Boston, 1951–1954
David Hume’s series of Boston transplants, which he wrote up in The Journal of Clinical Investigation, remains a fascinating and comprehensive summary of the experience of transplanting kidneys in humans without immunosuppression. Of the nine cases he was involved with in a three-year period, eight of the kidneys were placed in the right thigh of the recipient, as Hume thought this would be less traumatic for these sick patients, allowing monitoring of the kidney and ureter, and early identification and removal of a dying kidney. Hume knew these kidneys would not work long term; there was enough experience then in large-animal transplant and a smattering in humans that predicted this.
One major challenge was where to get donor kidneys. Given how new the practice of organ transplantation was, the general public was not familiar with the concept or even the possibility of donation. Hume had to find a source of healthy kidneys, and time their procurement so he would have recipients available. Then he learned of a procedure that had been developed by a surgeon on staff at the Brigham by the name of Donald Matson, whose specialty was the treatment of patients with hydrocephalus (or excessive accumulation of spinal fluid in the brain, causing swelling and pressure). Matson had developed a procedure whereby one end of a tube was placed into the ventricle in the brain and the other end threaded into the divided ureter, allowing the fluid to drain into the bladder. Matson, Hume learned, would remove and discard the kidney that used to be connected to the ureter. These discarded kidneys would serve as a perfect source for kidney transplants—until the Matson procedure was ultimately abandoned.
Five of the nine cases Hume performed were deemed failures. With the other four, however, he enjoyed some moderate success, and gleaned valuable information about kidney transplantation in man. First, he recognized that with deceased donors, the kidneys go through a period of anuria, failing to make urine for between eight and a half and nineteen days. The fact that Hume continued to follow these kidneys in the recipients, rather than remove them as failures, is critical and impressive. This period of anuria is something we still deal with today—we call it delayed graft function (DGF), or a “sleeper kidney,” and about 30 percent of deceased-donor kidneys experience this, even with our improved preservation solution.
Hume documented the pathologic response of kidney rejection, and even identified a case of recurrent kidney disease in a transplant. He showed that the kidneys do seem to last longer in humans than had been the experience in animals. He showed the importance of blood group matching (as a couple of the kidneys he transplanted that didn’t work were not matched). Although all his kidneys eventually failed and the patients died, there was one who stood out.
Case Number 9, as Hume called him, was a twenty-six-year-old South American doctor afflicted with Bright’s disease, or chronic nephritis. A year before his transplant he had developed high blood pressure and leg swelling, and months before it his blood pressure worsened and was accompanied by headaches with visual changes. By the time he got to the Brigham, he had gross (i.e., visible) blood in his urine; was pale, anemic, and swollen; and was vomiting. A donor kidney became available from a young woman who had died on the operating table undergoing surgery for a narrow aortic valve.
As with the other eight transplants Hume performed, the left kidney was placed in the patient’s thigh. But for this kidney, Hume came up with the idea of wrapping it in a sterile polyethylene bag and bringing the artery, vein, and ureter out through small holes in the bag. Why? Apparently, Hume thought that perhaps the factors in the serum and blood that had led to rejection of the other eight kidneys would not be able to permeate this bag. Once the kidney was perfused, the open end of the bag was sealed with heat from a cautery device. Skin grafts were needed to cover the wound despite the muscle and skin flaps Hume had constructed to do the job. The surgery itself went well, but the postoperative period was quite rocky. The patient bled extensively, receiving seven units of blood over eight days. His leg became massively swollen, and he was finally returned to the OR on that eighth day, in a “precarious state.” His kidney transplant had made no urine, although his native kidneys did produce some. Massive amounts of blood were evacuated from his thigh, but the kidney looked healthy and perfused.
The kidney made no urine for eleven days, but then, on the twelfth day, it made about five milliliters. The urine output slowly picked up, and by the thirty-seventh day it was a whole liter. Thereafter, the kidney continued to produce between one and three liters of urine a day for six months, a normal, life-sustaining amount. On the eighty-first day after the transplant, the patient was discharged and went home feeling better than he had in years. He would come back to the hospital every two to three weeks for follow-up. Sadly, after almost six months, he became ill when he happened to be back at the Brigham for a follow-up visit. It is not entirely clear whether he died from infection, pulmonary emboli, or possibly chronic rejection of his graft. While Hume writes about this experience in the scientific paper without any real reflection on the emotions this setback might have prompted, Franny Moore gives a more explicit description of the effects it had on all those involved in the young doctor’s care:
Five months later he returned, his kidney now failing. He knew that he was going to die, but like so many patients who have had some but not complete success with surgery at the frontier of knowledge, he was grateful for the 6 months of life he had been given. The magnificent human spirit of such patients cannot fail to impress everybody who sees them. He had a sort of calm assurance that the experience in his case would help others. Little did he (or we) know how right he was and how soon his prediction would be borne out . . . Our experience with this patient as much as any other single factor led to the successful initiation of kidney transplantation a little more than a year after his death.
Despite the ultimate failure of all the transplants in Hume’s series, the one relative success left those involved with the belief that things would work out. In what would be a fateful episode that would forever change the field, Hume was called to active service in the navy, at the tail end of the Korean conflict. The timing couldn’t have been worse for him. With his imminent departure, Franny Moore turned to Joseph Murray to take over the clinical transplant program.
The “Hump,” Kurmitola, India, December 23, 1944
Charles Woods was preparing to fly the Hump, the name given to the route over the Himalayas that World War II pilots took to supply Chinese troops under the command of Chiang Kai-shek and American troops in China fighting the Japanese. He had made the flight numerous times before December 23, but this time he was training another pilot to see if he was ready to fly on his own. It turns out he wasn’t, which Woods realized as the plane was accelerating along the runway in preparation for takeoff. Before the plane was able to leave the ground, the novice pilot abruptly put on the brakes. With the plane careening uncontrollably toward the end of the runway, Woods took over the stick and wrestled with it—to no avail. The plane fishtailed off the end and came to a stop after an encounter with a tree. Woods knew the plane was loaded with twenty-eight thousand pounds of fuel and figured it was going to explode.
I felt a first blast of heat, then my nerve endings must have seared because I lost all feeling. I knew what I had to do and I did it. I stayed calm and kept my eyes shut tight, hoping to protect them. I felt for the small Plexiglas window beside me, opened it and twisted through and slid down the fuselage. The plane was tipped over on its wing. I could hear the big old propeller still ticking over, and I knew I had to stay clear of that. I landed hands-first in a puddle of flaming gasoline, then ran until I could no longer sense the intense heat from the plane. Natives rushed out to help put out the fire that was consuming me. I discovered much later that they helped themselves to my watch and wallet as payment for their troubles.
Valley Forge General Hospital, Phoenixville, Pennsylvania, Six Weeks Later
“When I first saw the young aviator, Charles Woods, he had no nose, eyelids
, or ears, and his mouth—if you could call it that—was a raw opening.” So begins the autobiography of Joe Murray. Murray was twenty-five years old, a recent graduate of Harvard Medical School (1943), and had just completed his surgical internship at the Brigham. He was now on active duty at Valley Forge, where he would spend three years as a staff surgeon before returning to the Brigham to finish his surgery training. Murray had known his entire life that he wanted to be a surgeon, but beyond that, he didn’t know where his training would take him.
When Woods showed up in Pennsylvania, he was truly closer to death than life. He was dehydrated, malnourished, and infected, with 70 percent of his body burned and exposed to the elements. Knowing they had to find a way to cover Woods’s burned areas, Murray and his team contacted the next of kin of a patient who had recently died and obtained consent to use his skin to try to save an injured pilot. Murray knew the skin would last only ten to fourteen days, at which point a new donor would need to be identified while they slowly tried to cover what they could using Woods’s own skin. This would require multiple operations over many months, with many painful dressing changes for him to endure.
They embarked on Woods’s care as a team, with each of them working on different parts of his body and face. “What we were doing was analogous to planting seeds, optimally preparing the ‘soil’ to accept and ‘grow’ the precious pieces of skin. ” Much to Murray’s surprise, the deceased-donor skin stayed alive for a month or more. This was critical to Woods’s outcome—it gave him time to improve medically and nutritionally and his donor sites time to heal so that new skin could be taken again. After eighteen months and twenty-four operations, Woods had finally healed adequately to go home. He had suffered incredibly but somehow maintained his sanity, positivity, and drive. He went on to be a successful businessman, politician, and great friend and supporter of Murray. Of Woods’s case, Murray would write, “Charles was my introduction to the use of tissues from one person to save the life of another.”
In 1951, Murray completed his training at the Brigham with some time in New York learning plastic surgery. He knew at that point that he wanted to be involved in surgical research, and he also saw the connection between his prolonged skin grafts on Charles Woods and the problem of making a kidney transplant work. He liked the seemingly insurmountable challenge, and the idea that these were dying patients who needed something to be done for them. Murray joined Hume’s team, which was supported by Moore and Thorn. Dogs were the animal of choice. Most of Murray’s work in those first three years involved removing both of a dog’s kidneys and then transplanting one of them back into various parts of the same dog’s body. His goal was to identify the best spot to sew in a kidney. Over time, Murray settled on the same spot that Küss had used in 1951 and Hamburger’s team shortly thereafter.
Boston, Massachusetts, Fall 1954
“Like many twins, Richard and Ronald were best friends, ” said Murray of the Herricks, two identical twin brothers who would change the field of transplant. Richard and Ronald Herrick grew up in Rutland, Massachusetts, on a dairy farm. They both joined the military in 1950, at the outbreak of the Korean War, with Ronald serving in the army and Richard in the coast guard. At the time of their discharge in 1953, they were planning to move in together back in Massachusetts. Richard never showed up, and shortly thereafter Ronald received a letter that his twin was in Chicago being treated for chronic kidney disease. When Richard got sicker, he was transferred to Brighton, Massachusetts, where he could be closer to family when he died.
At the hospital, the twins’ older brother, Van, asked the doctor if he might give his little brother a kidney. The doctor was about to say no when he realized he was looking at the spitting image of Richard, in his identical twin, Ronald, standing there among Richard’s family members. Maybe there was something that could be done. He knew that a crazy “bunch of fools” was doing research on this topic at the Brigham, and he reached out to John Merrill to see what he thought. At the very least, they could offer Richard Herrick some dialysis.
When Merrill heard about the twin, he was quick to accept this particular transfer. Given that it was Van, not Ronald, who had offered to donate a kidney, one might wonder what was going through Ronald’s head at this point. “I had heard of such things,” he said, “but it seemed in the realm of science fiction. For the first time, we began to feel the faintest glimmers of hope . . . I did some serious soul-searching. I mean, here I was, 23 years old, young and healthy, and they were going to cut me open and take out one of my organs. It was shocking even to consider the idea. I felt a real conflict of emotions. Of course I wanted to help my brother, but the only operation I’d ever had before was an appendectomy, and I hadn’t much liked that.” In the 1950s, there had never been a successful kidney transplant in humans (or animals), and all surgeries were considered high risk. But in the end, Ronald Herrick really had no choice.
Murray and his team knew that what they were considering doing was radical, that it went against the surgeon’s oath to “first, do no harm.” They obtained consultations from physicians, clergy, and legal experts, a majority of whom supported their moving forward—yet not everyone. Henry M. Fox, chief of psychiatry at the Brigham, was asked to see Ronald in consultation, and wrote this in his chart: “I think we have to be careful not to be too much swayed by our eagerness to carry out a kidney transplant successfully for the first time . . . The important question would seem to be whether we as physicians have the right to put the healthy twin under the pressure of being asked whether he is willing to make this sacrifice. I do not feel that we have this right in view of the potential danger to the healthy twin as well as the uncertainty of the outcome for this patient.”
The situation was different from what we are faced with today. Patients with renal failure now have the option of long-term dialysis, so potential donors don’t have to feel they are killing the patient if they decline to donate. Also, each potential recipient has access to more than one potential donor; with the advent of immunosuppression, donor and recipient no longer have to be identical. Most important, when we talk to potential donors today, we are able to discuss in great detail what to expect during the surgery, the recovery, and the long-term risks of donating a kidney. At the time that Ronald Herrick was making his decision, there really wasn’t much data on how donating a kidney might affect one’s life expectancy. He posed the question to Murray and the team, and was told, “We approached insurance companies for their actuarial tables and discovered that there was no increased risk from living with one kidney.” In the end, it was truly a “leap of faith” for Ronald. In a lucid moment the night before the operation, Richard wrote him a note, “Get out of here and go home.” At that point, Ronald was committed, and he tossed the note away without further consideration.
First, though, Murray and his team ran every test available to ensure that Richard and Ronald were indeed identical. This included sending them to the police station to get fingerprinted (which ended up blowing their cover: a newspaper reporter at the station caught wind of what was going on and published their story, raising the pressure on the surgical team). Murray also performed reciprocal skin grafts, and confirmed that after four weeks the grafts showed no signs of rejection and had fully taken.
Once everything was set to go, it occurred to Murray that he had never done a transplant in humans and needed to practice before operating on the twins. He contacted all the pathology departments in the city, and on December 20, a snowy night, he and Moore performed the first kidney transplant in the United States in humans in which the kidney was placed down in the iliac fossa (where we still place it today)—only both donor and recipient were dead, and one and the same.
Boston, December 23, 1954
J. Hartwell Harrison, the Brigham’s chief of urology, performed Ronald’s operation. Harrison had the most experience with nephrectomies (taking kidneys out) in the group, but he was also taking the biggest risk. He was the one performing surgery on
someone who would get no (medical) benefit from the operation. As for Richard Herrick’s surgery, Murray took that on his shoulders. His chairman, Moore, brought the kidney over from Harrison’s OR after it was removed, and Murray proceeded to sew it in, connecting the artery and vein in one hour and five minutes (a bit longer than we take nowadays, but it was the first), with a total time of one hour and twenty-two minutes without blood flow. The kidney pinked up beautifully, and urine began to flow out of the ureter shortly thereafter. They had done it.
Richard Herrick went on to live eight more years, and in that time, he married and had children with one of the nurses who’d taken care of him. He ultimately died of renal failure, when his original kidney disease returned in the transplant.
As for the donor, Ronald Herrick, he died fifty-six years later, at the age of seventy-nine.
The response to this first successful transplant was massive. Stories about it were splashed all over the front pages of newspapers across the world, and discussions of kidney transplant filled the airwaves. Joseph Murray became an instant celebrity, and, amazingly, sets of identical twins with one in renal failure began flooding into the Brigham, including a thirteen-year-old pair and a seven-year-old pair.
In terms of lessons learned on the immune system, identical twin transplants didn’t uncover anything useful or surprising, but they were a real shot in the arm for those few surgeons and scientists already trying to make transplantation a reality.
But where to next? Back to the animal labs. Peter Medawar had recently published his Science article demonstrating successful skin transplantation in genetically mismatched mice, a finding that electrified Murray and everyone else working in the field of transplant. It was time to find a way to make this work in humans.
How Death Becomes Life Page 8