Progress in Transplants

Medical scientists this week reported a major advance toward one of their most cherished goals: the ability to replace diseased or worn-out human organs. Writing in the New England Journal of Medicine, a team of doctors from Harvard Medical School and Peter Bent Brigham Hospital described the first successful attempt to graft a man with a kidney from somebody other than an identical twin. The patient is alive and healthy after 18 months-long enough to suggest that he has a chance of living a near-normal life. Led by Dr. John P. Merrill, the doctors succeeded by subjecting the patient to what they call "heroic measures": an almost killing dose of radiation. They are well aware that this is not the final answer. They want less drastic, probably chemical, means of making grafts "take." The search is already under way, and will be speeded by the preliminary success now reported.

The first serious attempts to transplant organs by modern surgical techniques began in the early 1900s, when pioneering Dr. Charles Claude Guthrie, working at St. Louis' Washington University, created two-headed dogs by grafting. Today most of the surgical techniques have been perfected. Such surgeons as Stanford's Norman E. Shumway Jr. have developed grafting to the point where a dog with an unrelated dog's transplanted heart is up and hopping around within 24 hours, but it dies within three weeks.

The difficulty--and the reason doctors rarely try organ grafts on humans--is biochemical. One of nature's inexorable laws is that the mammalian body (like all animals' from amphibians up) will reject, attack and eventually destroy any invading material from another individualn.* In experiments with dogs, and in the few attempts on humans, this "rejection reaction" has invariably killed the graft. Only in the case of identical twins, who are in effect the same person biochemically, have grafts of skin or organs been completely successful. Since 1954 the Harvard-Brigham team has performed eleven successful kidney transplants between identical twins. But in 17 other cases where they tried to get the same result outside the identical-twin relationship, the transplanted kidney was rejected, and the patient died. That was until John Riteris came along.

Fraternal Grafts. Latvian-born son of an engineer father and a dental surgeon mother, John Riteris, 24, was found to have kidney disease while in the Army, was discharged and went home to Milwaukee. Easily tired, always short of breath, he developed severe high blood pressure, a failing and enormously enlarged heart, "dropsy" and anemia. When his 6-ft. frame was down to 98 Ibs., doctors despaired of saving him.

Then John went to the Brigham with his twin brother Andrew, who hoped to give him one of his healthy kidneys. One look at the twins raised doubts in Dr. Merrill's mind. John is 2 in. taller than Andrew, and less heavily built; tests proved that they were not identical but fraternal, and therefore different persons chemically. John was likely to have the usual rejection reaction. But a graft from Andrew's arm to John's had lasted long enough to be encouraging. Because of this, and hoping that John's uremia would be an advantage, the team decided to go ahead. To help the graft take, they had to knock out John's entire factory (mainly in the bone marrow) for making antibodies and blood cells. The knockout, they hoped, would be temporary.

Within a week, Radiologist James B. Dealy Jr. beamed a total of 450 roentgen into John in two doses; given in one shot it probably would have killed him. Then the team was ready to operate. Surgeon Joseph E. Murray opened John's abdomen and prepared a "bed" on the right side for insertion of a kidney. In an adjacent operating theater, Surgeon-Urologist J. Hartwell Harrison removed Donor Andrew's left kidney. A nurse carried it in a sterile basin to Dr. Murray, who stitched it into John's pelvis, carefully hooking up the ureter, main artery and vein.

How well Andrew's kidney had been grafted was soon evident: John, voided 33 quarts within 36 hours. In another major operation, the doctors removed both his own diseased kidneys. In ten weeks he was discharged and stayed fairly well. But after nine months, John's system started to react against his new kidney, and Dr. Dealy ordered an additional 200 r. of X rays. John's survival in good health since then, the Brigham team suggests, gives reason to hope that nature's primeval reaction against invasion has been sidetracked in this case.

Since the Riteris transplant, Paris surgeons using radiation have successfully duplicated the operation with another set of nonidentical twins, and a second Paris team has transplanted a kidney from a woman of 47 to her 40-year-old brother. The transplant appeared to take, but the patient died of cancer of the liver.

Search for the Ideal. Despite these achievements, Dr. Merrill and his colleagues consider radiation far from the ideal solution. Massive radiation exposes the patient to a higher-than-average risk of death from infection or hemorrhage; there is danger of cataracts or cancer, especially leukemia. What they want is a drug or chemical that will switch off the rejection reaction selectively, enabling the body to accept the transplant but leaving other antibody mechanisms unimpaired.

Some potent chemicals, like nitrogen mustard, suppress the blood-forming and antibody mechanisms, but at the same high price as radiation. Other anti-cancer drugs, which interfere with the metabolism of cells, may be more selective but are less effective. So the search goes on.

It is being pressed with unusual vigor at Stanford University. There, Radiologist Henry S. Kaplan is experimenting in animals with massive doses of cortisone-type steroids, which cut down the body's output of lymphocytes (the most aggressive type of white cells against foreign tissue) but do not knock out most other types of blood cells. "The hope," says Dr. Kaplan, "is that the lymphocyte system, recovering in the presence of the graft, may learn to live with it."

Across the courtyard in Stanford's department of genetics, other researchers are looking for answers at the submicroscopic level, inside the white cells themselves. Dr. Gustav Nossal is exploring the fundamental question of why nature evolved the rejection mechanism in the first place. Likeliest explanation: as a protection against infection by viruses and bacteria. The body actually develops two such defenses. It makes 1) antibodies, which circulate in the blood in the gamma globulin fraction (these can be transferred from person to person, hence the use of gamma globulin in measles and some other viral diseases), and 2) lymphocytes, which migrate rapidly to the site of invasion by foreign material, and launch a counterattack. But how?

The nub of the matter seems to be the nucleus of the lymphocyte cell. This contains chromosomes, the dictators of heredity, which in turn contain big molecules of nucleic acids. One type is ribonucleic acid (RNA), which shows up in tiny particles called ribosomes. They consist of a core of RNA wrapped in a coating of protein. The RNA contains a code of orders that dictate what proteins the body will tolerate.

This mechanism, says Dr. Nossal, may be nothing more than the body's primary defense against abnormal cells that appear in it by mutation. Unchecked, they might become cancer. The healthy body destroys such aberrant cells, probably every day. Dr. Kaplan theorizes that in Hodgkin's disease the abnormal cells treat the body's normal cells as foreign invaders, and in effect turn them out of their own house. A key finding from Manhattan's SloanKettering Institute bridges hitherto far-apart fields: advanced cancer patients, whose rejection mechanism has undergone a serious breakdown, will accept skin grafts not only from unrelated donors, but even from other species, e.g., pigskin.

From Monkeys to Men. At U.C.L.A.'s new medical center in Westwood, a research team headed by Surgeon Franklin L. Ashley has tried to make the ideal chemical switch by taking lymphocytes and breaking them down to get almost pure RNA. The researchers take both lymphocytes and grafts from one group of rats. If the concentrated RNA is injected into other rats before they receive grafts from the same donors, 25% of the animals will take the grafts permanently. The researchers expect to push the percentage higher when they get the best dosage figured out. After working up through monkeys, they hope to find ways of testing the technique in man within a year. This, like similar work in England, raises the inviting possibility of injecting a newborn child with RNA from a relative who can then serve him as a future donor of skin or organs.

In the near future of medicine and surgery, probably no problem is more fundamental than the rejection reaction. By understanding it, doctors may find answers to the riddle of cancer and a host of other ills. A prime example is the kidney inflammation that almost killed John Riteris. There is good reason to suspect, says Dr. Merrill, that his nephritis was the result of an "autoimmune reaction," in which some of the body's cells turn against its own tissues to destroy them. The same may be true of certain thyroid diseases.

In the field of transplants, the great target is the heart. Some victims of atherosclerotic coronary disease (the leading killer in the U.S. today) might be saved if they could receive a transplant of a healthy heart from, say, a traffic accident victim. Infants with certain inborn heart defects would have a chance of survival.

The time may come when doctors will be able to take out all sorts of damaged or imperfect organs and replace them with little more difficulty than changing the carburetor in an automobile.

*An outstanding and little understood exception is blood, which is tolerated for a while (after transfusions) if the main A-B-O and Rh groupings are matched. Another exception: the cornea of the eye, which contains no blood vessels. Occasional exceptions involve skin grafts (especially from mother to child): burn victims usually tolerate them better than healthy people; so do many patients with uremia.

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