Historical story

Skin download. Why did the zoologist become the father of transplantology?

What do English pilots, cow country and the dead have in common? Without them, skin transplantation would not be possible!

It is the first time I have benefited from someone else's death on a chilly October evening when I was in my sophomore medical college, one full year before my debut encounter with kidney transplantation. What happened that night was perhaps the most bizarre of all the gruesome things I had to do in my professional life. I just joined the New York Firefighters Skin Bank, an institution founded in 1978 by the burn center at New York Hospital to recover and store skin from freshly deceased donors. Several people from each student group were selected to work for the bank; we were to join an "elite" team that would set off into the city in the middle of the night to, well, simply put, remove the skin of the dead. Of course, the purpose was very important:the skin removed was later used by burn victims as a temporary transplant, covering the wounds until they healed enough to accept a skin graft from the burned body. (…)

(...) When recruiting for the "skin pickers" group, I had no idea who developed the procedure, how the skin grafts were going to the whole field of organ transplantation, or how important this experience will be for me one day . In my second year of medicine, I didn't have clinical classes with patients yet, never looked after a sick person and imagined becoming a pediatric oncologist. But I thought it would be interesting to participate in this project, and I was tempted to learn new skills and spend some time in the operating room. (…)

Peter Medawar became the father of transplantology

In those days, the skin seemed so insignificant compared to the heart, kidneys and liver. But as I got professional polish, I slowly began to understand that every organ, be it the liver, kidney, or heart, or, if we are to count it, bones, eyes, heart valves and - yes, skin - is a truly wonderful, wonderful gift. Not to mention the fact that the skin is the tissue that allowed to break the code and open the door to transplantation of other organs. Indeed, if it were not for the skin and Peter Medawar, there would be no transplantation .

North Oxford, Battle of Britain 1940

Peter Medawar was sitting with his wife and daughter in the garden of his home in Oxford, enjoying Sunday afternoon, when suddenly the three of them saw a twin-engine plane coming closer in the sky. Thinking it was a German bomber, Dr. Medawar and his wife grabbed their daughter and hastily hid in a shelter, a facility that had become a common addition to English households since the start of World War II. Less than two hundred yards away, they heard a loud explosion. It turned out that it was not a German bomber, but an English plane in trouble.

The aviator survived the crash and was taken to the nearest hospital - Radcliffe Infirmary, with third degree burns of the whole body. Knowing that treatment attempts would almost certainly be doomed to failure, his doctors turned to Dr. Medawar for help. Was Medawar a famous trauma surgeon? Intensive care specialist with many years of experience in saving patients in the most serious condition? No, he was a twenty-five-year-old zoologist who was primarily concerned with cell cultures, and strictly speaking, he studied the mathematical basis of the growth of… chicken embryo hearts. Did Medawar know Alexis Carrel's work in the last half of the century? Did he know that Carrel had successfully transplanted organs that, however, stopped functioning after a few days due to some mysterious "reaction"? If so, it was certainly not on these issues that his intellectual energy was focused. And he certainly did not know about the efforts made by Willem Kolff only five hundred and sixty kilometers away.

Peter Medawar was born in 1915 in Rio de Janeiro, Brazil to an English mother and a Lebanese father working in a dental equipment factory. As a young child, he moved to England at the end of World War I and went to school there, while his parents returned to Brazil. He endured difficult years at many boarding schools in various parts of England and entered Magdalen College Oxford University in 1932.

The article is an excerpt from the book "Spare Parts", which will soon have its premiere

In fairness, when the doctors caring for the young English pilot came to Medawara for help, he was not a complete newcomer to burns. After the outbreak of World War II, a military commission imposed on him the obligation to conduct research that could support the armed forces. So he started using his tissue cultures to see which antibiotics would be effective and non-toxic in treating burn wounds with a known high risk of infection. He published reports on the effectiveness of sulfadiazine and penicillin, which was an important discovery at the time, but still nothing compared to what happened next. The nightmare of living in England in 1940, plus good teachers together made him immersed in burn research. And that just changed everything.

For many years I could not understand why Sir Peter Medawar was considered the father of transplantology. Medawar's most famous discovery was the phenomenon of so-called acquired immune tolerance. He stated that if a fetal mouse from one strain is injected (directly into the uterus of a pregnant female) with an immunologically incompatible donor cell (i.e. another mouse from a genetically different strain), a skin graft from a donor from the other strain is in the recipient adult mouse. It is taken without causing rejection, without the need for any medications to suppress the activity of the immune system. In other words, the mouse has become "tolerant" to the donor. Medawar presented his preliminary results at a conference in 1944, and published a more comprehensive report in 1953. Immunological tolerance, referred to by some as the "Holy Grail" of transplantology, is not a state we achieve or strive for in modern practice, with the exception of some studies experimental. In our patients, we use chronic immunosuppression to prevent rejection of their new organs.

Before Medawar, all attempts to transplant human organs - and there were many - ended in a complete failure . The sewn organs died quickly (and so did their recipients), and no one knew why. At the turn of the century, Carrel made the assumption that there was some "biological force" that prevented the body from accepting a transplant. The concept of an immune response was completely foreign at the time. Most sane people have given up on the idea of ​​transplant, considering it a bizarre experiment that crazy scientists play in their laboratories.

Alexis Carrel Nobel Prize Laureate in Physiology or Medicine in 1912.

If Alexis Carrel represented the perseverance and manual genius technically necessary to transplant organs from one animal to another, then Peter Medawar took the next step - showing that it is possible to overcome this "biological force" and keep the transplanted organ in function for a long time. Medawar gave credibility to the issue by providing scientists with material in the form of a valid hypothesis for testing, and his vision inspired many more people to make the idea of ​​transplantation a reality.

He began by trying to solve the problem of the burned pilot. He first dealt with the question of how to enlarge a small area of ​​healthy skin that remains so as to create sufficient coverage for the remaining sixty percent of his body. He made his first approach from the side of tissue culture - he tried to multiply the skin cells left over from plastic surgeries. Without success. Then he reached for the autologous skin (i.e. the pilot's own skin) and cut it into very thin layers to cover as much of the surface as possible with what else was available for use. This also failed and the pilot finally died.

Disappointed, Medawar felt that he should turn to homografts - or as we now call them allografts (both terms refer to donors of the same species as the recipient) - rather than autologous transplants. He won a British government grant for research in this field and took a job in the Glasgow Royal Infirmary burn ward. His first venture, with surgeon Tom Gibson, was an experiment in an epileptic patient with severe burns when she fell into a gas fireplace. With Gibson's help, Medawar placed numerous four to six millimeters in diameter on the woman's wounds, and next to it, as control, autografts taken from her own healthy skin. They obtained allografts from volunteers (probably medical students). At regular intervals, they removed the grafts from the wounds and examined them under a microscope. Medawar noted that the allografts were infiltrated with lymphocytes (a type of white blood cell, part of the immune system), while the autografts were getting hold of, growing into blood vessels (from the recipient's vasculature), and minimal inflammatory response. Medawar and Gibson then placed a second set of allografts from the same donors on the wounds and watched if they survived longer than the first. It turned out that the second set was destroyed almost immediately, with a much stronger inflammatory response. Medawar published these results in an article entitled "The Fate of Skin Homografts in Man."

Peter Medawar made such a big impact on science because was persistent, he was able to admit mistakes , he conducted experiments for months or even years to get a comprehensive picture of the issue, had the ability to take appropriate action in most situations, presented the results obtained at international conferences and most importantly - published .

Upon his return to Oxford, Medawar focused entirely on testing the hypothesis that allograft rejection was an immunological phenomenon. He knew that he would not be able to study the subject in detail in humans, so he had learned to transplant the skin of rabbits, mice, guinea pigs, and cattle. In this research he was accompanied by his first PhD student, Rupert Everett Billingham, who played an immensely important role. And then it all changed one meeting.

The article is an excerpt from the book "Spare Parts", which will soon have its premiere

At the International Congress of Genetics in Stockholm, Medawar befriended the friendly New Zealander Dr. Hugh Donald. They got into a conversation about distinguishing between identical and non-identical twins in horned cattle. Donald tried to identify traits due to genetic differences as opposed to environmental influences, but failed to come up with a simple way to distinguish monozygotic from fraternal calves at birth. Medawar said it should be easy.
"My dear," he said with that expansive eloquence that a man eagerly demonstrates at international congresses, "the solution is extremely simple:you have to do a cross skin graft between both calves and see how long it takes. will keep. If the transplants work for good, you can be sure they are identical twins, and if they are rejected after a week or two, you can just as surely classify them as fraternal.
It turns out that Donald was raising his cattle just sixty-five kilometers away. from Birmingham, where Medawar was working at the time, so he invited him to carry out these transplants. Neither Medawar nor Billingham was drawn to the farm, but as soon as the word was spoken, they accepted the invitation. And here all the transplants have worked!

Medawar did not question the facts in defense of his hypothesis. Trying to understand where he went wrong, he sank into the literature and finally found an answer in Madison, Wisconsin - Cowland, of course.

Laboratory of Immunogenetics, University of Wisconsin, 1944

Ray Owen served as an assistant professor on L.J. Cole when a letter arrived from Maryland. He described a pair of twin calves who apparently had different fathers. This story fascinated Owen; he asked for blood samples to be sent to him. He found that the calves, although they were not identical twins - they were of different sex, for example - and came from different fathers, had the same blood type. He later determined that the blood of both calves contained maternal and fathers' group antigens. So they each had two blood groups; no one has described something like this yet! How was that possible?

It was already known that, unlike human fetuses, there were connections between the blood vessel networks of twin calves in the uterine cavity, thanks to which they could partially exchange blood while still embryonic. It was also known that it is because of these connections that females from a twin pregnancy, where the other twin is a male, are infertile. (Male twin hormones inhibit the development of female sexual characteristics in a female; this phenomenon was first described in 1916). But even with the mixing of blood in the intrauterine life, it would be expected that the red blood cells from the other individual would die after birth and each calf would have one blood type. The possibility that they would instead remain in the animal's blood throughout the animal's life was sensational. This would imply that hematopoietic cells are replaced, not red blood cells as such. These twin calves were chimeras - that is, cells derived from the genes of two different fathers remained in their bodies throughout their lives.

Owen published his observations of red blood cell chimerism in Science in 1945. In the version he submitted to the editorial office, he also discussed the concept of immunological tolerance and the potential use of this phenomenon in the future for the purpose of organ transplantation. Unfortunately, the reviewers from Science decided that it was not science anymore but science fiction and rejected this part of the article.

England again, 1949

After reading Owen's article, Medawar and Billingham suddenly realized what had happened. Calves did not reject skin grafts from non-identical twins because they came into contact with their cells during the intrauterine life, and thus became chimeras, possibly not only in terms of red blood cell properties, but also cells of the immune system. The scientists quickly published their conclusions and moved on to the next stage of the experiment:searching for a combination of mouse strains with the trait of tolerance acquired in utero. They managed to induce tolerance of skin grafts from unrelated mice by injecting donor cells into recipient organisms in utero. In other words, they developed one of the techniques for overcoming the so far insurmountable barrier in the form of the graft rejection reaction and called the phenomenon "acquired immune tolerance". They published this discovery with PhD student Leslie Brent in Nature in 1953. As Medawar wrote:

The real meaning of the discovery of immunological tolerance is to show that even if the experimental methods we have developed in our laboratory are not applicable to human beings, the problem of transplanting tissues from one individual to another is solvable. For the first time, it has been established that there is a possibility of breaking the natural barrier in the way of genetically alien tissue transplantation:although many have argued that it is essentially unfeasible (…). Thus, the ultimate importance of the discovery of tolerance turned out to be not so much practical as moral. It has poured new strength into the hearts of numerous biologists and surgeons working on the realization of the idea of ​​transplanting, for example, one human kidney to another.

This was the first time a tissue was transplanted between living organisms and the transplant was accepted.
Of course, when I was pacing around New York in the middle of the night, collecting the skin from the dead, I knew nothing about Medavara. But when I got the chance to wash for surgery with the retrieval team and watched the deceased's organs leave in separate refrigerators - to, temporarily asleep, fly off into the night somewhere, where they will be filled with the warm blood of the new owner and come back to life as if nothing had happened I was wondering how someone might have come up with the idea that something like this would work. It would never have occurred to me that it started with a British zoologist transplanting the skin of mice.

The impact of Medawar's discovery on the small group of surgeons and scientists who have tried to do something in this field cannot be overestimated. The first three pieces of the puzzle have fallen into place:the proof that it is technically possible to harvest an organ from one animal, sew it into another and work it by that organ was provided by Carrel, Kolff - a mechanism to keep patients with renal failure alive long enough for them to see a realistic strategy. organ transplantation in humans, and Medawar, the immune confirmation that there are ways to overcome the "biological force" that causes rejection of these organs. With its inherent elegance, integrity and optimism, Medawar gave those willing to follow his path the hope that organ transplantation could become a clinical practice, and inspired a whole generation of researchers to jump into that deep water.

The article is an excerpt from the book "Spare Parts", which will soon have its premiere

The article is an excerpt from the book "Spare parts", which will be published on October 16 by the Wielka Litera publishing house.