition of research. Games include skill, attention to detail, enjoying the struggle, getting the right team, planning to win, and exhaustive exertion in a single-minded purpose. What better?

The idea of transferring a tissue from one place to another in the same human body was first realized with the grafting of skin in the hospitals of Paris early in the nineteenth century. By grafting skin it was occasionally possible, successfully, to cover over the defect produced by a wound or burn. Heroic methods were described 200 years ago for trying

to make a new nose or a new thumb this way, by moving skin around. I am not sure any of these operations were ever accomplished. They made interesting pictures in history books. In all cases the skin was to be taken from the same patient, not another donor.

Before an organ could be taken from one person and put into the body of another person, obstacles in two critical areas had to be overcome: suturing (stitching) of blood vessels together and the problem of individual uniqueness. It was one man, Alexis Carrel, around the turn of the century, who surmounted the first obstacle. Although he witnessed rejection (the second obstacle), he did not recognize it for what it was, and he never tried to overcome it.

Carrel came to the United States from the University of Lyons in France in 1905 at the age of 32. After working briefly in Chicago, he joined the staff at the Rockefeller Institute in New York, where he was active in surgical research from 1912 to 1939. Carrel perfected the method of suturing blood vessels end to end. Like so many things in science, it was extremely simple: he used fine needles and very fine suture material to join the ends together, turning them outward a little as he did so.

Carrel’s experiments in transplanting kidneys were carried out in cats. After removing both kidneys from one cat along with the large blood vessels (aorta and vena cava) above and below the kidneys, he placed them in another cat from which both kidneys had been removed. The vessels were sutured by his new method, and the ureters were sutured into the bladder.

These operations were considered technically successful. This expression is ominous, sure to be followed by “... but the patient died.” And so it was here. At that time, transplantation alone was a triumph if the kidneys worked at all. The cats lived through the procedures, got along well, and made normal urine for a while. But within a few days they died. The kidneys had failed but did not seem to be infected, and blood flow had not ceased. Carrel was witnessing the process we now call rejection, but he had no word for it nor even a concept to dignify and identify it. He said it was neither infection nor infarction (loss of blood flow). It was something else that caused failure.

For his research on blood-vessel suture and transplantation, Carrel was awarded the Nobel Prize in 1912. He is usually referred to as the first

American to win the Nobel Prize. In fact, he was a French surgeon working in the United States, so perhaps it would be better to say that he was the first surgeon working in America to win the Nobel Prize.

During World War II transplantation science made two great leaps forward: the artificial kidney (Kolff) and immunogenetics (Medawar). These leaps were scarcely evident at the time—just little jumps—because at first they did not appear applicable to organ transplantation.

In the Netherlands during the war and under the eyes of the Nazis, Willem Kolff had the idea of treating patients who were dying of kidney failure by a new method: passing their blood across membranes that were permeable to small molecules. His first membrane was made of sausage casing (wound around tomato cans). This was immersed in a sterile salt-water bath so the poisonous substances of kidney failure (chiefly urea, potassium, and certain other waste products) could pass from the patient’s blood out through the tubing into the bath. The chemical name for this is dialysis; the popular name was blood cleansing or blood washing. A more sophisticated engineering version of Kolff’s original device was the artificial kidney.

Many years later Kolff wrote to me describing how he had worked on this project while his professor was away. It was he who mentioned the tomato cans. According to Kolff, the professor would have told him to cease and desist because all his patients died after treatment. So it was a good thing the professor was away.

Kolff’s patients were already fated to die because they suffered renal failure. Treated by dialysis, they got better, but for various reasons it did not work out as well as Kolff had hoped. He could see clearly from blood-chemical changes that the process of dialysis was doing its chemical job and that under ideal circumstances it would save lives. Kolff was convinced that the artificial kidney machine could temporarily take the place of a kidney and keep patients with acute renal failure (such as those with the crush syndrome) alive long enough for the injured kidneys to heal and come to the rescue.

The other wartime advance, seemingly far removed from organ transplantation, was the development in England of a new field of science: immunogenetics. During the Battle of Britain many aviators were severely burned around the face when they bailed out of burning Spitfires. A zoologist named Peter Medawar was assigned by the Medical Research Council of Great Britain to improve the grafting of skin for these burned aviators. He chose Thomas Gibson of Glasgow, a plastic surgeon, as his collaborator. Over the course of a few years Medawar made two brilliant discoveries for which he later received the Nobel Prize.

Using skin from one animal grafted onto another, Medawar established that the first set of skin grafts was rejected in 7 to 10 days, that is, the skin became discolored, began to degenerate, and was shed from the recipient animal’s body surface, leaving an open wound. Then, if a second set of skin grafts was put on, it was rejected much sooner than the first. This more rapid rejection suggested that an immunological response was involved, that the immune system was throwing off the skin as it might have thrown off an invading bacterium or parasite to which it had become partially sensitized by previous exposure. Medawar’s “second set” response, as it came to be known, provided an entering wedge to the understanding of tissue rejection after transplantation. The interaction of an individual’s inherited protein structure (genetics) and the rejecting foreign protein of the host (immunology) became known as immunogenetics. This is the science underlying tissue and organ transplantation. It is uniquely Medawar’s field, defined by him but now pursued by thousands of scientists all over the world and defining a whole new realm of discoveries in genetics and immunology. Whole departments and textbooks are now devoted to this field of study, so new in 1945.

Medawar’s second triumph was the demonstration of a “privileged time” for transplantation. It had been known for several years that there might be certain places within the body (such as the anterior chamber of the eye) where the immune process could not get at a transplant. Could not reach it. These were “privileged sites.” In 1953, Medawar,

working with Rupert Billingham and Leslie Brent, described a privileged time for transplantation in mice.

This privileged (safe) period for exchange of tissue occurs just before or around the time of birth. Medawar found that just before or at birth, cells from an unrelated donor could be placed on the newborn fetus without rejection. But then something unexpected was discovered. It is one of the earmarks of the beauty and wonder of science that, when carefully done, it can reveal important truths that were not anticipated at all. Now it was discovered that an animal grafted near birth could, throughout the rest of its life, take additional grafts again from that same donor animal. It became tolerant of that other animal’s proteins and tissues, apparently mistaking them for “self.” They termed this phenomenon actively acquired immune tolerance.

Medawar was a tall, handsome man, part Lebanese, with a commanding presence. He was a fine scientist, charismatic, friendly, and an inspiring lecturer. Later knighted for his work, he became known throughout the world of transplantation as Sir Peter. He died in 1987, the doyen of transplantation science throughout the world. Although he was neither a surgeon nor a clinician, his warm enthusiasm and the authoritative nature of his elegant scientific experiments influenced the whole field as nothing before or since. Rather than holding himself above clinical scientists and surgeons, he came to our meetings and knew the whole surgical community of transplantation. As a scientist he worked with his clinical colleagues, not apart from them.

The matter of identical twins is worth a bit of reflection. In the western European races, twinning occurs about once in 85 to 90 births. Most of these twins are fraternal, that is, two eggs are fertilized simultaneously by two sperm and are implanted at two different sites in the lining of the uterus, forming two separate embryos with two distinct placentas that grow close together, as siblings. Hence the term fraternal twin. They don’t look too much alike, are immunologically distinct individuals, and can be of opposite sexes.

Identical twinning is an entirely different process. Here, one egg

is fertilized by one sperm and then splits into two embryos that are supported by a single placenta. Just why this occurs is anybody’s guess. Possibly pure chance. It occurs at the same frequency in all races and ethnic groups but at differing frequencies in different animals. In human beings identical twinning occurs about once in every 250 to 270 births. That is, about one-third of all human twins are identical twins.

While fraternal twinning is an inherited trait, identical twinning does not seem to partake of any genetic or familial tendency. If you have had some twins in your ancestry or in the ancestry of your spouse, your children are more likely to be twins, most likely fraternal twins. The likelihood of identical twinning is independent of ancestry.

Many years ago it was suspected that because identical twins were so much alike and behaved so similarly, often having the same diseases at the same time, they might have similar body chemistry and, when it later became understood, immunologic identity as well. Barrett Brown, a plastic surgeon in St. Louis, had shown that this was indeed the case. By cross-grafting the skin of identical twins, he showed that skin could be traded back and forth between them with perfect success. No rejection. Between no other pairs of human siblings, parent or child, fraternal twins, or unrelated individuals is such tissue transfer possible. Crossed skin-grafting has become the acid test of identity.

On October 15, 1954, Daniel Miller, a physician at the United States Public Health Hospital in Brighton, Massachusetts, called John Merrill at the Brigham to tell him that he had a 22-year-old patient (R.H.) who might need dialysis on the artificial kidney. Miller was an extraordinarily perceptive physician. He knew that the patient had an identical twin brother. He understood the significance of this fact, noting in the patient’s record that the possibility of transplantation should be entertained.

At first, John Merrill (physician in charge of the artificial kidney) was a little hesitant to take on a patient for dialysis who had Bright’s disease and for whom dialysis would merely prolong the agonies of death. But when Miller told Merrill of the identical twin brother and the implied

possibility of transplantation, Merrill assented. The ambulance carried the patient from nearby Brighton to Brigham Circle on Huntington Avenue.

When the patient was first admitted he was very sick. Because he suffered from chronic Bright’s disease, he had severe hypertension, a common cause of death in such patients. He was incoherent, thrashing about and having frequent convulsions. The first thing the physicians did was to stop his drugs. Half the medication he was taking was discontinued. Soon, he got much better. It was then possible to test him and his brother to see whether or not they were truly identical twins. Such matching could be done in a variety of ways, including configuration of the external ear, fingerprints, thumbprints, toeprints, and several other tests to detect close physical similarity. Crossed skin-grafting was carried out by Joseph Murray, who at that time was concentrating on plastic and reconstructive surgery. Joe had recently completed his surgical residency and had a strong interest in research and a commitment to the study of kidney transplantation in the laboratory. The skin graft showed that the twin brothers could accept each other’s skin with ease and with no signs of rejection. They were truly identical. The push to transplant gained momentum.

After patient R.H. improved a bit on simple management, he was sent home for a while. When he failed to improve any further, he was readmitted and dialyzed on the artificial kidney. On December 23, 1954, the head surgeon of our urology division, J. Hartwell Harrison, removed one kidney from the donor twin, and Joe Murray transplanted it into the patient. The only role I assigned to myself was to carry this sacred kidney from one operating room to another, from Harrison to Murray, so it could be placed in its new host. Leroy Vandam, whom I had appointed Head of our Department of Anaesthesia only a few months before, administered the anesthesia—a touchy, difficult, and critical part of the operation, especially in such a sick patient.

The operation went well. The kidney was placed in the lower abdomen, with the ureter running directly into the bladder, according to the procedure Murray had perfected by experiments on dogs. The blood-

vessel suturing was done much as Carrel had taught 50 years before. The simplest of procedures was used for the recipient patient, since we were trying to avoid complicated or careless experimentation with dangerous drugs or medicines.

When both patients were taken from their respective operating tables, they were doing quite well. The transplanted kidney was making nice, clean, clear, yellow urine. Although you may never have developed any affection for urine, if you or your patients are unable to make any, you come to appreciate it.

A couple of days later the patient appeared to take a sudden turn for the worse, a bit of a nosedive. It proved to be only a temporary setback. His kidney picked up again, and about a month later he was discharged from the hospital, his twin brother pushing him along in a wheelchair toward the ambulance to take him home. This was only 18 months after the remarkably encouraging experience of David Hume with that South American doctor who hoped his treatment might help others even though, in the end, it failed him.

In this age of communication it does not take long for such discoveries to get around. Word of the discovery of ether 108 years earlier spread around the world in a few months. News of this first successful transplant took only a few days to be known wherever people were studying renal failure. Joseph Murray was soon recognized, along with his predecessor and collaborator David Hume, as a leading pioneer in surgical transplantation.

This first successful kidney transplant of 1954, although in the freak circumstance of identical twinning, demonstrated two basic truths: first, it showed that if transplantation of a kidney could be successful over time, the kidney would continue to work well, the elevated blood pressure would return to normal (usually requiring removal of the old, diseased kidneys), and the chemical imbalance would be corrected. The kidney could reside comfortably in the abdomen in that odd spot down in the pelvis, not too far from the usual site of the appendix. Second, and possibly more important, it showed that if the immune barrier could be overcome (as it was here by a fluke of nature), tissue transplantation would be here to stay.

We feared that the identical twin’s kidney, put in the sick patient’s

body, would acquire the same disease that the patient formerly had: Bright’s disease. After all, identical twins have the same sort of susceptibility to just about everything. That is exactly what did occur, and it was the ultimate cause of failure and death in that first identical twin transplant. Eight years later, in 1962, the patient, made well by the transplant from his twin brother, developed the same kidney disease in the transplanted kidney that he had suffered in his own kidney. The donor twin, fortunately, remained well and unaffected.

Even those 8 short years of life given to this young man had tremendous meaning for him. He had fallen in love with one of his nurses at the hospital. They were married and had a family. Like the South American doctor, neither of the brothers expressed anything but gratitude for the care, caring, and help they had received, even when it became clear that the outcome was headed for tragedy in the end.

If transplantation was to help the thousands of patients dying of kidney failure every year, it was necessary to move beyond the identical twin setting. This was a hard time, with black years of failure ahead.

Tom Starzl, the great transplanter of Denver and Pittsburgh (of whom more later), feels that I should not call these “black years,” even if they were plagued with difficulty. Better to call them years of hope. I will go along with that terminology, especially since Starzl was just then beginning his own transplant study, which would combine with Murray’s work in bringing hope to so many more patients over the coming decades. But for us at that time, when we saw so many dying patients for whom there was little hope, “black” would do.

No matter what we call this period, it lasted 7 years and 2 months. At the end of that time, we performed our first successful immunosuppressed kidney transplant between two totally unrelated people, using drug treatment to suppress the recipient’s natural immunity. Murray was again the operating surgeon with the collaboration of Thorn, Dammin, Merrill, and the whole team in the departments of both medicine and surgery. But before this could come about, we went through what was (for me at least) a period of storm and trial.

During these 7 years patients from all over the world were referred to our department for kidney transplantation. Most we declined. A few were identical twins, and we could go ahead. Sometimes we permitted other patients to come, thinking there might be a close enough relative in the family so we could make the transplanted kidney function. Methods for precise tissue typing had not yet been discovered, but closeness of blood relation seemed to be an obvious source of help. Usually we tried to discourage these referrals because we had so little to offer.

With the collaboration of James Dealy, who was in charge of the radiology department, we treated most of these patients with whole-body x-ray irradiation. It had been known for years that whole-body irradiation knocks down the immune system. Transplant teams in Paris were using it to inhibit rejection of the kidney grafts, hoping that patients so treated might accept the donor kidney. Despite many difficulties, they had a few successes.

On one occasion, in April 1958, a young woman was sent to us with no kidneys at all. This terrible fix was not an infrequent source of calls to us. In her case it resulted from the surgical removal, after accidental injury, of her injured kidney. The surgeon had not realized (because he did not take the proper precautions) that she was born with only one kidney. But in this case, even if the surgeon had known this key fact, he would still have been faced with a difficult decision because her solo kidney was so badly damaged that it could not function no matter what. We tried to prepare her body to accept a new kidney by giving her a heavy dose of whole-body radiation.

Because she was heavily irradiated, it was necessary to keep her in a sterile environment. In those days we did not have sterile isolation rooms or critical care units, so we just kept her in the operating room for 28 days. Alfred Morgan, one of our interns (later a surgeon in Washington, D.C.), assigned himself to her constant care. This was inconvenient—to say the least—for him and everybody else, including the nursing and surgical staffs. But in the spirit of our hospital in general and of the surgical and operating room staffs in particular, she remained in this protected environment and avoided the infection that so often followed whole-body irradiation. She died of bleeding because the coagulating power of her blood was lost—an ironic complication of the radiation

administered in a vain effort to save her life. Her kidney was still working without rejection, and at autopsy the transplanted kidney appeared virtually normal under the microscope. The balance of survival was a hard one to strike using radiation. We needed to find a better way of beating rejection.

There was one very bright spot in those black years. In 1959, for the first time, a pair of fraternal twins had successfully completed the same hazardous voyage. This successful transplant was accomplished using a smaller, survivable dose of whole-body radiation to suppress immunity. Murray was again the surgeon and James Dealy administered the radiotherapy. The patient was a 23-year-old man. Because the donor was his fraternal twin brother, the smaller x-ray dose provided sufficient immunosuppression to cover this less challenging genetic difference.

J. Hartwell Harrison, who had carried out the donor operations in all our living donors, was forced to remove the patient’s own now infected kidneys (leaving the transplant in, of course) as a midnight emergency soon after transplantation. Once again, as in all these early cases, Leroy Vandam administered the anesthesia for this critically ill young man. This rather complicated course of events resulted in prolonged survival for both these fraternal twins. This was really the first successful transplant in humans in which artificial means (here, irradiation) were used to reduce or suppress the recipient’s immune response.

Before this black period finally came to an end in April 1962, several more identical twins received new kidneys from their twin donors in transplants done by Murray. By 1966, a total of 23 twins had received kidneys from identical twin donors. Several of the married women in that group later became pregnant and have raised families.

Earlier, in 1960, Peter Medawar had been asked to give the Dunham Lectures at Harvard. In these lectures he opened new vistas of understanding and hopefulness in transplantation. Every medical school has one series of lectures considered to be of great importance. At Harvard it is the Dunham Lectures. We had four large amphitheaters at that time, but Medawar could speak in only one. Since this would clearly be an exciting talk at an exciting time, the amphitheater where he spoke was jam full. The other amphitheaters were wired for sound (this was before theater television) and were also crowded. The scientific community

knew something important was about to happen and that Medawar’s work was opening up a new field. By making use of the second set response and the privileged time, one could manipulate, change, examine, dissect, and ultimately come to grips with the newly recognized immunological phenomena of graft rejection and transplant immunology.

In time, the advent of drug immunosuppression would resolve the problem of rejection. While some work had been done prior to 1960 using chemicals to inhibit the activity of the immune system, these drugs had not appeared very promising. The drug most often used was nitrogen mustard, a close relative of the mustard gas used in World War I. Other substances were known to affect the immune system adversely, but most of them were highly toxic, similar to those used to slow the growth of malignant cells. Few of these drugs seemed to be satisfactory for transplantation. When used in experimental animals, they caused severe illness. We did not use them in patients.

Emergence from these black years is worth a chapter in itself.

Just at the height of our struggles with whole-body irradiation and its seemingly hopeless outlook, there appeared a flickering candle visible on what seemed to be the most distant scientific horizon. It is a matter of some nostalgia to all of us who saw this candle that even though it flickered faintly, we realized it could be the light at the end of our particular tunnel. It might indicate a way to suppress immunity without the uncontrollable hazards of total-body x-irradiation. Maybe the black years would give way to something brighter.

That flicker came from a point very close to us in Boston: Tufts Medical School. It took the form of an article about a new anticancer drug developed by the Burroughs Wellcome Company. The laboratories of this British-American company had a brilliant young chemist in their midst, George Hitchings. He and his assistant, Gertrude Elion, had synthesized a new drug originally intended for anticancer chemotherapy called 6-mercaptopurine (6-mp). For the synthesis of this and other key drugs based on the body’s own chemistry, these two scientists were awarded the Nobel Prize in 1988.

Obtaining this new drug from Hitchings, two hematologists at Tufts Medical School, Robert Schwartz and William Dameshek, had observed its effect on the immune system of experimental animals. They had injected human serum albumin into laboratory rodents. Today we

would call this a xenograft model, in which protein is traded between two different species. The animals usually rejected this very strange material rapidly and removed it from their blood. Because the protein was tagged with a radioactive tracer, the rate of removal could be measured. The tag and the foreign protein rapidly disappeared from the bloodstream of the untreated animal. Schwartz and Dameshek then gave the animals 6-mp to observe its effect on the rejection of this foreign (human) protein. The drug completely inhibited rejection, and the foreign protein persisted in the bloodstream. In 1958, these two clinical scientists published an article describing the immune suppressive potency of 6-mp. To all of us in the transplant field, this result was both important and exciting. Researchers are daydreamers at heart. It was not too difficult to imagine that this or some similar drug might be used to prevent the rejection of grafted kidneys.

Before we could pursue this important new concept very far in the Brigham/Harvard laboratories, Roy Calne, a young surgeon in London who had also seen this report, promptly went to an animal research laboratory where he could study this matter in dogs—not too easy in Great Britain because of their strict antivivisection policies. One such lab was the Buckston Browne Research Farm of the Royal College of Surgeons in London. He performed kidney grafting from one dog to another, giving the recipient 6-mp to determine whether this drug would abate rejection. How much of importance in science is accomplished with great simplicity!

Within months Calne was able to report that dogs given kidney grafts and placed on 6-mp held those grafts very well for as long as 6 weeks (about six times longer than usual). Examination of the kidneys under the microscope showed that the usual disastrous destruction wrought by rejection was largely absent. Calne told Sir Peter Medawar about his discovery. Sir Peter suggested that he come to our department at Harvard to work on this problem. Calne wrote me about it immediately, and I encouraged him to come over as soon as possible.

So the young English surgeon took the boat to America. On the way to Boston he stopped at the Burroughs Wellcome Laboratories at

Tuckahoe, New York, to spend a day with George Hitchings and Gertrude Elion; they gave him some more 6-mp and a number of other new compounds, including 57-BW-322 (described below). At this same time, Charles Zukoski of Richmond, Virginia, who was working with David Hume, confirmed that the Schwartz and Dameshek findings using 6-mp (that is, the abatement of rejection) could be reproduced in canine kidney transplants. Things were warming up fast.

In late June of 1960, Calne walked into my office at the Brigham with his manuscript describing the latest 6-mp work he had done in transplants in dogs. He and I went over to our surgical laboratories at the Harvard Medical School, where we talked with Joe Murray. This was to be an auspicious collaboration for the future of this new field.

Within a few months Calne explored several drugs in many more animals. One of them (mentioned above) was called 57-BW-322 (i.e., drug number 322 for 1957 from the Burroughs Wellcome Laboratory). He found it to be the most effective. This drug later traveled under the chemical (generic) name of azathioprine and the trade name of Imuran.

Moving rapidly, Murray and Calne perfected kidney transplantation in dogs in our laboratories, using azathioprine to suppress the immune system. To their delight, it did not do too much other damage. We introduced the term “immunosuppression” for this action of the drug and the term “immunosuppressive chemotherapy” to cover its clinical use.

With this laboratory success in hand it was time to give the drug a try in a human patient dying of renal failure. The first two attempts (1961 and 1962) were not successful. One of these patients received 6-mp and then azathioprine. We still did not know the right dose for people sick with kidney failure. Then came success.

The patient’s initials were M.D. Those initials were prophetic because he taught so many lessons to so many doctors. He was 24 years old when he was admitted to the Brigham on January 21, 1962, and referred to Dr. Merrill’s kidney study and dialysis unit, because he too was suffering from chronic Bright’s disease. In M.D.’s case, the disease had gradually worsened over many years. The reader will recall that several of

the earlier transplant patients (in the Hume series and the twins) had suffered from this same fatal disease of young people.

After admission, M.D. was treated by peritoneal dialysis, in which a plastic button is placed in the abdominal wall so a small tube can be inserted and replaced without pain or inconvenience for “blood washing” on the surface of the abdominal membrane. The patient was admitted to the hospital six times during his first month to learn how to perform this type of dialysis himself so he could use it at home instead of coming to the hospital for sessions on the artificial kidney. Eventually, peritoneal dialysis became less and less effective. So the patient became a candidate for kidney transplantation. He had no twin, and no close relatives were available to act as donors. He began the long wait, knowing that he would be one of the first to be treated by drug immunosuppression for transplantation and that previous patients had not survived.

For a week Murray and two of his colleagues took turns sleeping in the hospital to keep a 24-hour watch in case some severely injured or very sick patient died suddenly, making a kidney available for transplant. The others on the kidney watch were Nathan Couch, who later helped us to preserve kidneys better, and Richard Wilson, who would within a few years take over from Joe Murray as head of the transplant unit.

There were three false alarms before they finally had their donor. On April 5, 1962, an operation was scheduled on a 30-year-old man for severe heart disease. For this particular operation at that time the patient’s whole body was cooled. The operation was long and difficult, and when the patient was rewarmed his heart would not resume its normal beat. He died on the operating table despite a prolonged effort to restart his heart. After he died, his whole body was again cooled so that he could be put back on the pump-oxygenator (the heart-lung machine) to maintain his circulation artificially. His kidneys still functioned well; they were cool. And fresh. It took only a few minutes to complete the necessary arrangements with a helpful and understanding family. One kidney was removed only 40 minutes after the patient’s death and was cooled further to 4ºC. The total length of time from the death of the donor to the establishment of new, warm circulation in the kidney after transplantation was only 2 hours.

We knew from our laboratory work that all these circumstances

were clearly favorable to the transplanted kidney. In fact, over the course of a few years it was widely recognized that this was the ideal way to preserve organs for transplantation. At the present time, whenever possible, even though a patient may have a died of severe head injury or a brain tumor, the ideal setting for donation is total-body cooling and artificial maintenance of the circulation using the pump-oxygenator. This was the first such donation.

The recipient, M.D., was placed on azathioprine. Although the kidney started to put out normal urine at the time of the operation, function soon ceased for a full 10 days. It was a puzzle as to whether this was temporary renal failure of the reversible type or prompt immune rejection of the new kidney despite use of the new drug intended to prevent just that.

On the 12th day, M.D. started to make urine again, and on the 18th day he made 6 quarts (about 1½ gallons) in one day! This was reminiscent of some of Hume’s early thigh kidney transplants. The transplanted kidney can get wildly out of control and make much too much urine for a while, requiring extensive fluid treatment to keep the patient from becoming dehydrated by his own kidney. Such a kidney will literally piddle the patient to death if you are too slow in replacing the lost fluids.

On the 39th day, despite recovery of more nearly normal function and despite the drug, M.D.’s immune system tried to reject his kidney. He had a typical immunologic rejection crisis characterized by high fever, severe illness, and decreased urine output. This was treated with actinomycin D in addition to azathioprine. Actinomycin, like 6-mp, had originally been introduced to treat cancer. It interfered with cell genetics and was strikingly immunosuppressive.

When this crisis subsided, the patient began to improve but his blood pressure was still elevated. On the 50th day and again on the 62nd postoperative day, J. Hartwell Harrison performed an operation to remove the patient's own degenerated kidneys. Although the patient was a sick man for two such big operations, they were essential to his survival. Blood pressure now returned to normal. George Thorn’s original idea of removing the kidneys to treat hypertension was again corroborated by events, this time in an extraordinarily important patient: the world’s first transplant recipient on drug immunosuppression.

Four months later M.D. experienced another rejection crisis, and for the first time cortisone was given to help get over this hurdle. While on cortisone, the patient developed pneumonia, always a frightening complication during immunosuppressive treatment. We knew from experiments in the laboratory that despite the presence of immunosuppressive drugs, such disorders as pneumonia can be treated by antibiotics without stopping the immunosuppression, a step that would endanger the kidney. We followed such a policy here. Finally, the patient was sent home doing very well. The waste products in his blood were still slightly elevated, but they soon returned to normal levels.

Then, 18 months after his transplant—as if to put the entire procedure to a severe test—M.D. developed acute appendicitis. The appendix, located right next to the transplanted kidney, was badly infected and perforated and had to be removed. Under the microscope the appendix showed suppression of its normal lymph tissue response to inflammation and infection, demonstrating the adverse effect of immunosuppression on a local infection, this one in the appendix. Over the next several years we saw a good many kidney transplant recipients with infections in various parts of the bowel, especially diverticulitis, made worse by immunosuppression.

M.D. got over this setback and went home as well as could be expected (maybe even better, considering all he had been through). He was still on the immunosuppressive drugs. But that was not to be the end of the story. That transplanted kidney, although the first ever to show long-term function after transplantation on drug immunosuppression, continued to show chronic rejection. So, on January 22, 1964—21 months after his first transplant—the patient received a second kidney. Here again, M.D. was prophetic because now, 30 years later, chronic rejection is a continuing and unsolved problem in kidney transplantation, a problem not shared to the same extent by transplants of liver, heart, or pancreas. This time the new kidney for M.D. was one removed by Donald Matson from a child undergoing an operation for hydrocephalus, during which a normal kidney must be sacrificed.

Don Matson, a classmate of mine and head of our neurosurgical division, had perfected this operation, which consisted of draining the overabundant cerebrospinal fluid into the child’s bladder via the ureter so

the fluid could be passed from the body along with urine. This operation was eventually performed widely throughout the world and required the removal of one perfectly healthy kidney, often useful to a patient awaiting transplant. M.D. was the first of many patients to receive a “Matson kidney.”

M.D. had a hectic and troublesome time. Both he and his family, true to the stamp of these patients, remained grateful for the extension of his life. But it was not to last for very long, because on July 2, 1964, he died of generalized infection and severe liver damage. The latter may have been due to hepatitis virus from one or more of his transfusions. Also, azathioprine can be toxic to the liver. All three of these early transplant patients taught doctors important lessons that provided a model for the rest of the world. But only one, the fraternal twin, survived for a long time, remaining well and continuing his work for 25 years.

On the basis of our care of M.D., our experience grew rapidly. Of the first 13 patients operated on under immunosuppressive drugs at the Brigham between April 1962 and April 1963, 10 received kidneys from recently deceased persons, while three were given Matson kidneys. Matson kidneys are fresh when transplanted and require no preservation. Those three patients appeared to fare better than the others.

By 1963 kidney transplantation was spreading rapidly over the world. We were no longer unique. Most notably the technique was picked up again by David Hume, formerly of our department, who had become Professor and Head of the department at the Virginia Commonwealth University in Richmond; by Thomas Starzl in Denver, Colorado; and by René Küss and Jean Hamburger in Paris, where important work in transplantation had been going on for some years using both radiation and drug immunosuppression. Roy Calne had returned to London from our laboratory and then went to Cambridge, England, where he became Professor of Surgery and Head of the Department of Surgery. He was knighted by the Queen in 1986 for introducing transplantation to Great Britain.

Like transplantation in the United States, that of Calne in England clearly traced its origin back to the Brigham experience, at least in part.

This was not the case in Paris. There, over the course of several years, two French scientists had initiated a major effort in kidney transplantation that in many ways was parallel to ours. Because John Merrill spoke fluent French and was a particular friend of Jean Hamburger, one of these French scientists, we were kept pretty well aware of what they were doing. The French surgeon René Küss, senior surgeon at the Foch Hospital in Paris, had also been very active in this field.

On January 12, 1951, Charles Dubost and Nicholas Oeconomos transplanted the kidney of a guillotined criminal into a 44-year-old woman dying of renal failure. In 1955, the French surgeons transplanted several unmatched kidney grafts into unrelated recipients, much as we had done with the early Hume series at the Brigham. In Paris in those early years, about 25 patients were operated on, with no long-term survivors. Although on two or three occasions we had been offered organs from condemned criminals about to be executed, we came down hard against this practice as unethical in its unspoken bias toward the death penalty. That was our view, possibly too puritanical.

The French had perfected the use of the intra-abdominal location for the transplant, as had Joe Murray in our laboratories. As we had troubles, the French also experienced severe difficulty in the early days. Starting with an operation carried out on January 17, 1960, Küss achieved increasing success using radiation in modest doses, sometimes adding cortisone and 6-mp. In 1962 six patients were reported from the Paris experience, largely based on radiation for immunosuppression. The one long-term survivor was a nonidentical (fraternal) twin, similar to our patient. Professor Jean Hamburger was an internist, a nephrologist, who had several surgeons working with him at the Necker Hospital. In the mid 1960s he reported 13 patients surviving more than a year (out of 16 operated upon) using azathioprine and cortisone but without radiation. After this, the French went over completely to drugs for immunosuppression and abandoned radiotherapy, a method with which they had far greater experience and success than we had ever achieved.

In 1962 Thomas E. Starzl moved from the laboratories of Northwestern University in Chicago to take a position under William Waddell,

Professor of Surgery at the University of Colorado in Denver. On November 24, 1962, 3 months after going to Denver and only 6 months after our operation on patient M.D., he performed his first kidney transplant under drug immunosuppression with prolonged survival. Starzl’s work included experiments with several immunosuppressive drugs. He was a strong advocate of using cortisone to strengthen the immunosuppressive effect of azathioprine.

Starzl’s enthusiastic and intensive work in kidney transplantation soon outstripped ours in sheer numbers. Within 3 years he could report 127 kidney transplants. In those involving living donors (usually family members), the success rate (survival longer than one year) was 80%.

Neither here nor in the following accounts of early transplantation is there space to give the credit they deserve to all the collaborators in this field in Europe, Australasia, and America. The earliest successes seem to command attention: in the case of kidney transplantation, our early work at the Brigham, particularly the pioneering work of David Hume and Joseph Murray; those early successes in Paris, Cambridge, and Edinburgh; and the beginning work of Tom Starzl. These were the key initial researches that explored and opened up a vast, previously unexplored territory of surgery and biomedical science.

Within 25 years transplantation was to mushroom into the largest entirely new field of medical care in this century. It involved medicine, surgery, pediatrics, radiology, and applied immunology and has been a tremendous stimulus to basic immunologic science, as stated so clearly by Sir Peter Medawar. The story of twentieth-century surgery has as its centerpiece the story of organ transplantation, which began precisely at midcentury. Forty years later, in 1990, Joseph Murray was awarded the Nobel Prize for his work in kidney transplantation along with E. Donnall Thomas (a resident physician at the Brigham with George Thorn in the 1950s) for his work in bone marrow transplantation. As I look back on the colorful years of my surgical career, few can compete with the decade 1954 to 1964 for sheer and continuing excitement.

By 1962 we had already started work on the next organ to enjoy such undivided attention, and in 1963 I performed our first clinical liver transplantation under drug immunosuppression.

There were two principal reasons for us to start work on liver transplantation. First, we were interested in the immunological concept of antigen overload. An example would be an overwhelming infection in which the sheer burden of growing bacteria is more than the immune system can handle and so it retreats in disorder (as a form of immunodeficiency). The possibility of antigen overload leading to liver acceptance was part of our thinking. Transplanting the largest organ available in the body from one animal to another might somehow overcome immune rejection and enhance acceptance either of that organ or of others. The second reason was that there was an excellent team working on kidney transplantation, and it seemed important that we examine some other possibilities. For this we needed another team.

H. Brownell Wheeler was one of our residents. We had an exchange arrangement with St. Mary’s Hospital in London, as described in Chapter 18. Brownie Wheeler had just returned from a year there working with Charles Rob, a leading vascular surgeon who later became Professor and Head of the department at the University of Rochester. While working with Rob, Wheeler had become expert in blood-vessel surgery. Just at this moment, sometime in the summer of 1957, he was between jobs and had a little extra time.

I asked him to come over to my office so we could discuss a new

project. I told him that I was thinking of transplanting the liver in dogs. Although he was intrigued and wanted to help, he quite rightly wondered if that was going to be worthwhile. There was as yet no way to abort or abate rejection. I told him we would have a surgical problem right at the beginning, because the hepatic artery (the main artery to the liver) is complicated in the dog and does not lend itself as easily to surgical anastomosis (joining of the two severed ends) as it does in the human. So I asked him to look into this question of how we might anastomose the hepatic artery in the dog, and he promptly developed several plans.

A few weeks later, we carried out our first liver transplantation in the dog. These operations were long, difficult, and complicated. There was no prior experience to guide us. We had to devise new methods and new instruments. Louis L. Smith of the medical school at Loma Linda, California, was a prime assistant in this work, as was Peter Knight of Canada. Tom Burnap gave the anesthesia for these operations. We developed some special apparatus so the veins from the lower part of the animal (completely obstructed during the process of suturing in the transplant itself) could drain their blood through outside channels (shunts) back to the heart. Without this, no animal could survive the operation.

Almost immediately we witnessed some interesting things. First, the transplanted livers worked very well. We measured many enzymes and tested the liver function in these animals. The transplants did all the jobs that livers should do. Second, the operation was difficult and dangerous because of the tendency to hemorrhage with temporarily compromised liver function. Finally, the donor liver had to be handled with extreme gentleness to maintain its normal softness and circulation of arterial blood. The canine liver is much more sensitive to manipulation than is the human liver.

At that time (1958) we had no inkling of the imminent availability of immunosuppressive drugs. This was precisely in the midst of that black period that I described in Chapter 20, between the identical twins (1954) and the first successful drug immunosuppression (1962). All the livers we transplanted in these dogs were rejected at about 6 to 8 days.

Although we were also developing methods for transplanting the intact whole spleen, that work has now been forgotten because there is as yet no practical application. Immunologically, this was of interest because the spleen is itself an immunologically competent organ (i.e., it is an integral part of the body’s immune system), and it mounted a brisk reaction of the grafted spleen against the new host, a phenomenon soon dubbed graft-versus-host disease. The transplant became a warlike invader rather than a mere stranger.

We could not demonstrate any beneficial immune phenomenon, such as antigen overload, from the transplanted liver and we were not yet aware of the especially favored transplantability of the liver, later shown to be the case in pigs by Roy Calne when he returned to England, and also suggested several years later by the work of Starzl in humans.

As told in Chapter 20, Roy Calne of England had come to work in our laboratories 2 or 3 years after we first began the liver transplant work, so he was well aware of what we were doing in liver transplantation and why we were studying it. He himself was working intently with Joe Murray on kidney transplantation, and it was not until he returned to Cambridge that he became one of the world’s foremost experts in liver transplantation.

Although we were the first to report the operational details for removal of the entire liver, vascular shunts in place, and replacing it with a new liver in its normal position, we were not the first to consider transplanting the liver. Earlier, in 1953 or 1954, at about the time of the identical twin kidney transplant, C. Stuart Welch, Professor of Surgery at Tufts Medical School, was starting work on liver transplantation. Like us, he was experimenting on dogs, placing the liver in a new site in the abdomen, not in its normal position. For it to receive its normal anatomic double circulation of blood, it seemed best that the liver reside in its normal position. That was our endeavor. While Welch’s work showed several other points that were helpful to us, Welch himself gave up the work after a year or two and moved away from Boston.

Although we had quite a team on the project, three surgeons became most importantly involved in the evolving work on liver transplantation. Two, Roy Calne and I had exchanged ideas at the Brigham/ Harvard laboratories during Roy’s stay (1960-1962), as just mentioned.

The third of this triumvirate, Thomas Starzl, was working on liver transplantation at Northwestern University in Chicago, later taking his studies to Denver and working intensively on the kidney. Two of the three, Starzl and Calne, both considerably younger than I, were to become prime exponents of clinical liver transplantation in its early years (1963 to 1975) before it emerged as a widely accepted treatment.

Our first brief paper on liver transplantation was published in 1959. The next year we described our work in detail before the annual meeting of the American Surgical Association. At that time Tom Starzl discussed our work in light of his own, and it was clear we were working in parallel. We enjoyed a congenial relationship, not one of rivalry, but rather openness so important for scientific advance in a new field.

In 1962 Alan Birtch joined me in the liver transplant work and took charge. He was a Johns Hopkins graduate who had finished his residency at the Brigham and had spent a year studying liver blood flow in the Department of Physiology with Professor A.C. Barger. Alan devoted himself to this field for several years, was the first to describe the obstruction of blood flow in rejection of the liver, and was one of those liver transplanters who suffered a severe case of hepatitis himself (“the liver’s revenge”) during his work, as described below.

In 1963 we performed our first liver transplantation in a patient with a huge primary cancer of the liver. It was not successful; the patient died of pneumonia, at least partly traceable to the immunosuppressive drugs. The case was reported and illustrated in my book Transplant: The Give and Take of Tissue Transplantation, in 1974.

Tom Starzl performed his first human liver transplantation at about the same time as I did in 1963, but with a longer survival. Also in 1963, Roy Calne, now back in England, was starting his remarkable series of liver transplant operations. Within 2 or 3 years he reported his first human cases.

Roy Calne and Thomas Starzl were both to have a profound impact on the entire field of transplantation. Both are brilliant surgeons, teachers, and innovators, widely recognized throughout the world for

their work. Both have received many awards, prizes, and honors, in their own countries and abroad. These two men, one in England and the other first in Chicago, then Denver, and later Pittsburgh, were to devote their entire professional careers to the development of transplantation. My life was enriched by close personal and scientific contacts with these two remarkable surgeons.

Roy Calne (now Sir Roy) was born in 1930 in Surrey. He attended Guy’s Hospital Medical School in London and did his early surgical training there. After army service in Malaysia with the Gurkhas, he took a year at Oxford before coming to work with us in the summer of 1960. He returned to England in the late fall of 1961, just before that first successful immunosuppressed kidney transplant was carried out by Joseph Murray based on Calne’s early work with 6-mp (see Chapter 20). Professor of Surgery at Cambridge University, he was the first to explore the use of a new drug, cyclosporine, for transplantation. He has been a central figure in the development of transplantation throughout the world.

Thomas Starzl was born in Le Mars, Iowa, in 1926. He attended Northwestern University where he obtained a Ph.D. in physiology in 1950 and an M.D. in 1952. After internship and a residency at Johns Hopkins, he worked in Florida and was then appointed to the faculty at Northwestern, becoming an assistant professor in 1961. While he was there, we began to correspond about our mutual interest in experimental liver transplantation. We first met in 1960 at the meeting of the American Surgical Association where I presented my paper, as mentioned above.

About 1960 Tom told me he would enjoy working in my department. While I would have been proud and pleased to add this young star to our group, it was perfectly clear to me that he needed to be at a university not only with strong backing from his chief, but with an empty slate in transplant science. My small laboratory was already overcrowded, and the Brigham was soon to have a large proportional share of patients with kidney failure on both Dr. Thorn’s service and mine. We were doing as much experimental work in surgery, as much surgical transplantation, and as much dialysis as our small hospital and laboratory could possibly accommodate.

The surgical department of the University of Colorado at Denver was well known to me because my friend and Harvard Medical School

classmate Henry Swan had been Professor and Department Head there for many years and helped to give this Rocky Mountain university, new to the councils of world surgery, a growing and secure reputation. I had been visiting professor there in 1958. Swan’s work was in cardiac surgery. This was a perfect place for Tom Starzl to carry forward his work in transplantation under Swan’s successor, Bill Waddell, a colleague from my MGH years.

In 1962 Tom Starzl moved from Chicago to the University of Colorado, where he pursued his work on transplantation of both kidney and liver with his usual energy and increasingly wide recognition. There he began his custom of teaching others the art and science of transplantation, as Joe Murray and the Brigham team had done before him. In 1972 he was made chairman of the Department of Surgery at the University of Colorado. Nine years later, in 1981, he was appointed Head of the Transplant Unit and Professor of Surgery at the University of Pittsburgh. He has become a pioneer in the use of a new drug for immunosuppression, known as FK506, and has recently (1992) published a book—The Puzzle People—telling the fascinating story of his life as a surgical scientist devoted to the development of organ transplantation.

Throughout much of his scientific career, Tom Starzl worked with Kendrick Porter of London, who carried out the pathological and microscopic examination of both experimental and clinical material from Starzl’s work. This 4,500-mile collaboration, which lasted several decades, was in a sense a continuing link between Tom and our department, where Ken Porter had first started his transplant research in 1956.

Tom has contributed uniquely to transplantation science on a very broad base. He was one of the first to stress adding cortisone to azathioprine for treating rejection. Although we had used cortisone for this purpose as early as 1952, we did not report it as a separate drug regimen. Starzl also improved the use of cyclosporine in the same way, by adding cortisone. He has written several books that are widely used in the field of transplantation. By the magnitude of his enterprise in surgical care and the number of liver, kidney, bowel, and pancreas transplants he performed at Colorado and then at Pittsburgh, Starzl has become one of the leading transplant surgeons of his time. Several important physiologic facts have emerged from his study of liver transplantation, by which he has

demonstrated genetic and enzymatic mechanisms underlying certain disorders of the liver. In some of these he has shown that transplantation is an effective method of treatment, even though other aspects of liver function may be normal. He has also demonstrated the migration of donor cells to other places in the recipient body, a new clue to transplant acceptance.

In those early days (1960 to 1970) liver transplantation moved slowly. Six years after the first clinical transplants a meeting was held in April 1969 in Cambridge, England, at which the first 91 patients were reported. Of these, only 10 were still living and only 3 had survived the operation for more than 12 months. The longest survivor at that time, a patient operated on by Starzl in Denver, lived for about 16 months. A year and a half later the total had increased to 133, and at that time the longest survival was 29 months (one of Calne’s patients). A few years later I was asked to chair an international meeting on transplantation of the liver, examining the total record to date. While a half-dozen other centers were now carrying out the operation, Calne and Starzl had, between them, carried out over 90% of all the liver transplants in the world. Long-term survival was becoming much more frequent as the operation itself and the use of drug immunosuppression were both being perfected.

Beginning at that time (about 1975), liver transplantation came out of the research lab and underwent the same sort of expansion in use that kidney transplantation had shown about 10 years before. At the present time in most countries carrying out transplantation, liver and heart transplantation are second in frequency to that of the kidney, each involving about one-third as many operations as are done for kidney.

When I consider the tortured growth of science, the rivalries, ego trips, misunderstandings, backstabbings, fraud, misrepresentation, arguments over priority, and unhappiness that have marred so much of the story of scientists and science, I regard this period in early transplantation as a remarkably happy one. Only a few people were at work. They kept in touch, met together, bore good will toward one another, and together founded a new field of clinical and scientific activity.

Patients who need liver transplantation differ in important ways from those needing new kidneys. Chronic kidney failure is characteristically seen in teenagers or adults; only rarely are acute infections the cause. Cancer or other malignant tumors rarely warrant kidney transplantation. None of the kidney diseases is a result of self-indulgent lifestyles. Most of the diseases are chronic.

In sharp contrast, liver failure treatable by transplantation includes a large cohort of young children whose bile ducts fail to develop (biliary atresia); some of the greatest triumphs in liver transplantation have been in that childhood group. Chronic alcoholism is one of the commonest causes of fatal chronic liver disease. It was clear from the outset that no alcoholic should receive a lifesaving liver at the sacrifice of an alternative recipient unless a certifiably prolonged abstinence had been achieved. Acute fulminating fatal hepatitis, much to the surprise of all, can be treated by transplantation, with long-term survival. And livers with primary malignant tumors can be successfully replaced if the cancer is caught early. Late malignancy would almost never be an acceptable basis for transplantation because of the virtual certainty of spreading disease, visible or not.

The clinical experience of Alan Birtch and myself with only four cases (two adults and two children) in 1963, 1964, and 1965 yielded no long-term success. We felt we should await the perfection of immunosuppression before proceeding further with liver transplantation. Our former student (Roy Calne) and our collaborator in Denver (Thomas Starzl) took up the work with greater success and in far greater numbers, as mentioned above, and by 1975 liver transplantation was gaining general acceptance. We had been active participants in the years of struggle (1957 to 1965) but had passed the torch to others during the early years of success (1965 to 1975). While I have been criticized for not going ahead with clinical liver transplantation, it was in good hands, and I have no regrets.

Much of this story about transplantation has been upbeat and optimistic. Fair enough, since it was an entirely new, rapidly growing,

and increasingly successful way of treating sick people. But the picture is not always so rosy. Transplant operations (especially those of liver and heart) are still associated with significant mortality. For some patients the drugs simply did not keep immunity suppressed. For others, although the drug did its job at first, there was later a chronic rejection (seen especially in the kidney) that claimed the organ after several years. Kidney transplantation is associated with a 95% (or higher) survival rate at one year if living donors are used, with some diminution when cadaver donors are used. For liver and heart, this figure for early survivorship is only slightly lower.

In a dire sense, immunosuppression has also had its revenge. In Emerson’s words in his essay On Compensation, “It would seem there is always this vindictive circumstance stealing in at us unawares... this back-stroke, this kick of the gun, certifying that the law is fatal; that in nature nothing can be given, all things are sold.”

From the earliest days of the use of azathioprine (Imuran) and now with cyclosporine and FK506, reducing immunity has led to the growth of malignant tumors in a small fraction of cases (about 10%). In one case a lymph-related tumor appeared at the exact site where antilymphocyte serum had been injected. Cancers of several types have appeared long after transplantation.

The simplest explanation of this emergence of tumors in patients under immunosuppression is that the normal immune system constantly exerts a sort of roving policing or surveillance, killing off tumor cells (that may be immunologically distinct from the host’s own cells) when they arise. Then, when the policeman is suppressed or inhibited—when the cat’s away—the tumors emerge. The longer the followup, the higher the incidence of tumors under immunosuppression. Israel Penn, a world expert on this problem, estimates that at 20 years after transplantation the incidence of malignant tumors will rise much higher. That is why we need a better method of achieving graft acceptance, some way of inducing tissue tolerance without toxicity and global loss of immunity.

There was one other unexpected aspect of liver transplantation. Sort of a diabolical justice. The liver’s revenge. While working intensively on liver transplantation, Alan Birtch came down with a very severe case of hepatitis. Tom Starzl also contracted this disease, as did Roy

Calne. A nurse working on liver transplantation died of the disease. I had formerly been stricken with a severe case of hepatitis in 1946 and thought I was immune. During my liver transplantation days, I came down with the disease a second time, although a rather mild case. Several other liver transplanters contracted the disease. I do not know any explanation for this unexpected outbreak, this epidemiology. Did laboratory animals (dogs) carry this virus in the liver without showing the disease itself? That seems to be the most logical explanation.

No mere rhetoric can do justice to the role of patients and their families in the development of transplantation. Patients give so much of themselves and contribute so much to our understanding, often knowing their own gloomy prognosis. Understanding all the risks and travails of the course, they make their choice in hope and faith and always with the assurance of helping others should their own course falter or fail, as it so often did. In these crucial early years of our work (1951 to 1975) our patients were the real heroes.

Starting in the middle 1960s, a few years after the case of M.D., an increasing number of scientists, physicians, and surgeons began to explore the possibility of treating disease in other organs by transplantation. This work is still going on; new horizons for transplantation and new ways of transplanting human organs and tissue will be discovered for many years to come.

The story of heart transplantation recapitulated that of kidney and liver transplantation. Success depended on suppression of the immune system with drugs, as was first done successfully in M.D. There was another similarity: at the beginning only a few people were working on heart transplantation, as had been the case with the kidney, in only one or two laboratories. They were getting started rather quietly as far as the rest of the world was concerned. Few physicians or surgeons—let alone the media and the public—knew of the work. As a generality, if you would look for what is coming next in science, do not read the papers. Go to a scientific meeting or visit a lab. This was true for kidney, liver, and heart, but there was a difference. The first kidney transplant was scarcely noticed in the papers. I am not even sure it was mentioned. The first

human liver transplants were also neglected by the press, probably because reporters could not understand what people were talking about: transplanting the liver? How do you do that? What for? Where? Why? There was no frame of reference.

In heart transplantation the breakout from the laboratory to clinical reality made a splash that was heard around the world. Or rather, a typographical bang. Front-page headlines of newspapers appeared in type 2 or 3 inches high. Everyone knew where the heart was and what it did. While only a pump, it is rather central. As the ancients considered it the seat of the soul, so also most people still grant it some sort of special status in the hierarchy of internal organs. King. Or maybe Queen.

The major biological difference between the heart and the other organs that had already been transplanted (kidney, liver) lay in the fact that the heart consists almost entirely of muscle. It contains only a few specialized cells that do metabolic or glandular work in secreting hormones. It also contains an important nerve network—the conduction bundles—that coordinates its beat. While its muscle is a little different from the muscles that move our arms and legs, it is nonetheless muscle tissue. Because the heart is largely muscle, with less cellularity, there were some who thought it might be less antigenic. I was one who held that optimistic view. As it turned out, the heart can be rejected just like any other transplant and requires drugs to suppress immunity so it will remain secure and beating normally in its new host.

As was the case with both the kidney and the liver, three major figures in surgery and science were the prime movers. In heart transplantation they were Richard Lower and Norman Shumway (of Minneapolis and Stanford) and Christiaan Barnard of Capetown, South Africa. In addition, there was a fourth, a great friend and advocate of young people in surgical research: Owen Wangensteen of the University of Minnesota.

The work of these men on the experimental surgical transplantation of the heart started in Minneapolis in the late 1950s and early 1960s. Owen Wangensteen, a Minnesotan of Norwegian extraction, was for almost 50 years the leader of surgical research in the Midwest. What he liked to call his “small agricultural college” rapidly grew to be a great power among American universities, especially in surgical research. During the years 1956 and 1957 the University of Minnesota housed several

people who were to become stars in the field of cardiac surgery and cardiac transplantation. Curiously enough, Wangensteen’s own interests lay in the gastrointestinal tract and ulcer disease. He never appeared to have much interest in heart surgery or transplantation. But his laboratory and the milieu of inquiry he fostered were at the heart (or at least the root) of the matter.

Norman Shumway received his medical degree from Vanderbilt University in Tennessee in 1949, then enrolled at the University of Minnesota where he entered the surgical Ph.D. program of Wangensteen, receiving his degree in 1956. Christiaan Barnard, a graduate of the University of Capetown, came to the University of Minnesota in 1956 as a student under Wangensteen, working with C. Walton Lillehei and Richard Varco, two Minnesota surgeons who were developing open-heart surgery. Barnard worked in Minnesota until 1958, when he took a surgical appointment back home at Capetown. Shumway’s studies had to do with the effect of temperature on disturbed rhythms of the heartbeat, a topic of importance in open-heart surgery and later in heart transplantation because of the low temperatures required for preserving the heart while it is disconnected from the circulation. Shumway left Minnesota in 1957, soon moving to Stanford University for a notable career in heart transplantation.

Richard Lower was another Michigan transplanter (Hume was born in Muskegon, Shumway in Kalamazoo, Lower in Detroit). He had attended medical school at Cornell, with a surgical residency at the University of Washington in Seattle, whence, in 1957, he moved to Stanford and worked with Shumway. About 1959 they began to experiment with removing the heart and suturing it back again in the same animal. Richard Lower, working in Shumway’s laboratory and assisted by Eugene Dong, then performed the first successful heart transplantation in a dog, in December 1959.

Shumway carried out his first successful human heart transplantation at Stanford on January 8, 1968. By that time Richard Lower was developing cardiac and thoracic surgery under David Hume at the Medical College of Virginia; Lower could soon demonstrate one of the longest survivors of heart transplantation.

Meanwhile, that other Minnesota graduate student, the South

African Christiaan Barnard, had pushed ahead a little bit faster and was able to scoop the world by carrying out the first clinical cardiac transplantation in Capetown on December 3, 1967. For those interested in dates, this was 13 years after the first identical twin kidney transplant, 5 years after the first immunosuppressed transplant (kidney), and 4 years after the first two human liver transplants.

Barnard’s patient was a 53-year-old man, a diabetic with repeated heart attacks and now severe failure of both the right and left sides of his heart. The donor was a 24-year-old woman who had been struck by an automobile in an accident only about a mile from the hospital. Starting the operation in the middle of the night, Barnard completed the transplant, and the patient was back in bed the next morning. The threat of rejection was treated with azathioprine (patterned after the work of Murray, Calne, and Hitchings 5 years before) as well as cortisone and irradiation. The patient died on the 18th postoperative day from a combination of rejection and pneumonia, much as our first liver transplant patient had died 4 years before. Barnard carried out several more transplantations in the next year or two, achieving survival of 20 months in his third patient and over 12 years in his fifth patient. In his seventh patient a long-term survival approaching 20 years was realized, the kind of result all patients and transplanters seek.

While Barnard was thus the first, it was Shumway, working at Stanford, continuing his work at a slower and quieter but less erratic pace, who soon led the world both in numbers of hearts and in results. Twenty-three years later, in 1991, his department at Stanford could report 687 heart transplantations in 615 patients. Some required a second transplant when the first failed. The late survivorship was 81% at 5 years, and the longest survival was also about 20 years. Shumway’s program took the lead in cardiac transplantation, much as those of Starzl and Calne had in liver transplantation and the programs of Murray, Starzl, and Calne had in kidney transplantation.

In discussing liver transplantation, I mentioned that there was no fallback position, since there was no artificial organ analogous to the artificial kidney. The artificial heart later showed signs of becoming useful as temporary support for the heart. It is a machine that accepts blood from the great veins running toward the heart (the venae cavae) and forcefully

pumps it into the artery leaving the heart (the aorta). Blood clots tend to form in all mechanical devices, including this one. A major use for an artificial heart, as more practical versions have been developed, is to tide over a severely sick patient awaiting transplant. When the device is used for short periods as a bridge, the clotting tendency is less pernicious. On more prolonged use, clotting has been the principal agent of failure.

Cardiac transplantation was so spectacular both to physicians and to the public that two remarkable phenomena ensued, unprecedented in the history of science and surgery: national surgical chauvinism and an ego epidemic. Shortly after that first announcement by Christiaan Barnard, other nations considered it important to demonstrate that they, too, could do heart transplants. It was a matter of national pride. Several cardiac surgeons in several countries were anxious to jump on the bandwagon and demonstrate that their nation and its scientific resources could accomplish cardiac transplantation.

Laurie and I happened to be in London at the time of the first successful cardiac transplantation there. Considering the usual British soft-spoken undersell, we discovered that boasting and crass showmanship could be prominent even in Great Britain. The surgeons, in full operating regalia, appeared on the steps of one of the London teaching hospitals to the shouts of cheering crowds, bands playing “Britannia Rules the Waves” and “God Save the Queen” with the waving of flags, guardsmen in bear-skin busbies hovering around on horseback. British reserve was cast into those waves that Britannia rules.

Closely linked to this national chauvinism was an ego epidemic, personal chauvinism in a sense. This took the form of the performance, in 1968, 1969, and 1970, of a large number of cardiac transplantations (about 50 or so) by surgeons who were masters of cardiac surgery but had no experience with either experimental or clinical transplantation. In fact, none of their hospitals had shown any interest whatsoever in transplantation while other humble toilers in the vineyard had been sweating away at it for 15 years. The results were disastrous. Mortality was unacceptable.

At first the newspapers, even some of those in the United States

with a long tradition of scientific conservatism and responsible reporting, greeted all this with elation. Presumably a new era had arrived. One prominent surgeon declared that life expectancy for man would now rapidly move up to 150 years. Actually, there never was at any time, either then or now, any evidence whatsoever that transplantation of organs would prolong human life beyond its ordinary expected span. Quite the contrary, the name of the game in transplantation (as in most of surgery) is to improve the quality of life for a few threatened people during those short years allocated to them by a kindly providence. The public health impact of sporadic heroic treatments in any field will of course be near zero as judged by life expectancy data. The principal and daily mission of clinical care is the relief of suffering; only on rare occasions does it prolong lives in an aggregate or populational sense.

Even the press soon began to realize that something had gone dreadfully wrong during the ego epidemic of heart transplantation. There were articles in a few newspapers with strong bioscience reporters who suggested that, possibly, these transplant operations were being done by surgeons, by teams, who had no experience with the rest of the art and science of transplantation. Within 3 years the epidemic died where it began, while the work of Shumway proceeded steadily forward.

During the years of the first immunosuppressed kidney transplants (1959 and 1962), the early liver transplantations (1963 to 1966), and the first heart transplantations (1968 to 1973), great progress was being made in tissue typing, tissue groups, and immunogenetics as well as in the legal and ethical aspects of donor procurement. All these were to help progress in all sectors of transplantation science and practice.

Transplantation of the lung presents a special problem: to be useful the lung requires the simultaneous circulation of both blood and air. The entire lung is in minute-by-minute contact with the outside world through inhaled air that permeates its every segment. This distribution of outside air must be balanced by the distribution and circulation of the blood, so that red blood cells can pick up oxygen from the air and exhaust their carbon dioxide. Air and blood must reach every little air pocket

(alveolus) in the lung, and they must reach it together, at the very same instant. Once there, they are separated only by a thin and highly specialized membrane. Breathing a lot of air (ventilation) into the lung without good circulation accomplishes nothing. Pumping in a good flow of blood (perfusion) with no air to inflate that segment is also courting disaster. The ventilation-to-perfusion ratio (balance) is the key to lung function. A healthy ventilation-to-perfusion ratio is essential to success. Achieving this balance was a major problem in lung transplantation.

One of the first human lung transplants with at least a short period of survival was carried out by James Hardy and his associates in Jackson, Mississippi, in 1963. The patient had been suffering from emphysema (chronic lung insufficiency, often the result of heavy smoking) and survived for 18 days. Another early experience but with long-term survivorship was an operation done in Belgium by F. Derom at the University of Ghent in November 1968. The patient was suffering from silicosis, a form of lung scarring found among miners and industrial workers. He lived about a year. Both these patients underwent transplantation of a single lung. As I pointed out before, in surgery it sometimes pays off to take the bolder and seemingly more radical course. The inequality in perfusion and ventilation between the recently transplanted and the native (opposite) lung was often the source of trouble. If both lungs are transplanted at once, this inequality between the two sides is minimized. Healing of the bronchi (air passages) stitched or sutured together is also a problem, with failure bringing almost certain death. Joel Cooper of St. Louis has resolved this ingeniously by supporting the blood supply using a graft of peritoneum (from the abdomen).

In patients with severe chronic lung disease, the heart must work much harder. This applies particularly to the right ventricle of the heart, which in these patients must pump its blood through an obstructed circulation in the lung. Heart failure, especially right heart failure, is therefore commonplace in chronic lung disease such as emphysema. While the procedure of transplanting the heart and both lungs together seems an exercise in surgical heroics, in some cases it is the simplest choice. Considering the intricate circulation between the heart and lungs, which can be left undisturbed when both are transplanted together, the transplant is done with only a few blood-vessel suture lines. Despite its early severe

difficulties, transplantation of the lungs has now emerged from this troublesome period.

Most cases of diabetes are traceable to inadequate or poorly controlled production of insulin from those little islet cells, first described by Langerhans, in the pancreas. The administration of insulin regulates the blood sugar but does not prevent other complications of diabetes, which often affect blood vessels, the eye, or the kidney. Because insulin administration does not do the whole job, attempts to transplant the pancreas began in the early and mid 1960s.

Each organ transplanted presents its own special problems. Early efforts to transplant the pancreas failed owing to a special arrangement within this organ. The pancreas secretes highly corrosive enzymes that will digest protein and even the pancreas itself. These enzymes are secreted into the upper intestine to digest food. To isolate the delicate insulin molecules from these destructive enzymes had been the problem 40 years before, when insulin itself was isolated. In nature the two are completely separated even though coming from the same organ: insulin goes directly into the bloodstream, and the enzymes go into the intestine to digest food.

In telling the story of transplantation in our time, I have mentioned only a few names of pioneers and leaders. Some names have been essential to this history, and so it is with Richard Lillehei and John Najarian. Dick Lillehei, the younger of the two brilliant Minnesota brothers (his elder sibling had been a pioneer in open-heart operations), began working intensively on pancreas transplantation in the early 1960s. John Najarian, a native Californian and graduate of the University of California in 1948, was a key player and captain of a winning football team. He received his M.D. from the University of California and pursued his surgical residency and fellowship years there, becoming assistant professor and head of the transplant service in August 1964. In 1967, he was appointed Professor and Chairman at Minnesota, succeeding the remarkable Wangensteen mentioned above.

Najarian has focused on several special aspects of transplantation

science, particularly the development of antisera (usually horse sera) against lymphocytes and thymocytes, the cells responsible for rejection. These are sometimes an aid in immunosuppression. When he arrived at Minnesota he found an active pancreas program already under way under Richard Lillehei and David Sutherland, who performed several of the first pancreas transplants. As of 1991, Najarian could report 1,200 kidney or kidney-pancreas transplants in diabetic patients. His department has become a center for the study and treatment of severe diabetes, often the childhood or juvenile type, especially in patients with failure of both kidneys and loss of their sight. The relief of these crippling complications has revolutionized the expectations of childhood diabetics and their physicians.

Somers Sturgis, Head of Gynecology in our Department of Surgery, attempted in the 1950s to transplant ovaries in a way that would preserve their internal secretion of hormones (estrogen and progesterone) and help make patients who lacked normal ovaries more truly female. He did this by placing the ovarian tissue in small envelopes (Millipore filters). In animals, some ovarian function was observed and it looked encouraging. However, there were no clinically successful ovarian transplants.

Certain patients suffering from deficient thyroid or parathyroid function would benefit immensely from transplantation of those endocrine glands. These—as well as pancreatic islets—were studied in our department by John Brooks. As Sturgis had with the ovary, Brooks used a Millipore filter to protect the tiny transplant. The idea here was to place the organ in a filter that would let the oxygen of the blood plasma in and let the hormones out but exclude the destructive immune lymphocytes responsible for much of tissue rejection. This approach never became clinically useful.

The magnitude of this new field of science and surgery is indicated by the figures for transplantation in the United States. In 1989, there were 8,890 kidney, 2,160 liver, 1,673 heart, 413 pancreas, and 67 heart-lung transplants. There was continued growth in 1990:9,600 kidney, 2,700 liver, 2,100 heart, 549 pancreas, 202 lung, and 50 heart-lung

transplants. With donor availability as the limiting factor, these figures for transplant frequency seem to be attaining a plateau, as shown by the numbers for 1993:9,551 kidney, 3,062 liver, 1,607 heart, 384 lung, and 658 pancreas or pancreas/kidney transplants. There have been 2,000 bone marrow transplants annually in recent years.

Estimating the total worldwide experience, we can use data gathered from the Worldwide Transplant Center Directory (using Terasaki’s summary of May 1992). This showed a total of 241,048 kidney, 19,448 heart, 1,600 heart-lung, 1,184 lung, 41,764 bone marrow, 21,324 liver, 2,144 pancreas, and 2,854 kidney-pancreas transplants. While these are the best figures we have, there are gaps because of the failure in the early days to obtain data from Russia, China, and parts of central Europe. Thus, the impressive total endeavor in transplantation over the course of 40 years sought to relieve suffering and prolong life (or both) for about 360,000 patients, the great majority of whom were operated upon in the last 20 years, since 1975.

No matter what the numbers or the underlying science, no matter how arcane the methods or how hidden the secrets of the art, ultimate acceptance of organ removal and transplantation must rest entirely on one criterion: its effectiveness balanced against its risk, the latter in part a function of the extent of damage to the rest of the body by the disease in question. To be acceptable—and ethical—the benefits of a new procedure (once tested and adopted for general use) must far outweigh its risks.

Statistics—risk-benefit analysis—play a key role in the ultimate decision for transplantation whether the question be ethical, financial, or biological. What is the relative likelihood of success? Ironically, in transplantation, statistical values are the basis of ethics: is transplantation in this patient morally acceptable?

And yet statistics can never tell the whole story. For two reasons. First, early in the application of any new technology, whether it be space travel or heart transplantation, you cannot rely on statistics because there is not enough experience to provide a basis for statistical analysis. As new treatments arise, that special problem of insufficient numbers inevitably arrives for each. The numbers are too small. In most of transplantation, we are now emerging from that blurred area of uncertainty and anecdote. Second, statistics may be a false guide because the accumulation of a few

brilliant results in experienced hands, of sick young people now made well, may blind the eye to the likelihood of failure at the extremes of age or in less experienced hands.

There is no way that a central agency of ethical judgments can make rules for what is ethical and acceptable for all patients in all centers. Flexibility and individual judgment must prevail for mny years in any new field. The armchair ethicist devoid of personal experience or current knowledge has no way of assessing the advisability of new procedures. While we must beware the enthusiast who pushes his own operation or his favorite drug too hard, we must equally beware the detached Olympian. The opinion of an inexperienced ethicist may be ethically unacceptable.

Primum non nocere (“first do no harm”) is an ancient maxim of Hippocrates (though not part of the Oath) that is more honored in the breach than in the observance. No one ever took it very seriously, because it is often necessary to do harm so that good may later result.

Consider cesarean section, the most ancient of surgical heroics. With the mother almost dead, the procedure of saving the baby by removing it surgically from the womb was the final stroke of doom for the mother, certainly at the time of Caesar and right up to the middle years of the last century. One of the most dangerous of injuries done in the name of treatment was intentional hemorrhage, or bloodletting. All too often this “venesection,” “bleeding,” or “leeching” failed in its mission; if large in volume, it added to the patient’s burden. When carried to extremes (as it seems to have been in George Washington’s final illness), little benefit accrues and major injury results.

Think of amputation for compound fractures, universal during the Civil War. Or removal of the eye for a small cancer of the retina. Or minor insults such as taking blood from one person to give to another. Radiation treatment, chemotherapy, and surgery all do some harm so that the patient may then heal and return to family and society.

“First do no harm” should be changed to “Sometimes we must

hurt if we wish to heal.” Such a revised motto, enshrined in Latin, might go something like this: Nonnumquam, nocere est renovare—“Sometimes, to hurt is to heal.”

Transplantation epitomizes the fact that we must do injury so that healing may follow. While much of modern medicine and surgery undertakes risks and causes damage in the hope of conferring later benefits, in most instances the risk is to the patient and not to another person. In transplantation, the procedure sometimes places two people at special risk for the benefit of one. In this sense the revised medical motto cited above acquires an added social dimension.

The mounting lists of patients awaiting transplantation in this country far outstrip the rather constant and constrained numbers of organs available and transplants accomplished. The Europeans are about five times more successful than we are in this national effort. Even if we were to increase our success rate in cadaver donor procurement to that level, we would still fail to meet the need.

Some numbers will illustrate the problem.

As of late 1994, a waiting list of almost 4,000 patients is being treated by transplantation of human cadaver livers at a rate of only about 175 to 250 per month. The number of additions to the waiting list is about equal to (or slightly more than) the number of transplants accomplished. With the liver, as with the heart, lethal disease treatable by transplantation waits for no one. Deaths on the waiting list occur at a rate of about 15% a month. Additions to the waiting list occur faster than the death rate. An analogous situation applies to the heart, with 3,000 on the waiting list. In the case of the kidney, the availability of dialysis mollifies the situation because many patients can be carried along on the artificial kidney, but almost 27,000 patients are waiting. While there is no doubt that a newly invigorated public drive for donors and for better public understanding of this need will help save lives, we will never come close to an acceptable rate of donation as based on cadaver resources alone.

These facts make it essential that we succeed in establishing the use of animals as donors, otherwise known as xenotransplantation (xeno-,

by its Greek root, means stranger). It is not difficult to visualize animal farms where genetically pure, disease-free strains would be raised for this purpose. We raise animals and use them for our food, to obtain protein for our own use. Why not, with equivalent ethics, husband their growth to save lives with their organs? While zealots will press legislators to oppose the farming of donor animals, it is an essential next step for the United States. We use the pancreas of animals for insulin, pituitaries for growth hormone, bones for gelatin, and meat for meals. Why not use the heart to pump blood?

Far more of a hurdle than public education is the obstacle posed by the immune disparity between species. There have been six or eight heroic efforts at transplanting animal organs, carried out by teams of sophisticated surgeons and scientists. All have failed. The breakthrough is not yet here. There are portents of good things to come, such as the genetic engineering of molecules that bind or inactivate the harmful slings and arrows of the immune armory. But their clinical uses lie in the future.

It is important to stimulate, support, and encourage young scientists who are as single-minded in their assault on the immune barrier to animal organs as we were in arriving at immunosuppression to transplant within species. Some scientists now living will provide a solution—possibly one whose general shape we cannot even imagine now—for the vexing problem of xenotransplantation. The field of transplantation, cultivated by a few in the 1950s and yielding an immense harvest of welfare to the sick, now obstructed by lack of donors, will then take its next giant step. Not many years left in this century. Maybe the next.