Heart transplantation was moving ahead slowly everywhere but at Stanford, and was halted altogether in England. I decided to review the results of the Stanford program and write them up. The paper, “Cardiac Transplantation in 150 Patients at Stanford University,” reviewed all the transplants that had been carried out at Stanford between January 1968 and August 1978. This was a majority of all the heart transplants done throughout the world to that point. I submitted it to the British Medical Journal, which published it in January of 1979, along with an editorial noting that Stanford’s one-year survival rate had now reached 70 percent, comparable to the success rate for kidney transplants. The journal’s editors also pointed to the “massive research” effort at Stanford that explained our success. If heart transplants were to be restarted in England, they wrote, it should be in a cardiac center that followed the Stanford model.
As I later learned, one person in England who read the article with interest was a surgeon named Terence English. He’s now Sir Terence, and a close friend. English had done heart surgery at the Brompton before I went there and had also visited Stanford to study our transplant procedures. He thought it was time for England to get back in the game. The National Health Service had refused to allow heart transplants for a decade, but English had a private patient and private money to go ahead with one. Then, just one day after my journal article appeared, and probably because of it, English got a call from Addenbrooke’s Hospital in Cambridge with a donor.
English knew that any attempt to break the moratorium would attract attention, and so it had to be a success. His patient was a redo—someone who had already had heart surgery. That’s not uncommon. But it makes it difficult to open the chest because of all the scar tissue. Often, the heart is stuck to the sternum. So if you just saw through the sternum like we usually do, you risk cutting a hole in the heart before you can get the patient on the heart-lung machine.
English wanted to ensure that the donor heart was good, so he went to collect it while his senior registrar opened up the recipient. The patient arrested. They did CPR and managed to resuscitate him but had no idea if he was brain-dead. The registrar phoned English and asked what to do. I’ve often wondered what I would have done. What English decided was that the transplant was this patient’s only chance at life and they were going to go ahead.
The man never woke up, and they pulled the plug ten days later.
The press coverage was brutal. English never told anybody what happened, never made an excuse. Instead, he did another one. And this one worked. And then he did another and another. Heart transplantation in England was back.
I’ve always thought that if something happened to me, if I needed heart surgery, I’d want a surgeon like English. Someone who put the patient ahead of himself.
I’d completed six months on the clinical service. Shumway suggested I spend some time in the lab. The animal laboratory was on the same floor as the offices and the outpatient department. It was cramped, about eight paces wide and perhaps twenty paces long. Windows on one side opened out to the quadrangle. This was the room in which Shumway and Lower and their technicians had figured out how to make human heart transplants possible, mostly through their work in dogs.
My coworker in the lab was Nelson Burton, who was also a cardiac surgical resident. We had to store all of the lab equipment in the room overnight, so the first thing we did every day at six a.m. was move things into the corridor so we had space to work. There were two operating tables and an old heart-lung machine that had been salvaged from the OR after it was no longer used on patients. The machine had an early type of oxygenator that only worked for short periods. It was heavy and took a long time to clean after a procedure. Sometimes we’d spend the entire day cleaning and sterilizing equipment. But everything was reusable, so it was a cheap setup for experimentation.
I continued to investigate why atherosclerosis occurred in blood vessels after heart transplantation. I worked in rats, as I had done at St. Mary’s—until I managed to land a grant from a drug company to buy monkeys. They were expensive and harder to care for than rats, but using primates was important. It was the best way to be sure that what we were doing in the laboratory would be applicable to humans. After more than two decades of research in dogs, monkeys arrived at the Stanford lab in July 1978.
Shumway’s newest faculty member, Bruce Reitz, was in charge of the lab. He had finished his chief resident year in 1976 and subsequently done two additional years of general surgery to become board certified. Since Bruce was on the full-time faculty and had regular clinical duties, Burton and I did the day-to-day work. We had two technicians, Jesse and Grant, who were adept at putting in intravenous lines, giving anesthesia, and putting the animals on ventilators. They were excellent scrub nurses, too. It was a good team.
When we started the work in monkeys, I thought that we should be able to cut a donor heart out in such a way that we could replace it—swapping hearts between two monkeys. This meant we didn’t have to sacrifice the donor monkey, and would have two subjects to study in one experiment. The problem with that was that we only had one heart-lung machine. We decided to see if we could do a heart swap using only hypothermia, the technique that Lewis had used in Jacqueline Johnson twenty-five years earlier.
The monkeys were anesthetized, placed on ventilators, and then laid in blue plastic infant bathtubs. We packed them in ice and monitored their temperatures and the EKGs. As they gradually cooled, the heart rate slowed. We found that if they were adequately anesthetized and the cooling was carried out slowly, they could be cooled to approximately 26 degrees Celsius before the heart fibrillated. At that point we took them out of the baths, put them on the operating tables, and opened them up. Burton operated on one monkey, and I did the other. We switched hearts. When the new hearts had been sewn into place, we warmed the monkeys up by pouring warm saline into their chests and placing them on heating blankets while doing cardiac massage. Soon the new hearts began to beat. We were able to do the operations in less than an hour. The monkeys recovered normally.
In the laboratory doing heart transplantation in monkeys in 1978. Nelson Burton (left) is being assisted by Jesse Gutierrez. Grant Hoyt is giving anesthesia. I am taking the picture, about to transplant the monkey on the right.
Charlie Bieber, a pathologist and immunologist who worked for Shumway in another laboratory next door, made the antithymocyte globulin (ATG) that we used in the transplant patients. Antibodies and lymphocytes are made in the bone marrow and thymus, a gland in the front of the neck. The gland is large in babies and slowly disappears with age. Whenever we operated on babies, we had to remove most of the thymus to gain access to the heart. We called Charlie to the operating room, where he would take the gland back to the lab, grind it up, and inject it into rabbits. After about ten days, the rabbits had made antibodies to the human lymphocytes—proteins that would in essence reject the body’s own rejection response. The rabbits’ blood would be removed, the red cells taken out, and the remaining serum was ATG. It was injected into the thigh muscles of our heart transplant patients. This was excruciating because of the inflammatory reaction it caused, and the patients would hobble about for weeks. But it worked. The rabbit antibodies attacked the human cells that were trying to reject the transplanted heart. This close collaboration between the lab and the clinical practice was what enabled Stanford to perform more heart transplants than the rest of the world combined.
Although heart transplantation can extend a life by years or even decades, the patient is trading a lethal condition for a chronic one, because they have to take drugs to suppress their immune system for as long as they live. These drugs have side effects and also inhibit the body’s ability to fend off infections. As good as the current immunosuppression treatment was, we knew it had to get better.
By October 1978, Nelson and I had perfected our technique of heart transplantation in monkeys using hypothermia. Almost all the animals survived. We were testing immunosuppressive regim
ens to stop rejection and improve survival. That month, Charlie Bieber showed me a copy of an article in the journal Immunology, describing a new immunosuppressive drug. Jean Borel, the author, worked for a drug company called Sandoz in Switzerland. The scientists there had been analyzing samples of earth from various places to see if they could come up with useful new antibiotics. Borel, looking at a sample from a highland plateau in Norway, found a fungus with a new structure, from which he extracted a chemical they called cyclosporin A. Later on it would be called simply cyclosporin. It was a white powder. Its antibiotic properties turned out to be nonexistent—in fact, it had the opposite effect. It inhibited the immune response. I was intrigued and talked with Charlie about whether cyclosporin might be useful in transplant patients. A group in England working mainly on liver and kidney transplants began testing cyclosporin and by the end of the year had promising results that were published in the Lancet, a well-known British medical journal. They’d overcome a challenge in using cyclosporin: it doesn’t dissolve in water. This made it hard to work with in the lab, as it is difficult to make animals swallow a precise dose of a powder. But a young Greek researcher named Alkis Kostakis, who was visiting in England, had discovered that cyclosporin is fat soluble. You can dissolve it in olive oil.
Though Kostakis’s name has been lost to history, he was responsible for a major step forward in heart transplantation. After reading the Lancet article, Charlie and I knew we had to get our hands on some cyclosporin. I wrote to Borel. He offered to give us a sample if someone would come to Switzerland to get it.
Phil Oyer was going to Europe toward the end of 1978. He came back with about a pound of cyclosporin in a large brown bottle, probably the first sample of cyclosporin to enter the United States. Phil kept the bottle in a drawer in his desk in his office. We had to ask him for some whenever we needed it in the laboratory. We dissolved the cyclosporin in olive oil and gave it to the animals that had had heart transplants. We started with rats, which could take the drug orally.
The results were immediately clear. Cyclosporin worked better than any other immunosuppressive drug, or any of the combinations of drugs, I had tested. I wrote up the findings of our experiments and submitted the paper to be presented at the American College of Surgeons meeting. It was accepted, and I gave the paper at the annual meeting in Chicago the next year. The proceedings of the meeting were published in a journal called Surgical Forum in 1979. That paper and one from Boston studying lymphocytes were the first two reports of the use of cyclosporin in the American literature.
We lost no time in studying cyclosporin in our monkeys. Monkeys had to take the drug by injection. Again, the results were impressive. Cyclosporin was more effective than anything we had tried before. The monkeys lived and seemed normal. I wrote up these results, which were published in the Lancet. This was the first report of cyclosporin used in heart transplants in primates.
The first primates in the world to have been treated with cyclosporin after heart transplantation. The monkey on the left gave his heart to the monkey on the right, and vice-versa.
I felt that years of hard work, going back to my days as a student in Ken Porter’s lab at St. Mary’s, had paid off. What was most exciting about cyclosporin was that it did not impede the healing of tissues the way other drugs—especially steroids—did.
At the same time, clinical work continued to advance. Shumway was keen on revisiting the possibility of lung transplantation, which had been a clinical failure. The first lung transplant was done in 1963 by James Hardy in Mississippi. By 1978, my first year at Stanford, a total of thirty-eight lung transplants had been attempted in the world, with no long-term success. Only nine of the thirty-eight patients had lived for more than two weeks, and only one patient had been discharged alive from the hospital. He died within the year.
The main challenge in lung transplantation is that the airway does not have a rich blood supply, which is vital for healing. Most patients had died because the airway sutures broke down. Immunosuppressive drugs also interfered with the cell division that is essential to healing. Experimental work on lung transplantation in dogs had not been helpful because dogs have a different breathing mechanism from primates. After lung transplantation, dogs try to keep breathing in without exhaling. None survived for long. One glimmer of hope was an experiment in which Shumway and Dick Lower had transplanted the heart and both lungs in dogs. One of them survived briefly, and the procedure was written up in the journal Surgery in 1961.
That result had helped to convince Shumway that lung transplants by themselves would not work. He reasoned that if lung transplants failed because the sutures keeping the airway together didn’t hold, then a better approach was to, as he put it, “Do a transplant of the whole thing—the heart and lungs attached, the heart-and-lung block.” And because diseased hearts and lungs tend to co-occur in patients, being able to fix both at the same time made sense.
This approach would have two advantages. The heart has collateral arteries that also supply the airway where the suture line would be. Doing a heart-and-lung transplant would preserve much of the blood supply to the airway, which would help healing and prevent the breakdown of the suture line. In addition, the trachea, the main airway supplying both lungs, has a better blood supply than the bronchi, the smaller airways that branch off the trachea, which you had to sew together when you did a single-lung transplant. A side benefit was that rejection of the heart, which we had become good at monitoring, would signal rejection in the lungs as well.
Work on heart-and-lung transplants in the Stanford lab commenced at the end of 1978, just as I was due to return to the Brompton. Shumway approached me in the corridor one day. He never sent for anybody. He always came to find you. He wanted to know what I was doing the next year. I told him I was going back to London. He asked me what I would be doing there, and I told him I would be senior registrar at the Brompton and National Heart Hospitals—a position most people would have regarded as vastly beyond my junior status at Stanford.
“Why don’t you stay another year?” Shumway asked.
I told him that I would love to.
When I phoned Paneth, he said that they could get along without me. He would appoint someone to take my place for another year and said he would ask the British Heart Foundation to extend my grant for a year. They did.
The next twelve months were exciting. Bruce Reitz took the lead on heart-and-lung transplants in the monkeys, using our hypothermia method. At first we simply removed the heart and lungs and then put them back in. We found that monkeys did not experience the same breathing problems as dogs. And there was no problem with the sutures where we had connected the airways. The airways healed well in all the monkeys with a simple suture line of polypropylene, a type of nylon. We used the nylon sutures instead of the usual absorbable sutures so they could stay in for a long time under immunosuppression. The monkeys recovered well and breathed normally. These results seemed to bode well for heart-lung transplantation in humans.
In the beginning, we used no immunosuppression to see whether the heart or the lungs would reject first. I was in the lab one Saturday night and noticed that our first monkey was having breathing difficulties. This was probably the first observation of lung rejection in a primate. I called Bruce at home, and he came in. The breathing got worse over the next few hours. This proved to be a pattern. Lung rejection was manifested by shortness of breath and came before rejection of the heart. This suggested that maybe heart rejections wouldn’t be an early warning for lung rejection after all.
When we then treated the animals with cyclosporin, they did well. But cyclosporin was not a magic bullet. It had to be combined with other drugs to get the best results. We tried cyclosporin in combination with the drugs we were using in humans—Imuran, steroids, and ATG—and got long-term survivors. We called the first monkey to live for months after surgery Mom, because one of my coworkers said she looked like his mother-in-law. Mom was a milestone. We were convinced that
successful heart-and-lung transplants in humans were just a matter of time.
We continued to refine the immunosuppression regimen in early 1979. Some of the monkeys developed lymphomas, a type of cancer. This indicated that their immune systems were being suppressed too much. We deleted steroids from our drug cocktail and also cut back on ATG. This worked better. I was now doing what I had always wanted to do and felt, finally, that I was playing an important part in advancing the science of organ transplantation.
At the end of a year in the lab, Shumway approached me again.
“What are you going to do next year?” he asked casually.
I told him I was going back to be senior registrar at the Brompton and National Chest Hospitals.
“Why don’t you stay another year?” he said.
I called Paneth, who was not happy. But he said he would support me in whatever I wanted to do. He arranged for my financial support from the British Heart Foundation to continue. In July 1979, I became Shumway’s chief resident, running his service. I was also the chief resident in charge of the heart transplant program. Everything I’d given up to come to Stanford had been regained—and then some.
CHAPTER SIXTEEN
BLOOD AND AIR
At Stanford, the chief resident did all the surgery but was always accompanied by a senior surgeon, which was different from my experience in England. I had been on the clinical service only a few days when I did my first heart transplant, on July 4, 1979. Ed Stinson was the attending on call, and he came in from a Fourth of July party to help me. It was a transformative experience. I took out the swollen, dying heart and dropped it twitching into a bucket. The patient was on bypass. I looked into the empty chest, at a human being without a heart, kept alive by a machine. Nothing I’d ever done matched that moment.
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