How Death Becomes Life

by Joshua Mezrich

  It really was that simple.

  How did we get here? How is it possible that we can take organs from someone who has just died, plug them into someone who is in the process of dying, and have those organs suddenly start working? Livers begin making bile, kidneys start peeing on the table, pancreata start secreting insulin and regulating blood sugar, hearts start beating, lungs start breathing. It has all become so straightforward and predictable, but it wasn’t always like this. There was a time when sane people thought transplant was a pipe dream, something that could never happen.

  Lyon, France, June 24, 1894

  Marie-François-Sadi Carnot, the popular French president, had just given a speech at a banquet in Lyon, and was back in his carriage, when a man ran at him from the crowd. Sante Geronimo Caserio was a twenty-one-year-old Italian anarchist who had made up his mind to kill the president. He’d purchased a knife. He’d studied the program for the president’s visit to the city. When the perfect moment arrived, he jumped onto the president’s carriage and stabbed him. Carnot was taken to the town hall, where prominent local surgeons examined him. They probed his wound, and he briefly came out of his unconscious state, exclaiming, “How you are hurting me!” Shortly thereafter, he died. An injury to the portal vein was identified as the cause.

  One can only imagine the chaos and emotions that this assassination inflicted on the people of France, heightened by the complete inability of surgeons at that time to offer Carnot anything resembling treatment. His murder had a major impact on one young student, Alexis Carrel. An extern in Lyon (the equivalent of a medical student), Carrel wondered whether he could somehow improve the management of these types of injuries and decided to become a surgeon. He was a natural surgeon, ambitious, driven, and hungry for fame. He reportedly told people that doctors should have been able to save Carnot, that there should be a way to sew severed vessels back together. Surgeons of the day thought the idea was crazy.

  In 1901, once he finished his initial training in surgery, Carrel obtained space in a lab with access to surgical equipment and dogs. His focus was on designing a method to join together two blood vessels. It is hard to imagine that surgery ever existed without this, but at the time, there was no inkling of peripheral vascular disease, no real understanding of atherosclerotic plaques, no consideration given to operations on the heart, and most people didn’t live long enough to develop these types of problems anyway. While vascular injuries were seen secondary to battle wounds or trauma, the standard management of these injuries was to try to ligate (tie off) whatever might be bleeding; this remained the practice well into World War II. The main vascular issue surgeons saw in those days involved aneurysms (or the outpouchings of arteries), which nowadays are associated with smoking and atherosclerosis. Back then, though, these were often secondary to syphilis. If an aneurysm was found before it ruptured, causing certain death, surgeons would ligate the artery. Mortality was high, but not that much higher than the outcomes seen with virtually any abdominal operation in those days. Thoracic operations weren’t even attempted.

  Carrel recognized three things: First, he needed to find better needles and thread to sew vessels together, thus minimizing injury to the inner wall (intima); the needles in use then were causing clots to form at the needle holes. Second, he wanted a technique that would protect the intima more than he could do just by improving his suture material. Third, he needed to find a setup that would allow the repair to be done quickly, as he knew that clamping the vessel for too long would inevitably lead to clotting. Knowing that the needles and thread available for surgery were woefully inadequate, he visited a local haberdashery in Lyon to obtain finer material, which included straight needles and fine cotton thread. In addition, legend has it he took embroidery lessons at the home of Madame Leroudier, a world-famous lace embroideress, and practiced sewing with these needles on paper until his technique was perfect. He placed paraffin jelly over the needle and thread, to allow it to be pulled through the tissue more easily, and in 1902 published a paper describing his findings.

  Alexis Carrel has always been described as a gifted surgeon. Most surgeons fall somewhere on a bell curve of inherent surgical skill, which is adequate to obtain good outcomes, even in technically complex cases. That said, there are natural surgeons whose hands are so good that within just a few minutes of working with them, you can tell they are off the bell curve. There are no wasted motions, the moves are so efficient, every stitch is perfect, and their instincts are unnaturally good. Carrel was in this group; he was a physical genius.

  In addition to his physical skill and adoption of better equipment, Carrel was passionately committed to organ transplantation, a discipline that depends on sewing together blood vessels to supply the new organ. This is rather remarkable, given that organ transplantation was still in the realm of science fiction at this point, with a few sporadic attempts that were universally followed by rapid failure.

  Carrel presented his results at local scientific meetings in Lyon, with generally good reception. He hoped that his description and demonstration of the vascular anastomosis (or reconnection of blood vessels), along with some follow-up experiments in which he sewed the carotid artery (the main artery in the neck that goes to the brain) end to end to the jugular vein (the main vein in the neck that drains the head) in dogs, would help him secure a junior faculty position. The artery-to-vein experiment was also well received, and the technique was presented as a possible treatment for strokes or general mental decline by increasing oxygenated blood flow to the brain. We know now that this would have no beneficial effect, but it was a concept Carrel would explore over the next decade as a treatment for various failing organs. But as would become a recurring theme in the life of Alexis Carrel, some of his greatest achievements would be diminished by controversies he entangled himself in due to his diverse interests and beliefs. One local paper quoted him voicing his belief in supernatural healing forces at the shrine at Lourdes. Carrel had a mystical belief in the supernatural, and felt there existed powers that could allow the healing of various maladies and diseases in a rapid fashion. This notion was met with ridicule, and he was passed over for a staff appointment. Feeling betrayed and stifled in Lyon, he decided to emigrate to North America. After a brief stop in Montreal, he was recruited to work with Professor Carl Beck in Chicago, both working at Cook County Hospital on humans and doing experimental surgery on dogs. It soon became clear to him that he had no interest in performing human surgeries. He also had a fairly low opinion of American surgeons. He described “the crowd of imbeciles and villains who corrupt the world of medicine . . .” and declared that “to be a medical doctor in the United States is the lowest form of business. ” An opportunity arose at the University of Chicago, where he would not have to take care of human patients at all, and facilities were available for animal surgery. There he met Charles Claude Guthrie, a physiologist and researcher whose lab was performing dog surgery. The two men worked together for two short stints of three to four months, yet in that time, they published ten papers in American journals and almost twice that many in international ones. This productivity was certainly driven by Carrel’s appetite for fame and recognition as well as a sense of the competition that was arising in the field of vascular reconstruction and even organ transplantation in animals. It is truly remarkable how many different operations use the vascular anastomosis Carrel and Guthrie considered and described in that short period. These included connecting the femoral vein to the femoral artery in the leg of a dog (to improve blood flow to the leg); updating Carrel’s original technique of the vascular anastomosis, taking full-thickness bites through the entire wall of arteries rather than just the outer layer; performing vascularized thyroid grafts, by either removing the organ from and replacing it in the same animal or transplanting an organ between different animals; and attempting multiple kidney transplants. Encouraged by their success, they also transplanted a canine heart from the chest of one dog to the neck of another (which beat
for as long as two hours) and made attempts at transplanting both hearts and lungs (which invariably failed). In 1906, they published a paper on the use of the “Carrel patch,” which involves cutting a vessel out along with a rim of aorta to make it bigger, a technique we still use today to perform organ transplantation.

  This may have been the most critical year in Carrel’s illustrious career, for two reasons. First, he focused singularly on mastering the technical demands of the vascular anastomosis. This attention, obsession even, to getting the technique perfect with repetition and focus was crucial. As a transplant fellow at Wisconsin, it took me two years of sewing in organ after organ, day and night, before my muscle memory had developed to the point where I didn’t have to think at all when I sewed. When you first start sewing together vessels, you must constantly keep in mind whether you are inside or outside each vessel wall, and you are never sure how big a bite to take with your needle or how far to advance. At some point in your training, you load the needle on your needle driver and turn your body without even thinking about it, and something that originally might have taken thirty minutes to an hour becomes a ten-minute exercise.

  Of course, when I operate now, I have a scrub tech assisting me; a resident or fellow across from me; sturdy and complex retractor systems that hold everything out of my way; powerful overhead lights and a headlight to illuminate the field; super-sharp, well-designed, fine needles with even finer coated sutures that glide through the tissue; and spring-loaded needle drivers that I can operate with just my fingertips. Carrel had none of this.

  The second reason 1906 was such an important year for Carrel has to do with his obsession with publishing. Some of the publications from this year remain relevant to the practice of medicine today, and his predictions about the application of the procedures he discussed in them, particularly in the field of transplantation, are shockingly prescient. By far my favorite work of his has to be “Successful Transplantation of Both Kidneys from a Dog into a Bitch with Removal of Both Normal Kidneys from the Latter,” published in the premier journal Science, no less.

  The other avenue Carrel started traveling down that year was interacting with the lay press. Although the practice was rare, and looked down upon by scientists and surgeons of the time, Carrel developed relationships with members of the press and leaked sensational information about his experiments to them. He also shared his techniques with renowned surgeons of the era. When a surgical society was convened in Chicago, Carrel had the opportunity to demonstrate his vascular anastomosis in a dog to more than twenty prominent surgeons, including the rising star Harvey Cushing. Cushing was at the Johns Hopkins Hospital at the time, working with the great William Halsted, perhaps the father of American surgery. On April 23, 1906, Carrel traveled to Baltimore to present his findings at the Johns Hopkins Hospital Medical Society. In the audience could be found some of the premier surgeons and physicians of the era, including Halsted, William Welch (one of the founders of Johns Hopkins Hospital), and William Osler (a Hopkins founder and often considered the father of modern medicine).

  Carrel spoke that day of his vascular anastomosis, the use of vein grafts to replace sections of arteries, and the importance of asepsis (the absence of bacteria or viruses) in outcomes of vascular anastomoses. (Joseph Lister had been pushing the importance of this in surgery starting in the mid-to late 1800s, but it certainly was not accepted practice, and hand washing and the use of gloves were not yet the standard of care.) Finally, he spoke of his experience with organ transplantation, its possible future applications, and how these surgeries seemed to fail after a week for unknown reasons. While he certainly did not call this “rejection,” or appear to have much understanding of the immune response at this time, he did refer to possible inherited factors and discussed his plan to “perform a series of similar operations on pure bred animals” to understand this failure better. He also stated that “we intend to try and immunize the organs of an animal against the serum and organ extracts of another . . . The transplanted organ must be prepared to support the serum of the animal on which it is to be grafted.” As a practicing transplant surgeon with a lab focusing on the immune system, I am pretty blown away by the topics Carrel spoke about and the predictions he made. The fact that he did most of this work in such a short time is also mind-boggling.

  Carrel got a similarly positive response from the Hopkins crowd, and they tried their best to secure his appointment to their institution. But the infrastructure to support medical research was just starting to be put in place in America, and the lab space at Hopkins was just being built. Also, at the same time, another offer presented itself. Efforts were then under way to start institutes for medical research modeled after some of the great ones in Europe, institutes that could put American medicine on the map. The National Institutes of Health did exist at this point, but functioned essentially as a small laboratory and didn’t start giving extramural grants for research until after World War II. Instead, two fabulously wealthy businessmen, John D. Rockefeller and Andrew Carnegie, decided to spend large portions of their fortunes to support medical research. In September 1906, the first director of the Rockefeller Institute, pathologist Simon Flexner, was successful in attracting Carrel to the gleaming labs in the newly built institute on the banks of the East River in New York City.

  At Rockefeller, Carrel’s most remarkable experiments were surgical in nature, involving blood vessel surgery and transplantation. In the field of transplant, he did virtually everything. He performed vascularized transplants of spleens, thyroids, intestines, and an ear (supplied with blood by the external carotid artery). He performed numerous leg transplants between dogs, sewing the blood vessels together and nailing the bones in place. Perhaps his most important transplants were kidneys. He first perfected the autotransplantation of kidneys in dogs (taking the kidney out and then transplanting it back into the same dog). He then moved on to transplants between two different animals. He thought about his occasional longer-term successes and came to the conclusion that something about the close relationship between siblings could make grafts last longer. And most impressively, Carrel grasped what might have been the next step in making transplantation a clinical reality: he considered the idea of manipulating the donor graft prior to transplantation or applying some sort of conditioning to the recipient. It was this work that led to his Nobel Prize in 1912, “in recognition of his work on vascular suture and the transplantation of blood vessels and organs.”

  Shortly after this, James Murphy, working in the Rockefeller lab of future Nobel laureate Francis Peyton Rous, published a paper showing that lymphocytes (cells of the immune system) could “reject” tumors and stop their growth when they were transferred to other chicken embryos. This was essentially the first explanation of transplant rejection, and Carrel recognized this. Furthermore, Murphy showed in mice and rats that by either irradiating them or treating them with the chemical benzol, lymphoid tissue would be damaged, lymphocytes (and hence immune function) would be decreased, and tumors could be transplanted and survive in these animals. Carrel took the next step, in his mind, and considered that either radiation or chemicals such as benzol could be given to transplant recipients to extend the lives of grafts.

  In 1914, when he went off to France for his summer vacation, World War I broke out. Tragically, this concept of recipient treatment and the role of lymphocytes in graft failure would essentially be lost until the 1950s.

  When Germany declared war on France, Carrell was thrilled, as he loved the military and felt France had gone soft. War was just what was needed to cleanse the soul of the French people. Carrel had a particular interest in the management of wounds and wound healing, and he formed a relationship with an American chemist by the name of Henry Dakin, whom Carrel tasked with coming up with a strong antiseptic solution that could be used to wash out battlefield wounds. With it, Carrel devised an intricate and painful wound-perfusion system, which eventually fell out of favor due to its complexity. Dakin�
�s solution, with some modification, is still used in the management of open wounds today.

  After the war, Carrel spent an additional twenty years at Rockefeller. In the lab, he moved away from surgical work and turned to cell culture and made some minor advancements in that field, which he portrayed to the press as major breakthroughs. Ultimately, some of these breakthroughs would be exposed as fraudulent. In addition, he wasted time and money on expensive experiments that were badly designed. For example, he conducted a large mouse experiment looking at the role of diet and environment in the development of cancer, but it was poorly controlled and without any testable hypotheses. But overwhelming his life at this time was a growing interest in eugenics and his relationship with Charles Lindbergh, the famous aviator and eugenicist.

  From the turn of the twentieth century up until World War II, eugenics was widely popular in the United States and Europe. More than three hundred major universities offered the study of eugenics as part of their curriculum, and the scientific community considered it a legitimate science. A short list of famous people who subscribed to it includes Theodore Roosevelt, Alexander Graham Bell, John D. Rockefeller Jr., H. G. Wells, Winston Churchill, John Maynard Keynes, Woodrow Wilson, Henry Ford, and Francis Crick.

  So, what does this all have to do with Carrel? In the 1920s and ’30s, Carrel embraced the concept that Western civilization was in a decline. He became so focused on his concerns about mankind that he dedicated himself to the writing of his opus Man, the Unknown, which supports a positive version of eugenics. He wrote extensively about the loss of “natural selection” in mankind and a need to develop the strong.

  The book was released in 1935 and became a best seller. Many of its themes, particularly the general decline of Western societies, the potential for improving living things with selective breeding, and getting rid of criminals and those deemed insane, were popular and mainstream. Carrel was at the absolute peak of his popularity in these years, until his retirement and return to France in 1939, where he was supported by the Vichy government.