Dr. Fung,who joinedthe Clinic in2004, is aheavy hitterin the worldof transplantsurgery.Dr. Fung, who joined the Clinic in 2004,is a heavy hitter in the world of transplantsurgery. A member of the team that performedthe world’s first successful baboonto-humanliver transplant, he arrived at theClinic from the University of Pittsburghwhere he served as chief executive officer ofthe medical center’s renowned TransplantationInstitute. His impressive resume includesalmost 20 years of practice with one of themost prominent transplantation specialists inthe world, Thomas Starzl, M.D., who pioneeredorgan transplantation techniques inthe 1950s and performed the world’s firstsuccessful liver transplant in 1967. The Starzl-Fung team’s breakthrough work is standardreading in many a medical textbook.John Fung, M.D., Ph.D.A Short HistoryThe concept of transplanting a healthy organto replace a failing one is quite ancient.Reports going back as far as 800B.C. mention skin grafting for new nosesand the replacement of tissue damagedfrom burns, injury and disease. Yet it wasn’tuntil the early 20th century that the transplantof vital, solid organs became scientificallydocumented.In 1954, Joseph E. Murray, M.D., performedthe first successful human-to-humankidney transplant. Earlier in his careeras a surgeon at an army hospital, Dr. Murrayhad noticed that the skin grafts fromunrelated patients died quickly, while thegrafts between identical twins survivedlong enough for the patient’s own skin toheal. Dr. Murray and other surgeons discussedthis observation, hypothesizing thatthe closer the patients were genetically, the18 cleveland clinic magazine
slower the graft dissolution would be.After proving his hypothesis in animals,Dr. Murray performed the world’s firstsuccessful kidney transplant between theidentical Herrick twins, Richard andRonald, at the Peter Bent Brigham Hospitalin Boston.Despite new transplant successes, rejectioncontinued to be a source of frustrationand exploration for Dr. Murray andother transplant physicians, includingChristiaan Barnard, M.D., who is creditedwith the world’s first successful humanto-humanheart transplant. In 1967, Dr.Barnard transplanted the heart of a youngfemale automobile accident victim into a59-year-old man, Louis Washkansky.Washkansky, however, did not survivevery long. The drugs used to suppress hisimmune system had so weakened him thatpneumonia set in and he died 18 days afterthe operation. Dr. Barnard continued advancingthe science of cardiac transplantation,though the lack of effective immunesuppression hampered his progress.Tricking the BodyEven today, one of the most vexing butcritical issues in organ transplantation involvesbeating the body’s natural tendencyto reject the new organ or tissue. Thebody’s immune response is one of the keyways it fends off invaders. Unfortunately, itcannot distinguish between a harmful infectionand the “beneficial” invasion of atransplanted organ.It was this hurdle, in fact, that stymiedtransplantation advances for years after thefirst rush of excitement in the field withthe successes of doctors Murray, Barnardand Starzl. Transplant specialists noticed atthe time that, while they could successfullyperform the transplant surgery, patientsurvival rates were dismal.That picture changed for the better inthe wake of a new and more powerfulgeneration of immunosuppressive drugs -therapies that prevent the body’s immunesystem from rejecting foreign tissue. In1983, the Food and Drug Administrationapproved cyclosporine, which had an instanteffect on the field. “It was the drugthat most people would say revolutionizedsolid organ transplantation,” says Dr. Fung.“Everything took off from there.”Cyclosporine works by reducing thebody’s natural immunity, thereby preventingwhite blood cells from rejecting thenewly implanted organ.Even with the success of cyclosporine,chronic organ rejection remains a problem.The majority of transplant patientsrequire long-term treatment of large dosesof immunosuppressants, depressing theirimmune system and increasing the chancefor infection and malignancies.“The idea oftransplanttolerance is totrick your bodyinto thinkingthe new organisn’t fromanother body.”Peter Heeger, M.D.Peter Heeger, M.D., and colleagues, whoare part of an emerging transplant researchunit at the Clinic, are working on this problem.The Cleveland Clinic is one of fiveacademic medical institutions in NorthAmerica collaborating on a major five-yeartransplant study funded by the National Institutesof Health (NIH). This study intendsto follow the immune responses of heartand kidney transplant patients, and thensuggest ways to better calibrate and tailortherapies so that future transplant patientswill have positive responses.“Your body has a low-grade inflammatoryresponse to a new organ, thus creatingthe need for immunosuppressive drugs.We try to understand why an organ is rejected,what the cellular and other complicationsare,” explains Dr. Heeger. “Theidea of transplant tolerance is to trick yourbody into thinking the new organ isn’tfrom another body.”The goal driving much of the clinicalresearch on transplantation, he adds, is tounderstand how to improve the long-termsurvival rates of patients who undergothese procedures. As recently as 1985, theone-year survival rate for a transplantedkidney was between 50-75 percent. Today,the national average is well over 90 percent.“We’ve made great strides in shorttermsurvival for transplant patients,” Dr.Heeger notes. “But not for long-term.”The ultimate goal is to go beyond theuse of anti-rejection drugs. “What we needare ways to minimize the drug treatmentsand still have good results,” says Dr. Heeger.“It would be helpful to be able to predictthe immune response of a particular recipientto a particular donor organ beforea transplant occurs. This way, you couldpredetermine the strength of the immuneresponse, then tailor the [post-transplant]therapy to that response. By being able tomeasure the immune response, we havesomething to hang our hat on - before,during and after the transplant.”Building BridgesOrgan shortage and immune suppressionare the core motivators for innovation intransplantation. One of the areas showingpromise is in the development of variousassist apparatus. These are biomedicallyengineereddevices that can serve as a“bridge” strategy, helping patients survivelonger while waiting for an eventualorgan transplant.This strategy has worked, perhaps <strong>best</strong> ofall, in cardiac transplants. Nicholas Smedira,M.D., Director of the Clinic’s Heart TransplantProgram, says that with all the attentionbeing paid to innovative forms ofother therapies, the number of heart transplantshas stabilized in recent years. “Weused to do about 70 heart transplants a year,and in recent years it’s been closer to 60 ayear. My sense is that the number of hearttransplants is down all across the country.”What’s on the rise, however, is the implantationof innovative cardiac assist devices.Dr. Smedira has been a key innovatorin one such device, the left ventricularassist device, or LVAD. This battery-operatedsynthetic pump is surgically implantedand regulates the heart’s left ventricle,the source of most heart attacks and otherchronic cardiac problems.Heart pump devices have been used sincethe 1950s, but a new generation of these assistdevices, some of which purr along at anastounding 10,000 revolutions per minute,offer a real alternative to the need for transplantinga completely artificial heart. “Obviously,if you could put a device that’s thesize of a wallet onto the left ventricle, you’drather do that than transplant a totally artificialheart,” says Dr. Smedira.While ventricular assist device (VAD)technology for adults has constantly improved,currently available devices aremuch too large for children - in fact, someadult VADs are larger than the entire bodyof the smallest newborn.Last year a team of Clinic pediatric specialistsand biomedical engineers wereawarded a $4.2 million, five-year governmentcontract from the National Heart,Lung and Blood Institute, a part of theNIH, to continue the development of thePediPump pediatric VAD designed especiallyfor infants and small children.www.clevelandclinic.org 19
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