Somehow, I had managed to get myself chosen for this skin gig, had gone through the training, and was now going on my first “run.” Accompanying me were Brian and Lawrence, two more seasoned members of the team. Brian, who had been a part of the skin bank for about a year, was a fellow medical student, and would ultimately become a close friend. Lawrence, the most experienced “banker” around, was a graduate student and a sight to be seen. He was at least six and a half feet tall, with long blond hair, built like a truck, with a personality to match. To prepare for the run, I went up to the lab tucked away on the twenty-third floor of New York Hospital and loaded up a cart with the necessary supplies: sterile drapes, gloves, gowns, sponges, and any number of disposable items one sees in an operating room. The most memorable pieces of equipment were the infusion pump and the dermatome, with its blade—a kind of lawn mower for skin.
As the new guy, I got to wheel this huge cart down to the van, a big red vehicle with “New York Firefighters Skin Bank” stenciled on the side in gold letters alongside a picture of a fireman pulling a child from a burning house. The donor was somewhere out on Long Island, and we took the Queensboro Bridge that night. I sat mostly in silence, going over the steps of the procurement in my head.
When we got to the hospital, we were told that the donor was still in the operating room, where the other procurement teams had just finished with him. I would later learn that when the donors aren’t donating other organs, we have to pick them up in the morgue—an experience I would eventually come to find macabre. I put on my mask, shoe covers, and hat and wheeled the equipment cart into the OR. And there he was. My first recently dead patient.
There was no denying that he had just been alive. You could see it in his face; in the stubble on his jaw, which hadn’t been shaved in a couple of days; in his eyes, his hands. At the sight of him, I pictured my own dad (who was, and is, still alive and healthy), thinking that he might have looked like that in death. As I was drifting off into these thoughts, starting to wonder what the hell we were about to do, a piercing voice pulled me back in.
“Let’s go, dumbass!”
The procurement of organs is a surreal process. (In those days, we still called it harvesting, a term we’ve since dropped in favor of the more respectful “procurement.”) What I remember is seeing the long incision running from the top of the donor’s chest all the way to his pubis, an incision that had been stitched back up with a big suture like you’d see on a baseball, only black, indicating that the chest and abdominal teams had preceded us. The other thing I remember were the long incisions running down both legs, made by the bone guys, who would have replaced the bones they’d taken with broom handles, so that there would be some structure to the legs when we (or the funeral parlor) moved the body around. The donor’s eyes were taped shut, signaling that the eye team must also have slipped in before us.
We flipped the donor onto his front and prepped him, just as I would do years later on living people. Then we scrubbed in and draped him with sterile sheets. Next came the weird part.
Brian turned on the infusion pump, which would allow us to pump saline, now in two large bags hanging high above on IV poles, through a couple of long, sterile plastic extension tubes and into the donor’s body through sixteen-gauge needles attached to the ends of the tubes. The pump whirled into action, generating a soothing, rhythmic sound, and with saline squirting out of the needles and into the air, Lawrence began poking the needles into the donor’s back, and his skin started to lift up like a balloon, turning this guy into the Stay Puft Marshmallow Man. Once we were done inflating the donor’s skin, we opened a few bottles of mineral oil and greased his back and both his legs. Then I watched as, with one stroke of the dermatome, Lawrence removed a piece of skin from the top of the donor’s back to just above the ankle. (I remember thinking how incongruous it was to see such a graceful move from such a big, scary guy as Lawrence.)
We finished skinning the donor’s back, taking turns getting a feel for the dermatome, which resembles an electric paint remover and works like a razor. It is fitted with a long sharp blade, and you set the distance from the blade to the dermatome surface, depending on the width of skin you want to harvest. For a perfect strip running from the back to the ankle, you have to constantly adjust the width and the pressure you apply as the thickness of the skin changes. Lawrence was a master at this. (By the end, I can happily say I managed to harvest a few nice strips.) We then flipped him over onto his back and repeated the process, harvesting skin from his chest and the front of his legs.
Many more nights like this would follow, and I finally mastered the art of harvesting skin. There was always a small moment, during each case, when I would think about who the donor might have been in life—but it was fleeting. I had a job to do, and found it easier to focus on that. In a typical case, we’d have music blaring, tell jokes, talk about things that seemed important in our lives, where we would go to eat after we were done (a tradition after every skin run)—never really grasping, I confess, how incompatible these thoughts might have been with the tasks we were performing.
In a few cases, we arrived early (or the teams before us were late), and I would get to scrub in with the organ transplant teams. They would have flown in from all over the country, coming to get the heart, lungs, liver, kidneys, while back home, their recipients waited to find out if tonight was the night their lives would be saved. I remember thinking how cool it would have been to fly back with those guys to their respective hospitals and watch the organs they were harvesting come back to life. I imagined it as an adventure.
At the time, the skin seemed so meaningless compared to hearts and kidneys and livers. But then, as I advanced in my career, I slowly came to understand that the gift of any organ, be it a liver, kidney, heart—or, for that matter, bones, eyes, heart valves, and, yes, skin—is truly a wonderful gift. Not to mention that skin is the tissue that cracked the code to organ transplantation. Indeed, without skin, and Peter Medawar, there would be no transplant surgery.
North Oxford, England, The Blitz, 1940
Peter Medawar was enjoying a Sunday afternoon with his wife and daughter in the garden of their house in Oxford when they saw a two-engine plane approaching in the sky. Expecting this to be an attacking German bomber, Dr. Medawar and his wife grabbed their daughter and rushed into their air-raid shelter, a structure that had become so common in English homes after the start of World War II. They heard a loud explosion two hundred yards away. It turned out this wasn’t a German plane making a bombing run, but an English plane in distress.
An airman survived the crash and was brought to the local Radcliffe Infirmary with third-degree burns all over his body. Knowing that caring for him would be almost futile, and with his chance of survival next to nothing, his physicians came to Dr. Medawar to ask for help. Was he a celebrated trauma surgeon? A critical-care specialist with years of success attending to the sickest patients? No, he was a twenty-five-year-old zoologist whose most significant work had been in the discipline of cell culture, studying the mathematical basis of growth in . . . embryonic chicken hearts. Was Medawar familiar with the work of Alexis Carrel spanning the previous half century? Did he know that Carrel had successfully transplanted organs only to watch them stop working over a few days from some mystical “reaction”? If he did, he certainly wasn’t focusing his intellectual energies on these things. And he certainly didn’t know about the efforts of Willem Kolff, just 350 miles away.
Medawar was born in 1915 in the city of Rio de Janeiro, Brazil, to an English mother and a Lebanese father who worked for a dental supply manufacturer. He moved to England as a small child at the end of the First World War and stayed there for his education while his parents returned to Brazil. He was able to make it through trying years in various boarding schools around England, and ultimately entered Oxford University’s Magdalen College in 1932.
To be fair, when the physicians taking care of that young English pilot came to Medawar for h
elp, he wasn’t a complete neophyte in the study of burns. After World War II began, the Recruiting Board told him he had a responsibility to do research that might help the war effort. So he began using his tissue culture system to investigate which antibiotics would be effective and nontoxic to burn wounds, known to be at high risk for infection. He published papers touting sulfadiazine and penicillin, an important finding in those days, but nothing compared to what was coming next. Then, some combination of the horrors of life in England in 1940 and good mentorship turned his attention to the study of burns. And that changed everything.
For many years, I couldn’t understand why Sir Peter Medawar was considered the father of transplantation. Medawar’s most famous discovery was the concept of “acquired immunological tolerance.” He found that if he injected a fetal mouse from one genetic family (directly through the pregnant mother) with cells of an immunologically mismatched donor (meaning a different mouse that wasn’t genetically identical), the recipient mouse would then accept skin grafts from this same donor type without rejection once it grew into an adult, with no need for any medications to block an immune response. In other words, it was “tolerant” to that donor. He presented his initial findings on this topic at a conference in 1944, and ultimately published a more complete report in 1953. This idea of tolerance, which some people have called the “holy grail” of transplantation, is not a state we achieve or try to achieve in modern transplantation, except in animal research or some very small experimental protocols. Instead we treat patients with chronic immunosuppression to prevent rejection of their organs.
Prior to Medawar, all attempts at transplanting human organs—and there were many—ended in complete failure. Organs would be sewn in and quickly die (along with the recipients), and no one knew why. Carrel, at the turn of the century, thought there was some sort of “biological force” that prevented successful transplantation of organs. The idea of an immune response was totally foreign in those days. Most level-headed people had given up on organ transplantation as anything more than a crackpot idea that some crazy scientists were doing in the lab.
If Alexis Carrel displayed the persistence and physical genius that was necessary for the technique of transplanting an organ from one animal to another, then Peter Medawar took the next step and demonstrated that it might be possible to overcome this “biological force” and have the transplant enjoy sustained function. Medawar brought credibility to the field, providing researchers with a legitimate mechanism to study, and a vision that would inspire so many to make transplant a reality.
He began by trying to solve the problem facing the burned pilot. First, he addressed the question of how to expand the small amount of skin left to sufficiently cover the remaining 60 percent of the pilot’s body. He initially approached this dilemma with tissue culture, obtaining skin left over from plastic surgery operations and trying to get the cells to grow. No luck. Next, he tried to take the autologous skin (that is, the pilot’s own skin) and slice it thinner and thinner, in an attempt to maximize burn coverage from what was available. That didn’t work, either, and the pilot ended up dying.
Medawar’s frustration led him to believe he should explore the use of homografts, grafts from donors (now called allografts—both terms refer to grafts from the same species as the recipient) as opposed to autologous grafts. He successfully wrote a grant to the British government to study this and went to work in the burn unit of the Glasgow Royal Infirmary. The first thing he did, with his collaborator, Tom Gibson (a surgeon), was to experiment on an epileptic who had suffered severe burns after falling into a gas fire. With the help of Gibson, Medawar placed numerous small homografts four to six millimeters across, on the woman’s burns, next to autografts, taken from her own unburned skin, as controls. They got the homografts from willing volunteers (probably medical students). Grafts were removed at regular intervals and examined under a microscope. Medawar noticed that the homografts were invaded by lymphocytes, the white blood cells of the immune system, whereas the autografts were accepted on the recipient, with ingrowth of blood vessels (meaning recipient blood vessels grew into the donor graft) and minimal inflammation. Next, Medawar and Gibson placed a second set of skin grafts from the same donors as the first, to see if they would last as long as the first set. They found this second set was destroyed almost immediately, with an even stronger inflammatory reaction. Medawar published these results in an article entitled “The Fate of Skin Homografts in Man. ”
What made Medawar so impactful was his ability to be persistent; admit to mistakes; follow a course of experiments over months and years, in order to tell a complete story; be right about most of the things he did; present his data at international conferences; mentor students and junior colleagues who went on to do great things themselves; and most important, publish.
After returning to Oxford, Medawar turned his full attention to testing the hypothesis that homograft rejection was an immunologic phenomenon. He knew he couldn’t study this in great detail in humans, so he learned to do skin transplantation in rabbits, mice, guinea pigs, and cattle. He was joined by his first graduate student, Rupert Everett Billingham, who played a huge role. Then an encounter changed everything.
Medawar was at the International Congress of Genetics in Stockholm when he met a friendly Kiwi by the name of Dr. Hugh Donald. They got into a conversation about distinguishing between fraternal and identical cattle twins. Donald was trying to identify characteristics that were based on genetic differences versus the environment, but he couldn’t figure out an easy way to distinguish between identical versus fraternal twin calves shortly after birth. Medawar thought that would be easy.
“ ‘My dear fellow,’ I said in the rather spacious and expansive way that one is tempted to adopt at international congresses, ‘in principle the solution is extremely easy: just exchange skin grafts between the twins and see how long they last. If they last indefinitely you can be sure these are identical twins, but if they are thrown off after a week or two you can classify them with equal certainty as fraternal twins.’ ”
It turns out Donald kept his cattle a mere forty miles from Birmingham, where Medawar was working at the time, so he invited Medawar out to do the skin grafts. Medawar and Billingham had no interest in going out to a farm, but true to their word, they accepted the invitation. Lo and behold, all the grafts were accepted!
Medawar questioned his hypothesis rather than the data. He delved into the literature to try to understand what he was missing and found the answer in Madison, Wisconsin—cow country, of course.
Immunogenetics Laboratory, University of Wisconsin, 1944
Ray Owen was working as a postdoctoral fellow in the lab of L. J. Cole the day the letter from Maryland was delivered. It described a pair of twin calves that appeared to have different fathers. The cattle breeder had mated his Guernsey cow with a Guernsey bull. The Guernsey ended up delivering twins, but it was clear from the color patterns that the twins had different fathers. Owen was fascinated by this story, and asked to be sent some blood. He found that the calves had identical blood groups, despite the fact that they weren’t identical twins—they were of different sexes—and had different fathers. He further identified that each twin had blood group antigens from the mother and from both fathers circulating through its bloodstream. Each twin had two blood types, a finding that had never been described before! How could that be?
It was known at that time that cattle twins in utero, unlike humans, share blood vessel connections, and hence can exchange blood while embryos. It was even known that these connections were the reason “freemartin” cattle—that is, female calves who are twins to a male—were sterile. (Hormones of the male twin suppress sexual development in the female, a concept that was first described in 1916.) But even though the blood would have been shared in utero, the red blood cells that had come from the twin would have been expected to die off after birth, leaving the calves with a single blood type. But the idea that these cells remained
present for life was startling. This implied that blood precursors were being shared, not just the red cells themselves. These twins were chimeric—that is, they harbored cells throughout their lifetime derived from the genes of two different fathers.
Owen published the findings on red cell chimerism in Science in 1945. In the version he submitted, he discussed the concept of immune tolerance, and how this could be applied to organ transplantation someday. Sadly, the reviewers at Science thought this was more science fiction than science and rejected this portion of the paper.
Back to England, 1949
Upon reading Owen’s original paper, Medawar and Billingham suddenly understood what had happened. The nonidentical twin calves had accepted the skin transplants because they had been exposed to each other’s cells during their development in utero, and were therefore chimeric, probably not just in regard to their red blood cells, but also other cells of the immune system. The researchers quickly published their findings and moved on to the next set of experiments: to find a strain combination of mice in which fetal tolerance worked. They succeeded in making mice tolerant to skin grafts from unrelated mice by injecting donor cells in the fetuses of the recipient mice in utero. In other words, they found one technique to get over the insurmountable barrier of transplant rejection and named the phenomenon “acquired immunological tolerance.” Medawar and Billingham published these findings in Nature in 1953, along with their graduate student Leslie Brent. As Medawar said:
The real significance of the discovery of immunological tolerance was to show that the problem of transplanting tissues from one individual to another was soluble, even though the experimental methods we had developed in the laboratory could not be applied to human beings. What had been established for the first time was the possibility of breaking down the natural barrier that prohibits the transplantation of genetically foreign tissues: some people had maintained that this was in principle impossible . . . Thus the ultimate importance of the discovery of tolerance turned out to be not practical, but moral. It put new heart into the many biologists and surgeons who were working to make it possible to graft, for example, kidneys from one person to another.
How Death Becomes Life Page 6
