On February 2, 1999, Chicago Bears Hall of Famer Walter Payton tearfully announced that he needed a liver transplant due to a rare liver disease. Like thousands of people who lose the functioning of their organs, he clings to life while waiting desperately to receive a transplant (1, Fig. 1). Since the first successful human kidney transplant was performed in 1954, the technical difficulties of transplantation were gradually overcome. Rejection of the donated organ due to mismatch in the major histocompatibility antigens or the blood group antigens between donor and recipient, however, became a barrier to success. With improvements in organ matching and immunosuppression, transplant survival increased significantly so that by 1995, kidney, lung, liver, heart, bone marrow, and cornea transplants were considered routine. Donors, however, were scarce with 36,000 waiting for allotransplantation in 1994. Over 10,000 people died between 1988-1993 while waiting for a transplant (2). Because of the scarcity of donors, researchers are moving toward procuring organs from animals or producing them through tissue engineering. The fast evolving xenotransplantation and tissue engineering offer hope as adjuncts to human donation in the challenging field of organ transplantation (1).
Xenotransplantation intrigued the public in 1984 when a baboon heart was transplanted into a 15 month-old baby with a defective heart. Baby Faye survived for 20 days. In 1992, when a 35-year-old father of 2 children received a baboon liver, PETA protesters poured into the streets. Three years later, an AIDS victim Jeff Getty received a marrow transplant from a baboon (3). In early transplantation, primates were selected as donors because of their close relationship to humans. Although chimpanzees share 98% of the genes with man, the differences are enough to require greater immunosuppression than allografts to prevent rejection. Of the 31 xenotransplants performed in the U.S. and South Africa between 1963-1993, few survived beyond 3 months (4, Fig. 2).
The turning point in xenotransplantation occurred when scientists discovered a new way to prevent hyperacute rejection, which causes organs to turn black within minutes of transplantation. Professor Jeffrey Platt of Duke University, with Nextran, a biotech company, engineered pigs that express two human genes, decay accelerating factor and CD 59. These genes inhibit the complement cascade that initiates rejection (6, Fig. 3). A baboon that received a humanized pig's heart survived for three months without immunosuppression because its immune system would not recognize the "pig heart" as foreign (7). The second milestone was removing the sugar molecule normally present on the cell surface of all animals excluding apes, monkeys, and humans "that acts as a flag for the human immune system" (6). Organs from transgenic mice and pigs free of this sugar molecule became "invisible" to the human immune system. A third approach was trying to prevent acute vascular rejection due to blood clots forming in xenografts, weeks after transplantation (6). Although some transplant patients live beyond 20 years, chronic rejection can only be reduced by enhancing graft-host matching. Companies like Nextran are inserting "human genes into the germ lines of animal embryos" to make xenografts more compatible with the human genome (8). Dolly's cloning provided the technique for the mass production of transgenic animals "uniformly suitable for xenotransplantation" (9).
With the growth of xenotransplantation, society feared cross-species transmission of retroviruses to man. The finding that retroviruses may hide in a primate genome and be activated only after transplant and immunosuppression raises the possibility of a public health epidemic much like AIDS (10). A recent study reports that AIDS, which now infects 35 million people, originated from African chimps, increasing this fear (11). Research now focuses on pigs that are readily available, easily bred under sterile conditions, and are "good potential donors because their organs are about the same size as human organs and work like human organs" (6). The 1997 discovery, however, of a Porcine endogenous retrovirus was a major concern, but researchers believe that this virus can be removed from transgenic pigs. Transplant recipients can also be vaccinated against this virus (7). Although the U.K. Institute of Biology believes that it is ethical to use xenotransplants to meet the needs for donors, it bans primate donors until the infection issue can be resolved (12, 13). The U.S. Institute of Medicine believes that stringent screening would minimize the risk and concludes that "the potential benefits of xenotransplantation are great enough to justify the risks" (9).
Aversion to xenotransplantation often stems from animal rights activism and cultural issues. Animal activists denounce the breeding of transgenic animals to act as human spare parts and accuse proponents of speciesism in which man favors his own species over animals (14). Primates are endangered and have an advanced family structure which would cause them to suffer if a member is removed. But selective breeding of animals for food has been accepted for centuries. If a pig is used to save the life of an individual, is it any worse than killing pigs to make sausages, or hunting for sport (15, 16)? Many animal activists are vegetarians, but will they propose the "wholesale boycott of a medical system in which training and research [are] drenched in the blood of non-humans" (17)? Would they refuse pork insulin or a pig valve (5)? Two studies from Australia suggest that there may be cultural aversion to xenotransplantation. Only 40% of nurses and dialysis patients were willing to accept xenografts, while 60% of dialysis patients were willing to accept allografts or cadaver donors (18, 5). In the U.S. 51% polled were willing for a xenograft (19). Aversions are likely to fade away gradually. In the Gulf countries, which consider removal of cadaver organs as an assault, organ donation is now seen as a "way of saving lives and of helping others" (20). However, is a Muslim likely to accept a pig donor? In India, where organ removal from a cadaver was considered "mutilation," the first transplant bank for brain-dead individuals was organized (21).
The high cost and disparity of transplant waits are major issues in transplantation. In the 1970s, Medicare began paying for kidney dialysis and transplants, but not donors. If families are allowed to sell organs, it would increase organ donation but also create more unacceptable socioethical problems (22). Many transplants are still considered experimental, so they are not covered by insurance, thereby limiting access to these procedures. Commercial production of xenografts and patenting would add organ costs to an already expensive process. Although many oppose the patenting of medical innovations, precedents for this have already been established (23). Transplant waits will decrease with increasing success of xenotransplantation. Waiting lists in the U.S. are maintained by 11 regional transplant registries overseen by the United Network of Organ Sharing. Organs are first offered locally, then regionally, then nationally to patients with the most critical needs. Despite this protocol, there is a "crazy quilt of differences [in transplant waits] from coast-to-coast" (24). In Nebraska, the median wait for a liver transplant is 596 days, while in Iowa, it is only 56 days (24, fig. 4) A proposal by the Department of Health and Human Services to form a national registry to equalize the waiting time was recently blocked (25). Concerns about preferential treatment surfaced when baseball legend Mickey Mantle received a liver transplant within days of being placed on the list (26). To avert such controversy, physicians treating Walter Payton stated that although he was a celebrity, he may have to wait two years to receive a liver. Since over 100,000 Americans would die each year while waiting for a human transplant, biotech firms believe that xenotransplantation would be the answer. Salomon Brothers project that by the year 2010, 450,000 people worldwide would have received a xenotransplant, a market value of over 6 billion dollars (8). Therefore, the sale of xenografts should be regulated through an ethical, humane distribution system driven by need rather than cost.
Joseph Vacanti, a surgeon from Harvard and Robert Langer, an engineer from MIT, pioneered efforts at tissue engineering designed to "make organs rather than simply move them" (27) In tissue engineering, an ultra pure, biodegradable polymer is molded to the shape of the desired tissue or organ. After treatment with a "sticky" compound, it serves as scaffolding on which functional cells are seeded. As the cells multiply, with the help of signals from growth factors and nourishment from neighboring blood vessels, the scaffolding disintegrates, and a new permanent tissue grows in the patient (28). In 1996 a 16-year-old boy with severe burns survived after receiving artificial skin produced by Advanced Tissue Sciences (27). With burns over 60%, there were few donor sites for skin autografts. Simulated skin consists of a silicone epidermis to prevent dehydration and infection and a collagen/chondroitin sulfate dermis to reduce scarring and promote healing. Epidermal cells from the patient inserted into the dermis reduces rejection, but it would take 3-4 weeks to grow. Human neonatal dermal fibroblasts cultured in vitro and cryopreserved would grow more rapidly. The present technology appears suitable for engineering of skin, bladder, islet cells of the pancreas, and hepatocytes (1).
Although the miracle drug insulin began saving lives 75 years ago, many diabetics are succumbing to long-term complications due to poorly-controlled blood sugar. If islet cells are transplanted, they would respond to fluctuating blood sugars. The first human allograft trials in 1986 were performed on kidney transplant patients who were already immunosuppressed. In an effort to extend this technique to uncomplicated diabetics, islet cells are now encapsulated to protect them from rejection and auto-immune destruction. Because of the scarcity of human cadaver pancreases, islet cells from aborted human fetuses and from pig islets are implanted (29). Soon, genetically engineered human cells are likely to be used for islet transplantation (1).
On January 30, 1999, the L.A. Times reported that fabricated bladders, which had been successfully transplanted into six beagles by Dr. Anthony Atala of Harvard Medical School, had functioned for 18 months. This organ was produced by seeding smooth cells on the outside and urothelial cells on the inside onto a bladder-shaped scaffolding. This was a significant breakthrough because it demonstrates the cells' innate capacity to regenerate and form organs. Atala has been growing a bladder in a glass jar with cells taken from a 10-year-old boy. He hopes to transplant this bladder shortly without immunosuppression (30). Fabricated bladders would improve the quality of life of 54,200 Americans who lose their bladder to cancer every year. In another exciting breakthrough, hepatocytes have produced albumin, removed bilirubin, and formed bile ducts in animal experiments. Hepatocytes, which could have been cultured in vitro placed between collagen layers within a hydrogen capsule, could be injected into humans to simulate the liver. Such hepatocytes may replace traditional liver dialysis and may even act as a permanent replacement for the liver (1). Tissue engineering became a reality when a new thumb was transplanted onto a patient in August 1998 (31).
With the culturing of embryonic stem cells(ES) reported in November 1998, it is likely that ES cells will be increasingly used to produce tissues and organs on a commercial scale. Most human cells differentiate into specialized cells, but ES cells remain totipotent. John Gearhart of John Hopkins reported sifting through aborted fetuses to discover these cells (32). These have been cultured and steered toward differentiation into specialized cells, including nerve cells (34). Some cells from neonates and fetuses have been used with permission, but research on fetuses would invariably call forth strong opposition from Right to Life Groups. ES technology can manipulate the embryo, so that it can expand into "a mass of undifferentiated tissues of any size" (35). This makes it possible for a tissue to be grown without forming an embryo and may decrease opposition. In February 1999, the U.S. government granted permission for research in stem cells, paving the way for the use of fetal cells for tissue engineering.
Although xenotransplantation and tissue engineering are likely to revolutionize organ transplantation in the new millennium, allotransplantation is the gold standard today. Every effort should be made to improve the impact of allotransplantation by increasing the harvesting of cadaver donors from its present low level of 20%. Education, broadening the donor criteria, development of new immunosuppressives like Tacrolimus, and promotion of tolerance should be pursued relentlessly (36). The "opt-out" donor system in some European countries assumes that everyone is a donor unless he opts out. This would not gain favor with the Americans. The magic of genetic engineering with the knowledge gained from ES, cloning, and artificial chromosomes will be able to customize grafts for individuals and remove the element of chance prevailing with cadaver donors (37-40). Xenotransplantation and tissue engineering are cutting edge technologies that will blossom in the new millennium but have significant applications even today.
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