Charlestown Labs, Massachusetts General Hospital, Boston
I was the new guy. I felt the sweat dripping down my back. I couldn’t figure out why I felt so nervous. I had presented patients on rounds loads of times, and always enjoyed it. But something was different here.
After medical school, I had matched in a surgical residency at the University of Chicago, still thinking about that kidney and wondering what it would take for me to become a transplant surgeon. I had signed on for a five-year residency, but in my second year, I was so exhausted that I wondered if I could keep going. After learning that doing a few years of dedicated research during my residency could enhance my application to a transplant fellowship, I pretty much stumbled into this lab at the MGH (or “Man’s Greatest Hospital,” as they like to call it). The truth is, I had never done any research; I’d been a Russian language and literature major in college. Still, never one to let my own lack of skills stand in my way, I jumped at the opportunity to spend a few years in the premier transplant lab in the United States.
Looking around now, I felt massively unprepared. Present were five attendings, including the chief of cardiac transplant surgery, the chief of transplant surgery, the head of infectious diseases, the head of bone marrow transplant, and of course, the director, David Sachs.
“Okay, who’s next?” David asked. “Josh, why don’t you go?”
I walked over to the chalkboard and reached up to the magnet representing my first patient. “This is Zero-two-seven-eight-five,” I said. “He received a combined heart and kidney transplant. His donor was radiated with one thousand rads. He was matched for class two, and received twelve days of tacrolimus. Kidney function is perfect, but his last biopsy showed some mild rejection.”
I saw David motion me to stop. “Okay, back up here. Remind us again why the donor was irradiated? What is your hypothesis?”
I replied, “Okay, a little background. As you all know, kidney transplants across a class one mismatch, matched for class two, become tolerant after a short course of high-dose tac, but hearts do not. I am trying to prove that kidneys—”
“Stop,” David said. “You don’t prove, you test. You form a hypothesis and you test it with experiments that gather data with controls.”
“Right, sorry. I am trying to test if kidneys have a population of cells that are radiosensitive, that traffic to the thymus and render the heart tolerant.” There, got that out.
Then the head of bone marrow transplant spoke: “So, what can you tell me about the history of radiation in kidney transplantation in man? Have we used it before? Has it ever been used to achieve tolerance?”
I was pretty sure radiation had been used at some point, at least to treat rejection. “I know it was used,” I said, “but I’ll have to read about it more.”
“Yes, good idea.”
After all the patients had been presented, we walked down the hall and entered the ward to do bedside rounds. We started with those patients who had just undergone transplants: hearts, kidneys, and even a thymus and a spleen. We palpated their heartbeats, or looked at their urine output. It was just like the countless rounds I had been on over the last couple of years as a junior resident, with two differences. Multiple senior attendings had joined us, which was unusual, and the patients were of the four-legged variety: they were pigs, and their beds were cages. We could feel their heartbeats, since we had performed heterotopic heart transplants—we transplanted the hearts into their bellies as auxiliary hearts that we could monitor for rejection, without removing their own hearts. These can be palpated by simply putting your hand on the belly of the recipient.
Those three years in Boston opened my eyes to a world I never knew existed. In the pig lab we explored strategies to trick the recipient’s immune system into accepting a transplant without the need for ongoing immunosuppression. That, in a nutshell, is tolerance, the very concept Sir Peter Medawar described in 1953. A tolerant recipient would have normal immune responses to other stimuli, just not to the transplanted graft. We were successful with a number of different strategies in the pig lab, including transplanting bone marrow cells along with the transplanted organ and transplanting the thymus of a donor along with another organ—allowing the donor thymus to reeducate the T cells in the recipient, preventing them from attacking the transplanted organ.
Franklin, Ohio, Nighttime, 1958
The story of nonidentical human transplant began in earnest in the middle of the night in rural Ohio when a surgeon removed an inflamed mess of tissue thinking it was an appendix. It was actually a kidney. Gladys was only thirty-one, a mother of two boys, married to John, a young roofer. Her husband had brought her to the emergency room when she developed pain in her belly. While examining her, the surgeon was impressed with her tenderness; she was clearly infected, and it looked for all the world like appendicitis.
Nowadays, Gladys would have been whisked off to the CT scanner and treated with antibiotics and IV fluids, and maybe everything would have been okay. But this was 1958, and CT scanners were still almost twenty years away. Without a CT scan, the surgeon wouldn’t have known that Gladys had been born with only one kidney, and now she had none. In a few days she would be gone. But the surgeon had seen the news about the successful kidney transplant in Boston. Gladys’s brothers convinced their boss at the Armco Steel Corporation to fly her there on the company plane, and Gladys made her way to the Peter Bent Brigham Hospital, under the care of Joe Murray.
In the years since Murray transplanted the Herrick twins, he was focusing his research on how to extend this phenomenon to the vast majority of patients with renal failure who did not have an identical twin. At the time, there were no immunosuppressive drugs available other than steroids, but there was one treatment that had been known to alter the immune system: radiation. A number of studies had used radiation successfully to transfer cells and cancers between animals, the same finding Alexis Carrel had considered just before the start of World War I but had never followed up on. Investigation into the potential relevance of radiation to the immune system was accelerated in 1945, after atomic bombs were dropped on Hiroshima and Nagasaki. John Merrill himself was a flight surgeon with the 509th Composite Group responsible for deployment of nuclear weapons and had studied the effects of radiation on survivors, many of whom had died from infection because their immune systems had been destroyed. He surmised that radiation might be able to play a role in kidney transplant.
Gladys was to be the first of twelve nonidentical kidney transplants to be performed with total-body irradiation to knock out the immune system and give the donor kidney time to “take,” followed by a bone marrow infusion to restore immune function and prevent infection. The bone marrow was taken from various sources—the surgeons could not always obtain bone marrow from the kidney donor, so sometimes it was from a recipient family member. In the case of Gladys, shortly after her arrival, a kidney became available from a four-year-old patient undergoing the Matson procedure.
Gladys was kept in an operating room throughout her post-op recovery, as it was known she was at high risk for infection and this was the most sterile environment they could provide. After three weeks, the new kidney kicked in, and her dialysis sessions were discontinued. Gladys did well for a month, and both her care team and her family had high hopes. Ultimately, it was the bone marrow, and not the kidney, that failed. She became hopelessly infected and died.
Murray was crushed. He had stayed with Gladys day and night, and the loss devastated him. Yet his next case seemed even more hopeless: a young boy, age twelve. Like Gladys, he was irradiated before receiving donor bone marrow, but he died of infection before he could even get a kidney.
Then came case number three: John Riteris, who received a donor kidney on January 14, 1959. Because of the dramatic failures of the first two cases, with both patients dying from infection, Murray and his team altered their protocol to use sublethal, rather than lethal, irradiation. With this lower dose, and the close relations
hip between donor and recipient, fraternal twin brothers, no bone marrow was used. John Riteris was suffering from Bright’s disease, and was close to death. After the transplant, the kidney kicked in right away, and initially things went well. Then, eleven days after the transplant, he fell ill from infection in his native kidneys. These were removed, and he slowly recovered. Over the ensuing months, John received booster doses of radiation and steroids, and ultimately, he recovered normal function. He lived with this kidney for twenty-nine years, with no immunosuppressive drugs and completely normal kidney function. His death was due to complications from heart surgery.
They had done it! A successful transplant across an immunologic barrier with normal long-term function. Still, despite this exhilarating success, the remaining patients in the trial of twelve all died fairly rapidly, of either rejection or infection.
This was a difficult time for all those involved, from the nurses to the residents to the surgeons. Although Murray sat with his patients day and night, and carried their heavy stories in his heart forever, he never considered stopping. “Some have wondered why we continued in the face of so many failed attempts,” he would write in Surgery of the Soul. “With each failure, we learned a little bit more about preparing the patient, treating rejection, and timing the diagnostic tests. We were all focused on helping patients with end-stage renal disease. I was never discouraged. If we gave up, patients would have no hope at all . . . The identical twin experiences—by then 18 in number—were bright beacons leading the way toward our goal.”
Enter Roy Calne
Oxford, 1958
“The lecture theatre was crammed full of students and graduates, a testimony to Medawar’s celebrity in his field and his enormous power as a lecturer. The man stepped on to the platform, the buzz of chatter stilled, and he held the room spellbound with his brilliant oratory and extraordinary subject matter. Afterwards, a student asked if it was possible to apply the results of Medawar’s research to the treatment of human patients. After a pause, Medawar said, ‘Absolutely not. ’ ”
This was just the kind of talk that would inspire one member of the audience, Roy Calne. He was always drawn to problems people told him he couldn’t solve. When he was a medical student at Guy’s Hospital in London, he took care of a young boy with renal failure. This was 1950, and Calne and his team had nothing to offer the boy, other than a bit of morphine and a bed to die in. This didn’t sit right with Calne. Little did he know at that point, but others were already working to overturn this belief, especially David Hume and his team in Boston. Over the next eight years, Calne continued to train as a surgeon, always thinking about the possibility of transplant, and always frustrated with the negativity and learned helplessness regarding its potential, at least in England.
Then, in 1954, Joseph Murray performed his successful identical twin transplant. That and subsequent work going on in Boston had a major impact on both Calne and his teachers. Once he completed his training, Calne learned to perform kidney transplants in dogs and pigs at the Royal Free Hospital. Radiation treatment as a form of immunosuppression was all the rage, and he secured access to a cobalt irradiator, but quickly realized that radiation was not a realistic strategy for his patients. While searching the literature for some other way to suppress the immune system, he found an article in Nature, written by two hematologists, Robert Schwartz and William Dameshek, that reported the use of the drug 6-Mercaptopurine (6-MP) in rabbits to suppress an immune response to human serum. Calne decided to try it in dogs receiving kidney transplants, and it worked. He published this major finding in The Lancet in 1960, the first report of prolongation of kidney transplant survival in large animals using chemical immunosuppression. The paper gained Calne admission to the world of transplant immunology and an important relationship with Sir Peter Medawar, who insisted he go to Boston to work with the group at the Brigham. Medawar personally wrote a letter to Franny Moore, and shortly thereafter, Calne had a spot in the lab of Joe Murray.
When Calne and his young family disembarked from the Queen Elizabeth in New York City, he took a quick detour to the Burroughs Wellcome laboratories in Tuckahoe, New York. There he met George Hitchings and Trudy Elion, two scientists (and future Nobel Prize winners) who had synthesized 6-MP along with other related chemicals that were developed for the treatment of cancer. These two scientists were impressed with Calne’s work and informed him of some newer agents they thought might be even better. They gave him a few different derivatives of 6-MP to try, and he was on his way.
When Calne arrived at the laboratory of Joe Murray in 1960, he asked Murray if he could experiment with some of the drugs he’d gotten from Hitchings and Elion. Murray, who also was doubting the future of radiation, acquiesced. The two tested roughly twenty different drugs, and settled on B.W. 57-322, later to be called azathioprine, or Imuran, as the best agent. As Calne recalls, “The high point of these experiments was the presentation at the Brigham of the first canine patient to survive a kidney graft, treated with azathioprine, with normal kidney function at six months. After the case history had been read, the door was opened and my dog Lollipop pranced into the crowded auditorium, making friends with the distinguished professors in the front row.” These victories in the lab, in addition to the intermittent injection of successes from identical twins, encouraged those involved in transplantation to continue moving forward. As Medawar remembered, “The whole period was a golden age of immunology, an age abounding in synthetic discoveries all over the world, a time we all thought it was good to be alive. We, who were working on these problems, all knew each other and met as often as we could to exchange ideas and hot news from the laboratory.” After all these successes in the lab, the decision was made to move azathioprine into the clinic. Sadly, this was precisely when Calne was to return to England. He was disappointed to go but knew his path would continue in London.
After three consecutive failures with azathioprine, Murray transplanted Mel Doucette on April 5, 1962. A twenty-three-year-old accountant, Doucette was undergoing dialysis at the Brigham when a thirty-year-old man died on the operating table during heart surgery, and his kidneys became available. After the transplant, Doucette suffered a couple of rejection episodes, which were reversed with steroid pulses. Doucette’s new kidney lasted twenty-one months, at which point he got a second transplant, which lasted an additional six months, until he died from hepatitis, which he likely contracted from his transplants or associated blood transfusions. This was years before there would be testing for the hepatitis virus. Given that this was 1962, that the kidney was from a deceased donor, and no radiation was used, this outcome was considered a massive success. According to Murray, “In just eight years, beginning with the day the Herrick twins walked through the doors of the Brigham in 1954, we had reached our goal . . . the successful transplantation of an organ from a dead donor—was now firmly in our grasp.”
This was just the beginning for kidney transplantation. With a strategy finally in place to prevent rejection, chemical immunosuppression, surgeons now started the hard work of making kidney transplantation, from both living and deceased donors, a clinical reality. The number of centers devoted to transplantation began to grow, and those clinicians and scientists interested in it began meeting and vigorously presenting results and debating strategies. In addition to the Brigham, and Roy Calne in London, a few others joined the fray.
When he arrived at the University of Colorado in late 1961, Thomas Starzl, who is best known for his contributions to liver transplant, jumped wholeheartedly into the kidney transplant business. In his standard fashion, Starzl attacked kidney transplant both in the lab and clinically, using living and deceased donors. By 1963, he had presented and published his findings from more than thirty kidney transplants, obtaining better results than anyone had yet shown. His main contribution was in increasing the doses of steroids given in combination with azathioprine and also convincingly showing an ability to reverse rejection crises with high doses of stero
id pulses.
By the mid-1960s there were more than twenty-five programs doing kidney transplants, and more and more long-term survivors. At the same time, there were still many failures. Late into the 1970s, the one-year survival rate for kidney transplant was no better than 50 percent. Literally half the patients transplanted would lose their grafts in the first year, many of them dying. If the 1960s was the decade of excitement in transplant, when it was finally shown that it could be done, the 1970s exposed the depressing reality that failure was as common as success.
The Penicillin of Transplantation
One drug changed everything. In 1958 the leaders of the Swiss drug company Sandoz (later, part of Novartis) set up a program by which employees traveling for business or pleasure collected soil samples to be screened for fungal metabolites that might have immunosuppressive or anticancer properties. Each week, twenty samples were tested. On January 31, 1972, sample 24-556, which had been collected by an employee vacationing in Norway, showed remarkable immunosuppressive abilities. Over the following year, the sample (named cyclosporine A, due to its cyclical structure and its derivation from fungal spores) was purified and studied. Jean-François Borel and Hartmann Stähelin at Sandoz conducted extensive testing on it, and confirmed its impressive immunosuppressive properties.
Calne, who had spent the last twenty years searching for new compounds that could prevent graft rejection, attended a talk in 1977 with immunologist David White at the British Society for Immunology. There, Borel presented the findings on cyclosporine A. Calne and White were most impressed, and they managed to obtain a small amount of the drug to conduct some initial experiments in rat heart transplants. The results were too good to be true. After repeating the tests with similar results, Calne contacted Sandoz to obtain larger doses of cyclosporine A to test in large animals. He was told that Sandoz had abandoned its interest in the drug, but he could have what was left lying around the lab. With it, Calne performed kidney grafts in dogs and heterotopic heart grafts in pigs—again, with remarkable results. He was ready to move on to humans.
How Death Becomes Life Page 9
