The following is a chapter from Composite Tissue Allograft (published in 2006 by Imperial College Press and distributed by World Scientific Publishing) and reprinted with permission. Sources used in the chapter are shown in the References.^1-3 Earl Owen, a world-renowned pioneer of microsurgery and a good friend of mine, first voiced the idea of a hand transplant more than 30 years ago during a speech at Edinburgh University. However, it was not until the mid-1990s that he decided the procedure was both technically and immunologically feasible. The only previous reported attempt at a hand transplant had taken place in Ecuador in 1964, but it failed due to the absence of any anti-rejection drugs, resulting in immediate severe rejection. Earl trained and practiced in London for many years; he was awarded a Hunterian Professorship in 1968 and had hoped to perform the world’s first hand transplant in the United Kingdom. With this in mind, and encouraged by the successful results of human skin, nerve, and joint transplants, he approached me in 1998. I contacted the Royal College of Surgeons and the UK’s Transplant Service Authority to request permission for such an operation. However, the Ethics Committee at St. Mary’s Hospital, London, where I worked, was not convinced and expressed doubts about performing the procedure on a single limb. They believed that exposing a healthy patient to potentially dangerous immunosuppressants could not be justified at that stage, despite the long-term successes of experimental animal composite tissue transplants using a combination of recently developed powerful drugs. Earl was keen to form a team of experts in preparation for the procedure. I suggested contacting Max Dubernard in Lyon, Head of Transplantation and Urology at Edouard Herriot Hospital, where Earl had been a visiting professor for 20 years. Max had performed France’s first pancreas transplant in 1976 and was not only one of France’s leading surgeons but also a prominent local politician, serving as Deputy Mayor of Lyon while heading his department. He was excited by Earl’s proposal and agreed that the forearm transplant could proceed in his department. Earl quietly began assembling an international team of transplant, orthopedic, and hand microsurgeons, anesthetists, a psychiatrist, and a psychologist specializing in body image disturbances. Hand surgeons knew how to attach a hand, and transplant surgeons understood how to control rejection of donated internal organs. However, we could not predict how the body would react to receiving a hand, an organ made up of many tissue types: nerve, artery, tendon, muscle, bone, and most challenging of all, the skin, which tends to reject most violently. Experiments on primates using earlier immunosuppressants had yielded abysmal results; most animals died due to complications from the drugs. Primates may be the closest animal model to humans, but, following transplantation of any organ, they require more immunosuppression than humans. These experiments took place in the mid-1980s using only one drug. Since then, combination therapy using much lower doses of several drugs has improved outcomes significantly. There was still an ethical objection to putting someone on potentially life-threatening immunosuppressants for a “quality-of-life” operation. However, one could argue that kidney and pancreas transplants, which spare patients from lifelong dialysis or insulin injections, are not themselves life-saving but are routine. Some members of the international team preferred our first case to be a double amputee, where the benefits would be potentially greater. However, Earl conservatively argued that the skin area involved in a double forearm and hand transplant might be too large for the immunosuppressive cocktail to protect. Failure of the transplant would set back the field of limb transplantation by years. We agreed to proceed with a single hand transplant, knowing that skin is the most difficult tissue to immunosuppress. When internal organs are donated, recipients are naturally grateful. However, when the donor provides their hands, the recipient must cope psychologically with the constant reminder that their hands belonged to another person who used them daily. The recipient had to be carefully chosen and possess characteristics to sustain motivation through the early postoperative months. Unlike internal organs, which must function immediately but remain unseen, a hand transplant cannot function fully for a considerable time (as nerves regenerate slowly) yet is immediately and permanently visible. A man named Clint Hallam was well known to Earl and was one of three shortlisted candidates for a hand transplant. Hallam, determined for many years to have the operation, contacted Earl and confirmed his willingness to travel for surgery anywhere, at any time. He underwent psychological and physical evaluations and began a regimen of forearm strengthening exercises. He was deemed a suitable patient by the consultant psychiatrist, described as having a “strong constitution and solid resolve.” Legal contracts and augmented consent forms were drawn up with Australian and French lawyers, clearing surgeons of liability for any risks or complications. Hallam agreed to comply with a strict postoperative physiotherapy and immunosuppressive medication schedule, including regular follow-ups, blood tests, biopsies, and nerve function assessments. The surgical team, drawn from around the world, needed to agree on a date and await a suitable donor. The operation was planned for early September 1998. However, after a week, no suitable donor matching Hallam’s hand in size, shape, color, and hair distribution was found, and Hallam became restless and agitated. With plans to reconvene in November, the team began to disperse. The Australians boarded planes back home, Max Dubernard took a train to Paris, and Marco Lanzetta drove back to Milan, when the excellent Etablissement Francais des Greffes organization found a matching donor and alerted the team. A 41-year-old Frenchman had died in a motorbike accident, suffering a fractured skull and fatal blood clot. His next-of-kin granted permission for organ donation, hoping some good could arise from the tragedy. Hallam was prepared for surgery the following morning. The Australians were stopped from boarding their flight, Max travelled from Paris to procure the forearm, and I flew to France after performing two kidney transplants early that morning. Marco, who had reached Milan, turned back to Lyon to join the team. The operation proceeded smoothly, a testament to the entire team, which had rehearsed the procedure multiple times. The experienced theatre staff from the transplant, orthopedic surgery, and anesthesia departments volunteered to be available “at any time while the team was in waiting.” The surgery began mid-morning and ended before midnight on September 23, 1998. Preparation of donor and recipient limbs was meticulous and took longer than expected, despite practice sessions at Lyon University’s anatomy school. The orthopedic team joined the forearm bones 10 cm from the wrist using plates and 6 screws for each bone. Several muscles and tendons were connected before the Zeiss motorized operating microscope was used to join the ulnar and radial arteries with microsutures. A large vein was then joined, and the tourniquet was released, the most anxious moment. Earl described giving the order as defining a new level of “stress.” The white limb gradually turned pink, and the team relaxed as anesthetists checked vital signs. The surgery continued at a more measured pace: the median and ulnar nerves were joined under the microscope. Donor nerves appeared thinner and pale yellow, contrasting with the recipient’s thicker white nerve fascicles. Tendons, muscles, and finally skin were repaired. Skin grafts were taken from the right thigh to allow for postoperative swelling and provide observable islands of recipient skin within the donor skin. A loose dressing was applied, and the patient was moved to recovery. A brachial block was administered before awakening to prevent immediate muscle use that could jeopardize joint repairs. The block continued for one week. The surgery was technically successful, and the patient adhered to the immunosuppressive regimen, which started preoperatively with intravenous anti-lymphocyte serum and the first doses of the immunosuppressive cocktail. “My hand’s back,” said Hallam upon waking. “It’s almost like I’d lost an old friend years ago, and suddenly it’s back.” Congratulations came from Jacques Chirac, the French President. Dan Rather of CBS News called it “a quantum leap in modern medicine… stunning… transplant surgery that is simply staggering because it holds so much promise.” Over the next 3 months, Hallam was closely supervised, following his observation, exercise, and medication schedules. The team was surprised by the rapid nerve regeneration and fast nail growth in the donor hand. Hallam left the hospital on January 1, 1999, assuring us he would continue making satisfactory progress and was expected to return to Australia. The team then prepared to perform the first successful double arm transplant, another world first! Throughout late 1998, we awaited a suitable donor for a man who had lost both arms in an explosion. Each time a donor was found, next-of-kin refused permission. Although French law presumes consent for organ donation unless stated otherwise, we felt the family’s cooperation was necessary in such unusual cases. The eminent hand and transplant surgeons flew to Lyon 3 times since June 1999, awaiting a donor. Finally, 12 days into 2000, the call came. I abandoned a lecture tour in California; Earl flew from Sydney, and 4 Italian specialists drove from Milan to join Max Dubernard and the French team. The donor’s father, paralyzed on one side, understood the impact of limb loss and consented when many others refused. The 19-year-old donor had fallen from a bridge and was on life support until his death. His hands and forearms were removed alongside his organs. Prosthetic hands were fitted for his funeral. Donor limbs were preserved in fluid and transported on ice. Earl led the first transplant; Max was in charge this time. Surgery began at 6 a.m. Fifty surgeons, specialists, and nurses worked on the recipient, Denis Chatelier, a 33-year-old house painter and father of two who lost his hands in a homemade rocket explosion. He wished to live a normal life again. After seeing the first single hand transplant on TV, Chatelier contacted Max Dubernard. Describing himself as a “battant” (fighter) and “croyant” (believer), he was fit and ready for the 17-hour operation and up to 2 years of physiotherapy. Max agreed to proceed, calling him “strong-willed and tenacious,” he told colleagues. In the early hours of Thursday, January 13, along with his kidneys, liver, and heart, the young donor’s hands and forearms were removed. Prosthetic hands supplied by our team were fitted to provide a normal appearance for his funeral. The donor limbs were perfused with preservation fluid, placed in dry plastic bags, and carried in a cool box. Chatelier layed with arms outstretched on the hand surgery operating mini-tables as if crucified; a separate team of 4 surgeons worked on each donor hand and each host arm. He had been sedated and then anesthetized. The procedures followed the protocol of the Hallam operation. Some of the details are now described. Tourniquets were applied to his arms, and incisions were made on each to expose the deeper structures. The nerves, arteries, veins, and muscles were dissected and tagged, and the forearm bones were transversely cut with an electric saw so that the grafted limbs would be the same length. At the same time, in an adjoining theatre, the donor hands were similarly dissected and tagged. About 10 cm of the donor arm was also used. First, the two forearm bones, the radius and ulna, were joined using small titanium plates with holes for 4.5-mm stainless steel screws; then the arteries and cephalic veins were connected, and the first arterial clamps were removed. The tourniquets were loosened, and the hands’ cool white color turned pink. The surgeons left them undisturbed for 20 minutes, covered with warm, wet sponges. Next came the muscles, then the tendons interwoven with the muscles where possible, and finally, the skin. The procedure took until 11 p.m. Although confident in attaching the hands, we were wary of unforeseen complications. Patients can lose a lot of blood when 2 wound sites are opened, and if either of our first 2 transplant patients had died, it would have meant halting any further such transplants. However, by midnight in each case, we could relax and watch as the patient’s arms were bandaged following the successful operation. In the days that followed, Chatelier’s progress was good. A cocktail of 4 immunosuppressants and steroids was administered—the same mix used in the first transplant 15 months earlier, which had proved very effective. The patient was advised not to try to move his fingers yet; that would come later, after extensive passive physiotherapy, initially supported by thin rubber bands attached to provide gentle resistance, followed by intensive active physiotherapy over the next 3 months. At the time of writing, a total of 165 new arms have been transplanted worldwide. It was not until 2012 that the first hand transplant took place in Leeds, UK, performed by Prof. Simon Kay, a consultant plastic surgeon. The international experience has included in addition centers in Lyon (France), Louisville (USA), Guangzhou (China), Innsbruck (Austria), Monza (Italy), Guangzi (China), Harbin (China), Brussels (Belgium), Malaysia, Poland, Spain, Germany, Mexico, and Australia. An International Registry on Hand and Composite Tissue Transplantation has been initiated. Unfortunately, the final chapter in the story of the world’s first successful hand transplant patient, Mr. Hallam, ended less than satisfactorily. Over the months following his operation, it became clear that Mr. Hallam had been less than honest with the transplant team. He initially told the team that his hand had been lost in an industrial accident; however, it later emerged that it had been severed during an accident in prison in New Zealand, where Mr. Hallam was serving a sentence following convictions for fraud. The psychiatrist later admitted that Mr. Hallam had not been a good candidate for the transplant. He proved to be unreliable, disappearing irregularly, traveling around the world, and being unreachable for weeks. He missed check-ups and did not comply with his anti-rejection drug therapy, taking the medication inconsistently, which led to illness and gradual rejection. I supplied him myself with immunosuppressive drugs as much as possible because he could not afford the cost of medication. However, at one point, he stopped taking the drugs altogether. At the transplant’s peak function, Mr. Hallam could use the hand to grab objects, use a knife and fork, write with a pen, and even play basketball with his children. On one of his trips to London, he visited my home and managed to play some piano, as he used to do before his accident. Following his noncompliance with treatment, however, he began to lose some function, and the hand became inflamed from chronic rejection. In November 2000, Mr. Hallam requested amputation of the hand but then changed his mind and pledged to try again and take the necessary medication. He was given a supply of drugs by me and others, but when these ran out, he did not obtain more. He then pleaded with Max to have the arm amputated in Lyon; however, this was declined by the French team, who believed the hand could still be salvaged. He then approached Loma Linda University Hospital and was scheduled for amputation, but, at the last minute, the surgeons changed their minds and canceled the surgery, saying they did not want to be blamed for amputating the arm transplanted by the French. On January 31, 2001, more than 2 years after the transplant surgery, Mr. Hallam contacted me once more, begging me to perform the amputation. He flew to London, and I saw him at his hotel. One look at his hand convinced me that there was no alternative but to amputate, as the chronic rejection was severe, though, surprisingly, there were no symptoms of systemic rejection. The hand was painful, suggesting, I believe, successful nerve regeneration. The problem was that I was still a young consultant surgeon, aged 38, and had nowhere to perform the surgery within the NHS. The only option was to do it in a private hospital. Fortunately, I was good friends with the CEO of the Harley Street Clinic Miss, a private hospital in London, Pat MacCann, who gave me permission to perform the surgery at no cost. I was assisted by my registrar, Adel El Tayyar. We were both general transplant surgeons, not orthopedic surgeons, and the hospital was not an orthopedic hospital. Therefore, everything was improvised, including having to remove the screws with improvised tools. It was with sadness that I removed the hand. To keep it a complete secret, I obtained consent from Clint Hallam for a below-knee amputation to avoid drawing the attention of the nursing staff, and he was admitted under a different name to avoid the story leaking to the press. Luckily, the procedure was uneventful, and he was discharged home 2 days later. When I completed the surgery at midnight, I informed Earl in Australia that it was done. By the time I woke up, the whole world was aware of the news, which was highlighted in the global press. We had given Mr. Hallam the chance of having the new hand he had repeatedly requested, and the surgery was successful. He destroyed his chances by failing to take his medications. I was just relieved that there were no serious complications. He admits full responsibility for the rejection. Pathologists have studied the amputated hand to determine the rates of rejection of various tissue types. I kept the amputated hand in my home for several months, regularly sending samples to investigators in the US who had requested access to this priceless specimen. Eventually, I took the remaining samples to St, Mary’s Hospital where it was incinerated. However, Mr. Chatelier is doing well and is adhering to the anti-rejection therapy. The hands show no signs of rejection and are functioning particularly well with good sensation. His town on France’s west coast has given him full support, and he was making wooden model seagulls for sale until recently! In recent years, we have made significant advances in hand transplantation and learned much. Although the necessary expertise and immunosuppressant drugs have been available for some time, the hand remains a special symbol representing personal identity in ways other tissues do not. The hand represents a sort of halfway point in terms of personal identity, between internal organs and brain tissue. Opponents of brain tissue transplants argue that these are not simply about restoring normal function to the recipient but may also alter the recipient’s identity in a profoundly problematic way so that the person who consented to receiving the tissue is no longer the same person after the transplant. Similarly, we need to consider the broader function of the hand in relation to identity as an instrument of physical intimacy, contact with others, consummate skills in artists and musicians, and agency itself (for example, the use of “hand” to represent agency in phrases like “the hand of Fate,” “by his own hand,” or “the hand of God”). It is given in marriage, washed to escape blame, expresses our feelings, and carries out our commands. The hand’s intimate function might, more speculatively, be thought to give rise to rights in those with whom the donor and recipient have been intimate. To the hand, humanity owes its survival and achievements. I have written this chapter on behalf of the original international transplant team of which I was a part, including Professor Earl Owen (Sydney), Professor Jean Michel Dubernard (Lyon), Professor G. Herzbert (Lyon), Professor Xavier Martin (Lyon), Drs. Hari Kapila (Sydney), Marco Lanzetta (Milan and Sydney), and Dr. M. Dawahra (Lyon).