Soon, he was sated with knowledge of the human body’s rejection or immunity mechanism. This was the reticulo-endothelial system. It consisted of antibodies and powerful white cells known as lymphocytes in the blood that protected man by killing off bacteria, viruses, or any strange or foreign cells that entered the body. This rejection mechanism was everyman’s friend, but Garrett came to regard it as his personal enemy. For if the rejection mechanism warded off diseased cells, it also murdered healthy new cells, since it could not tell the difference. This, then, was the difficulty. If a man were dying for want of new kidneys, or small intestines, or lungs, or heart, you could not transplant a fresh vital organ for the old, because the rejection mechanism, antagonistic to foreign tissue, would murder it-and its host.
The rejection mechanism became Garrett’s target. And what confirmed his aim were the exceptions to the rule. Toiling side by side with his colleagues in the Medical Centre, he found that transplants of pieces of artery, sections of bone, the cornea of the eye were long-practised grafts that had nothing to do with the rejection mechanism. A new cornea in place of an old one survived because antibodies and assaulting white cells could not get at it. As to transplanted blood vessels and bones, they did not need to survive for they were merely scaffolding across which normal host tissue could grow.
What interested Garrett even more was another exception to the rejection mechanism. There had been case after case of successful organ transplantation in identical twins. Chemically, identical twins were the same person. They emerged from the same fertilized egg. Their tissues were not foreign to each other. A kidney from one identical twin could be grafted into his ailing brother, and it would endure, because the rejection mechanism would not recognize it and would leave it alone. But the moment that the same transplantation was tried on non-identical human beings, the kidney, or any other organ, would die.
During 1958, in Boston, a risky non-identical transplantation had been desperately attempted. A young woman from Ohio had lost her only kidney and was dying. A courageous team of physicians had taken the healthy kidney of a four-year-old and grafted it into this young woman. To thwart the rejection mechanism, the physicians had given the young woman massive treatments of X-rays. The young woman lived twenty-eight days. The rejection mechanism had, indeed, been neutralized, but the excessive radiation was fatal.
For a brief period, Garrett was discouraged. Then came a major breakthrough. Sir Macfarlane Burnet, of Australia, and Dr. Peter B. Medawar, of England, proved that the rejection mechanism in one human being could be taught to accept tissue transplants from another, under certain circumstances. Experiments with rodents showed that if a mouse embryo were injected with cells from a non-identical donor mouse, then later, when the embryo was an adult, it could accept skin grafts from the same donor without rejection. For this, Burnet and Medawar won the Nobel Prize in 1960. And, at once, John Garrett, along with hundreds of others in his field, was encouraged to believe that soon it might be possible to make a homograft of legs, kidneys, lungs, and hearts.
In that optimistic period, Dr. Robert A. Good, of the University of Minnesota, was saying, ‘Though much more basic research is needed, the first successful organ graft between non-identical human beings could conceivably, with luck, take place tomorrow.’ And Garrett, one midnight in bed beside Saralee, was telling her, ‘I believe it, I absolutely believe it-and I’m going to be the one to do it-with a living heart.’
The days spun ceaselessly past, and he had no knowledge of date or week or month. It was as if he were on a perpetual hamster’s wheel. He isolated himself from his colleagues, because he had no time for small talk or relaxation. He went ahead alone against the enemy, trying to find a weapon to overcome the immunological barrier, the rejection mechanism. He experimented with massive X-ray treatments, with steroids, with nitrogen mustards. Each led to a dead end. No matter how slight or drastic the modifications that he made, these weapons, while they did indeed neutralize the rejection mechanism, also destroyed white cell production, stripped the body of immunity to disease, killed in other ways what he was trying, after all, to save. The problem remained as large as ever: to discover a treatment or serum that was selective, that would not destroy all reactive or immunity mechanisms, that would neutralize whatever it was that rejected a foreign graft, and leave unharmed that which protected the body against disease.
Once, depressed by the impossible maze, Garrett tried to find a path around it. In that time, he fancied that he could simply ignore the rejection mechanism by circumventing it, by inventing a compact artificial heart of plastic material, that could be grafted inside the chest cavity and that would be accepted because it would be non-reactive. For months, the idea excited him. A plastic heart replacing a failing or damaged natural heart inside the human body would give its host-literally-a new lease on life.
Methodically, he studied all the mechanical hearts then in existence. These ranged from the heart pump and oxygenator created by Dr. Clarence Dennis in 1951, to a two-chamber pump run by batteries (it had kept a dog alive nine hours) produced by a team at the University of Illinois. Garrett saw that these mechanical heart-lung devices all had one factor in common-they were used outside the patient’s body to keep the patient alive during cardiac surgery. What Garrett envisioned was such a device inside the body-the natural heart removed, the machine heart substituted-located in exactly the same place: orthotropous transplantation, with an external power pack. But there were question marks here, too, not the least being how to keep the plastic bag, between the two lungs, contracting and relaxing without failure. It might be resolved in the future, Garrett decided, but he preferred to grapple with the present, the probable.
Unhappily, he returned to his maze. He must find his way on the battlefield where the familiar enemy, now so well known to him, was the rejection mechanism that barred his transplantation of a living heart, either animal or human. He abandoned the radiation treatments, the nitrogen mustards, and plunged into unknown byways. And then, it happened, came to him, as simply and undramatically as waking or walking or laughter.
It was late morning. He had been toiling over his laboratory specimens-the mice, dogs, calves-checking, noting, noting again, modifying, when he discovered the new substance that apparently-yes, it was clear, plainly evident-neutralized the rejection mechanism but did not, at the same time, destroy all immunity. For a week, Saralee and the children knew nothing of his existence except on the telephone, and after that week he was almost certain. He had a serum-the serum-and with Lincolnian simplicity and straightforwardness he christened it Anti-reactive Substance S.
Once he had his serum, and having proved it out on lower mammalian creatures, not yet on man, he gave parallel devotion to surgical techniques of organ grafts. He considered all aspects of the homograft-an organ moved from one human into another human-and vetoed it as too formidable. More logical, more probable, and his skittering mice and tractable dogs and climbing simians supported him, was the heterograft-the transplantation of an animal heart into a living man. Exulting months followed, and by then he had settled upon the heart of a calf, a calf weighing what a potential patient might weigh, as the likeliest possibility for success.
Twice, he grafted calves’ hearts into dogs, and one dog died and one lived for a while. More modifications of the serum and the surgical technique, and on a black and forbidding winter’s night in Pasadena-he had already telephoned Saralee that he would not be home for dinner, and that she need not wait up for him-he prepared for his third transplantation of the heart of a calf into the chest cavity of a huge dog. He had assistance now, and by eight o’clock all was in readiness. The donor calf’s heart was under perfusion and cooling. The host dog had been treated with improved Anti-reactive Substance S, and was already hooked to the heart-lung bypass machine. What remained was the crucial surgery. But Garrett never accomplished it, not on the dog, at least.