A Matter of Life and Death

Great, developments in surgery and tissue-typing make possible the transplantation of most vital organs, but with this ability to prolong life come serious problems. The scientific advances 2nd the ethical questions they raise are here examined by a professor of pathology at U.C.L.A. and a leading authority in the tissue-classification method. Dr. Walford, a sometime poet and gambler, is an adviser to the National Institutes of Health in transplantation and immunology.

by Roy L. Walford, M.D.

MODERN surgeons have the skill to transplant almost any organ from the body of one human being into that of another. Hearts, lungs, livers, pancreases, even extremities can all be transplanted with some degree of success. Kidney transplants have received more attention than other kinds ot tissue grafts in humans simply because of the relative availability of this organ. If a person chooses, he can donate one of his kidneys for transplantation to a sick relative without appreciably shortening his own life-span.

The case of a twenty-two-ycar-old man recently operated on at the University of California Hospital typifies the current status of kidney transplantation in humans. The young man was in advanced renal failure due to infection. For three months he had been kept alive by having his vascular system hooked up twice weekly to an artifical kidney. I his procedure is costly and can be regarded only as temporary treatment.

In the meantime, however, his white blood cells and those of his five brothers and sisters were “typed” in the laboratory of Dr. Paul Terasaki. The typing procedure is similar in concept to ordinary red-blood-cell typing. It permitted the selection of that brother or sister who was most similar to the patient for certain important genetic factors, and whose kidney therefore had the best

chance of surviving in the new environment of his body. All the siblings were willing to donate one of their two kidneys to their brother. Which one to take? The typing indicated that one of the sisters was the best choice.

On the day of surgery, brother and sister were wheeled into adjacent operating rooms. The left kidney of the sister was removed by one operative team, while the second team cut open the lower abdomen of the brother and prepared the graft bed. The sister’s kidney was placed in its new bed, arteries and veins were hooked together, and the ureter was connected to the patient’s bladder. As manifested by secretion of urine, the transplanted kidney began functioning within five minutes. The technical part of the operation was therefore successful.

The patient recovered fully and was alive and well three months later. However, and this is the crux of today’s problem, how long his new kidney would continue to function could not be exactly predicted. A transplanted organ, be it kidney or other tissue, may behave well initially and for a very long time, but at length it is likely to fail. The recipient’s body tends to react to the transplant in about the same way it reacts to bacteria. It creates antibodies and mobilizes cells to destroy what it regards as “foreign” tissue.

Now transplantation of other organs besides the kidney is also quite possible. Let me give several examples. A few years ago six physicists received a near-lethal dose of irradiation in a nuclearreactor accident in Yugoslavia. The bone marrow, where blood is made, is one of the organs most susceptible to irradiation injury. One physicist died in a few days. The five others received bonemarrow transplants under the supervision of Dr. G. Mathé of Paris. One of them died despite treatment. The remaining four survived. The transplanted marrows functioned for at least a period of weeks, sustaining their lives until their own damaged marrows had time to recover. Dr. Mathe has also treated a few leukemia patients with large doses of irradiation, followed by transplantation of healthy bone marrow. He has had temporary remission in a few patients and one possible cure. In the last case, the diseased leukemic marrow was completely wiped out by the irradiation, whereupon the transplanted marrow “took” and has continued to supply blood to the patient. This method of treatment is still experimental and hazardous, but it does illustrate that marrow transplants are feasible in man.

Transplanted hearts in dogs have survived up to eight months and lungs for over three months. Dr. Tom Starzl of Denver has transplanted livers in 116 dogs. Twenty-four survived over fifty days and fifteen for a much longer period. Five transplantations of livers from fresh cadavers have been performed in humans. These livers have functioned for one to three weeks before failing. Dr. Richard Lillehei of Minnesota recently performed the first successful transplantation of a pancreas (again from a cadaver) to a human being. The thirty-twoyear-old severely diabetic patient has required no insulin since the operation.

In an automobile-train accident in Denver in 1965 the left arm of a twcnty-one-month-old girl was completely severed at the shoulder. An alert policeman found the severed arm along the tracks and brought it to the hospital with the child. The arm was re-implanted by surgeons at the University of Colorado and has regained about 80 percent of its function. About twelve successful re-implantations of accidentally severed limbs have been accomplished in the United States and abroad in the past five years. The point here is that if re-implantation of an arm torn off by the cataclysm of a train accident can be successful, then actual transplantation of an extremity under controlled operating room conditions is entirely possible.

The above illustrations (many more could be cited) indicate that from the standpoint of surgical technique alone, transplantation of most human organs is feasible right at the present time. In all, 1200 kidney transplants have been done throughout the world. Of these about 600 have been successful. The incidence of successful grafts augments each year as a result of our increasing ability to control the “rejection” process responsible for most of the failures.

Greater success with kidney transplants — and equivalent success with other organs — is no longer a matter requiring really basic research-. It is a question of the development and application of what biologists already know. A major revolution in medicine and a minor one in moral philosophy are in the offing. How did all this get started, where is it headed, and what does it mean for society?

HISTORICALLY, transplantation biology has not always been very respectable. It has been plagued by false claims for sexual rejuvenation and retardation of the aging process following testicular transplantation from animals to man. John R. Brinkley, a bogus physician who was one of the great quacks of the twentieth century, gained his first great notoriety by boasting — falsely, according to most authorities — that he had successfully transplanted the testes of goats into elderly men, with considerable restoration of their virility. These “goat glands” were supposed to cure almost anything. In 1920 Dr. Serge Voronoff performed the first testicular grafts from ape to man, and in the next two years chalked up 162 such operations. Not permitted to air his extravagant pronouncements at the French Academy of Medicine, he called a press conference and paraded before the reporters an aged man, a billy goat, and a ram, all allegedly “rejuvenated” by transplantation of monkey glands. Voronoff became a world sensation in short order, and cartoons were published depicting grandfathers swinging from chandeliers. The Irish poet William Butler Yeats was, in his maturer years, also the recipient of a monkey-gland graft. Indeed, if the fine eroticism of Yeats’s later verse may be taken as scientific proof, one might argue that in his case the grafted monkey testes actually survived. But we know this could not really have happened. Even when transplanted between individuals of the same species — to say nothing of goat or monkey to man —— the organs in these early days always died after a relatively brief period of functional activity.

So for transplantation biologists the first big question was, Why do transplanted organs function initially and then rather abruptly die? Many theories were concocted to explain this rejection phenomenon, most of them wide of the mark. There was the fifteenth-century story of the slave’s “sympathetic nose.” This nose, cut from a slave and transported to a new recipient, survived only so long as the sinvc himself lived; at his death the nose, now on the other person, promptly fell off.

One of the first real insights into the cause of transplant rejection was a by-product of World War II. Large numbers of soldiers and civilians were badly burned in the London blitzes. One treatment for extensive body burns is to cover the raw surface either with skin from a person who has recently died or with small pieces of skin cut from living volunteers. The transplanted skin heals in place and acts as an effective dressing lor the burn. In medical vernacular, it ‘hakes.” Eventually, however, it dies and sloughs off. It is “rejected.”

In 1941 Peter Medawar, the British scientist who later won the Nobel Prize for his work in transplantation biology, began investigating the cause of this rejection. He found that transplanted skin in rabbits is rejected just as in humans. He then performed the simple but important experiment of taking skin a second time from the original donor rabbit and transplanting it to the rabbit who had already rejected the first skin graft. The second transplant was always rejected much more quickly than the first. Apparently the recipient rabbit had developed some kind of biological memory of the first skin graft, recognized the second graft as being from the same source, and rejected it sooner. Medawar called this the “second-set phenomenon,” and correctly theorized that rejection of organs is an immune reaction quite analogous to the body’s mobilization of cells and manufacture of antibodies to fight off infection. Unless the transplanted organ comes from an identical twin, it is not quite the. same genetically as the tissues of the recipient. His body therefore recognizes it as being “foreign.” Initially it functions because a certain amount of time is required for the body’s immune response to be initiated. Subsequent organs arc rejected even sooner than first organs because biological memory shortens the response time.

By a series of skin-grafting experiments with various mouse strains, scientists next proved that the speed and strength of rejection are precisely determined by the degree of genetic difference between donor and recipient animals. When the mice arc genetically identical, the grafts survive permanently; when they arc slightly different, the grafts may survive for as long as three months; when they arc very different, the grafts arc rejected in ten days.

Finally, work began on the human species. In the 1950s a group of surgeons at Boston’s Peter Bent Brigham Hospital, under the leadership of Dr. Joseph Murray, undertook a series of kidney transplantations in man. Their activities were looked upon rather askance by more conservative biologists. Such undertakings were said to be “premature.” Nevertheless, the surgeons persevered, and as it has turned out, were quite justified in their perseverance. Into individuals with severely damaged kidneys they grafted a healthy kidney obtained either from a living relative or from a fresh cadaver. They promptly found that kidney transplantation in the human — and in fact, any organ transplantation — follows all the laws already thoroughly studied in rabbits and mice. In some hundreds of operations Dr. Murray and his coworkers saved a number of lives, extended the span of many, lost many that would have died anyway, and perfected the methodology of renal grafting.

THE basic knowledge about the “why” of graft rejection in humans is therefore now at hand. The next problem Is, What can we do to avoid the rejection? Two areas of current research promise a solution within the next two to five years: the use of drugs or other agents to suppress the rejection process, and tissue-typing.

Since organ rejection is an immune process, if one could suppress the immune mechanism of the recipient person in just the right way and to the right extent, one might inhibit the rejection reaction. It is, in fact, already possible to do this, albeit imperfectly, with drug therapy.

SURVIVAL OF TRANSPLANTED KIDNEYS IN 431 PATIENTS

Source of Organ

Percent of kidneys functioning

4-6 months

7-12 months

2 years

3 years

Identical twins

89 89 85 85

Brother or sister

61 54 52 52

Mother or father

59 53 32 32

Unrelated donor

17 14 9 —

The table shows how many months or years transplanted kidneys have survived in humans. Many of these people are still alive. It is of course clear that the genetic relations are very important. Nevertheless, most of the prolonged survivals shown could not have been achieved except by means of drug-induced suppression of the immune process. Unfortunately, nearly all drugs potent enough to do the job are also rather toxic to the patient. Much research is therefore under way to discover effective drugs which arc less toxic.

It has been proved that the rejection response is mediated by those white blood cells known as lymphocytes. Most of the immunosuppressive drugs act by inhibiting the metabolism of these cells. Investigators have also recently employed a serum made by injecting human lymphocytes into horses. The horses produce antibodies against the white cells: The horse serum containing these antibodies is then injected into the person receiving an organ graft. One theory holds that this antilymphocytic scrum “erases the immunological memory” of the animal. In any case, very significant prolongation of skin grafts in animals and good results with kidney grafts in human beings have already been obtained by treatment with the serum.

Now, the closer the genetic relation between donor and recipient, the lower the dose of drug or antiserum required for adequate immunosuppression. Scientists are therefore learning how to “type” people, to determine if the organs of one individual arc of the right genetic makeup to be accepted by another. A quantitative idea of just how foreign the tissues of a particular donor will appear to a particular recipient can thus be obtained. We know that one must type human red cells (the major cell component of blood) before blood transfusion, or one may provoke a transfusion reaction, itself a kind of rejection process. Redcell types, however, are on the whole not related to organ compatibility — to the ability of “tissue,” as opposed to blood, to survive in a new body.

Methods for determining tissue “types” in humans have been developed only in the last few years. Instead of the red cells, the white cells are used. The genetic characteristics of these cells are the same as those determining survival of grafted organs. White-cell analysis requires a battery of typing sera, each selected to detect a particular character or antigen. Blood from the person to be typed is drawn, and a pure suspension of his white cells is prepared. These cells are mixed with the test sera and examined under the microscope. If a serum reacts with the white cells, they are killed. The test is fairly simple. However, reliable and specific reagents are still hard to come by. They can be obtained either from persons who have reacted against organ transplantation by production of antibodies, or sometimes from women who have had many children. Pregnancy occasionally leads to production of antibodies against fetal tissues. These are not injurious to the fetus, but they can be used to type human white cells.

Progress in the development of the typing sera, including their large-scale collection and manufacture, has been greatly stimulated by the Collaborative Research Program of the National Institute of Allergy and Infectious Diseases. It will soon be possible to do tissue-typing on a large scale and to select from among available organs the one most suitable genetically for the intended patient. A moderate amount of drug or scrum therapy will then circumvent residual rejection processes. Organ transplantation will become a practical and widespread scientific reality. Indeed, the United States Public Health Service is already setting up large regional tissue-typing and organ transplantation facilities — notably in New York, Los Angeles, Boston, Seattle, and later in other areas throughout the country.

I HAVE referred to the “scientific” reality of organ grafting. There is another form of reality that must also be faced in the future. We shall witness a tremendous demand by sick persons for all kinds of fresh and functional human organs. If present methods of procurement are adhered to, there will simply not be enough organs to go around.

The kidney is a rather special case. Everybody has two of them. Members of the same family are usually willing to donate one kidney to another family member. Even so, procurement is not always easy. Often no family member is available, or those available are not of the right white-cell type. A pretty nincteen-ycar-old girl named Glinda Thar has been waiting nearly a year in a Michigan hospital for the gift of a healthy kidney taken from the body of a deceased person promptly after death. The cadaver kidney must be of the right type, and permission to take it promptly from the body of the deceased has to be arranged for in advance. So Glinda is still waiting.

Even when all the scientific problems arc totally solved, very few persons among the 100,000 dying yearly in the United States from advanced kidney disease will have the chance for a new kidney unless procurement methods are greatly expanded. And what about other organs? Heart failure is a far more frequent killer than kidney disease. Everybody with a malfunctioning heart would like a healthy one; individuals with cirrhotic livers would like new livers; with worn-out lungs, new lungs.

Any program for large-scale organ procurement will run head-on into legal barricades and raise disturbing moral Issues. There arc limited sources from which functional human organs of all kinds might be obtained in sizable numbers, and squeamish persons will shrink from most of these.

The first source is that of terminal patients, those expected to die in a few weeks or months but most of whose organs are still in good condition. A number of fatal diseases strike just one organ, and do not involve other parts of the body. A patient dying of brain hemorrhage may have a perfectly healthy heart, liver, lungs, and kidneys, all suitable for transplantation to other people. Patients dying of cancer (the second major cause of death in the United States) can unfortunately be used as organ donors only in special cases, depending upon the type of cancer. Several cases are already on record where a few cancer cells, having spread to an otherwise healthy kidney, were transplanted along with the kidney, survived, multiplied, and killed the patient.

The white cells of twenty patients dying of diseases other than the spreading types of cancer could be typed. At the same time the cells of, say, twenty individuals with heart, kidney, or other disease, could also be typed. Each of the twenty recipients might thus be compaicd via typing with all twenty donors. This allows twenty times twenty, or 400, different possible donorrecipient combinations. At least some of these combinations will be good matches from the typing standpoint. Physicians could thus select combinations which ensure maximum tissue compatibility.

A small number of such cadaver kidney tiansplants have been performed at the University of California Hospital by Doctors Willard Goodwin and Donald Martin. Donors have so far been limited to patients dying of brain disease who desire to leave their organs for transplantation. All such persons are typed before death. A number of potential recipients are also typed. As soon as the donor is pronounced dead, the surgical team rushes his body to the operating room, where a full-scale surgical procedure is carried out. Both kidneys arc antiseptically removed from the dead body. In the meantime, those two recipients from the waiting list whose white cells gave the best match with the cells of the deceased are called into the hospital. They come in from their homes or wherever they can be found and are taken right to adjacent operating rooms. One kidney from the dead body is put into one recipient, the other kidney into the other. Three separate operating rooms are thus functioning at the same time. In the future when lungs, heart, liver, extremities, and other organs are also transplanted, a donor’s death will lead to a flurry of activity because each organ recipient will require a separate operating room and his own surgical team. The dead man will become diversified to the extent that matching recipients arc at hand.

In many states individuals can will their organs for transplantation, just as is already done with the cornea of the eye or as bodies are donated “for scientific purposes.” The terminal patient source outlined above is therefore feasible now and depends only upon the availability of adequate tissuetyping methods. However, one dilemma does introduce itself if we are limited to this source. If a patient has terminal heart disease, shall we allow him to die in order to obtain his kidneys for a kidney patient, or allow a kidney patient to die to obtain his heart for the heart patient? .Obviously, as many will have to give as receive..

Accident victims might constitute a second major source. Their organs would be kept frozen in liquid nitrogen until required. Large organ banks will need to be established for this purpose in major cities, similar to the blood banks of today but vastly more expensive and complicated. Admittedly, techniques for the freeze-preservation of whole organs are not yet fully developed. Ice crystals form at the point of freezing, the salt concentration in the residual water is markedly increased, and the proteins are denatured. Freezing procedures which avoid the ice-crystallization effect will almost certainly be worked out eventually with further developmental research. Indeed, the carpenter ant of North America has already worked it out. As winter approaches, the ant manufactures and saturates his tissues with the oily compound glycerol. Glycerol happens to be a good freezepreservative. The saturated ant fieezes solid throughout winter. In spring he thaws and comes to life again. New insights into methods for freezepreservation of human organs have come from studies of the carpenter ant.

IN THE widespread organ banks of the future, hearts, lungs, livers, kidneys, and other tissues from accident victims of known white-cell types will be kept frozen until required. Accident victims must be dismembered promptly after death to stock these banks. But legal barriers will hist have to be surmounted, and that, as everyone knows, can be the devil’s own job. As recently as September of 1966, the Massachusetts State Senate defeated a bill that would allow citizens to will their organs at death for transplantation to others. Under present Massachusetts law, permission of the next of kin must be obtained. It is not easy to locate the kin and obtain their written consent within the one or two hours before the needed organs undergo irreversible changes.

The state of Michigan enjoys a more enlightened view than Massachusetts. In November of 1966, the Michigan Kidney Foundation opened its campaign to obtain kidney-donor pledges. The first pledge was signed by Garo Yepremian of the Detroit Lions football team, and reads as follows: “In the hope that it may save the life of another, I hereby consent, at my death, to the immediate removal of my kidneys for the use of the kidney donor program,” This one campaign will eventually save up to 200 lives each year in Michigan. It is hoped that those who have made this worthwhile pledge to save others wall not then die in Massachusetts.

The current status of the Los Angeles Coroner’s Office affords yet another example of the legal asininity that prevails about the disposal of dead bodies. It is technically unlawful for the coroner to remove and retain for indefinite reference even a minute fragment of tissue from an autopsied body. After determination of the cause of death, he is enjoined to return to the body for burial all the little bits of tissue he has used for his examination. This even includes microscopic slide preparations. To remove an entire organ for transplantation within an hour of death without express permission of relatives would be legally unthinkable, no matter how urgent the need of some hopefully waiting patient.

A generalization is in order at this point. Perhaps a third of future humanity will at some time during the course of their lives need an organ transplant. Terminal patients, victims of fatal accidents, condemned criminals who might be persuaded to will their healthy organs to society, and suicides, who number 22,000 a year in the United States, all die anyway. It will be a tragic waste if their organs are not made available to patients whose lives could be prolonged. With certain obvious qualifications, obtaining these organs involves questions of legal and social machinery rather than basic morality. We have not yet run quite full tilt into the moral dilemma.

Another possibility is the sacrifice of mentally defective human beings in order to harvest their organs. There are two categories of such humans. The first consists of tnosc individuals with brain damage secondary to accident or major disease, and of such severity that they can only be regarded as human vegetables. Although their higher brain centers are dead, their other organs may be very healthy. In some cases the brain damage is sufficiently extensive to interfere even with the central nervous system control of the breathing process. These patients require maintenance indefinitely in artificial respirators.

Recently, a Washington University professor of medicine sought help from theologians in a campus meeting to determine the morality of “turning off the respirator” on such hopelessly decerebrated patients so that their organs could be used in transplants. The theologians were unable to make a definite recommendation.

The second category consists of those with congenital mental defects. The actual number of these persons depends on where one draws the line of mental retardation. If organs were taken from all individuals in the intellectually lowest 10 percent of the population, disposing of them before the childbearing age, the procedure would in itself exert evolutionary pressure toward the intellectual betterment of mankind. Now men will not often kill each other for the abstract betterment of their species. Indeed, the science of eugenics has never enjoyed great popular appeal. History suggests, however, that they will consent to slaughter one another for what they regard as their mass individual preferment. Is not war itself such a monster of preferment, justified with all the fanfare of morality and necessity?

It is a good bet that the scientific problems of organ transplantation are nearly solved. The solution is less a matter of basic research than of further development of what is already known. Thousands of organs of all types will be needed for transplantation. This need will raise sociological, legal, and ethical issues. If we are limited to procuring transplants from terminal patients, one can predict a continuing shortage of organs. A strong and steady social pressure will inevitably develop to go elsewhere. One of the things that people like most is just to stay alive, whatever the price. To avoid facing individual death, they will look with quite a new light at the problems involved in obtaining organs from accident victims without permission, at suicide, capital punishment, or euthanasia.

With successful transplantation the rule rather than the exception, the dilemma of organ procurement cannot be avoided. To the extent that we decide not to expand organ sources, individuals who require nonavailable organs will die. Practical reality will alter our moral conceptions of the sanctity of the human body, of human life.

Should scientists therefore pull back from solving the remaining problems of organ transplantation? I hardly think many people will answer yes, but it doesn’t really matter if they do. We shall solve them anyway. In truth we scientists arc averse to throwing real bombs at society, and as a group we have been in the forefront of the ban-the-bomb movement. But thought-bombs, problem-bombs, that’s quite a different matter. These we toss with all the elan of an old-time Russian anarchist.