Xenotransplantation is the transplantation of living cells, tissues, or organs between members of different species. In the human clinical context, xenotransplantation refers to the use of living biological material from any nonhuman species in human recipients for therapeutic purposes. The practice began with attempts to develop whole animal organs as “spare parts” to replace failing human organs. Current efforts also involve cellular applications.
Xenotransplantation is currently experimental. However, some applications have progressed to clinical trials in humans and could become available therapeutic options in the early twenty-first century. Decisions about such trials must draw on areas in which science currently offers inexact guidance, raising interrelated issues of ethics and social policy. Forging consensus on appropriate public policy is multinational in scope, often pits different stakeholders against each other, and has triggered heated debate among scientists, ethicists, and the public. In this respect, the issues raised by the exercise of social policymaking for xenotransplantation provide a good case study for more general discussions of how biomedical technology should be developed and implemented.
Organ transplantation has been hailed as one of the most remarkable achievements in medical history. The original kidney transplant successes of the mid-1950s were between genetically identical human twins, whose immune systems would not recognize each other’s organs as genetically foreign (and therefore would not reject them). Soon thereafter, kidneys for transplantation were obtained from non-twin siblings, from unrelated living donors, and, finally, from cadavers. These transplants between members of the same species are known as allotransplants, and apart from the rare identical twin transplants, all require some form of manipulation of the recipients’ immune systems to prevent rejection of the donated organ.
Medical advances, particularly the discovery of powerful new immunosuppressive drugs, have greatly increased the number of transplants performed worldwide. Today, where facilities and expertise are available, it is fairly routine to transplant kidneys, hearts, livers, lungs, and other organs and tissues between human beings. However, this very success has created a disparity between the demand and supply of organs. As a result, thousands of patients die every year while waiting to receive a suitable organ for transplant. The situation is particularly severe in developing countries. Were xenotransplantation to become an effective and inexpensive method of addressing end-stage organ failure, however, the same social and economic issues that limit the ability to maintain transplant programs in developing countries today will hinder efforts to develop and maintain xenotransplantation programs. Basic healthcare needs (such as vaccination, basic diagnostics, and drugs) and accessible clean water will compete with any advanced technology for limited healthcare dollars.
Allotransplantation raised important ethical issues, many of which continue to be debated (Dossetor and Daar). While xenotransplantation raises similar issues, especially in terms of equity of access and diversion of resources, it also raises issues pertaining to human rights, animal welfare, and public health risks.
While consensus is not universal, xenotransplantation is defined as “any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source; or (b) human body fluids, cells, tissues, or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs.” This is the definition adopted by the U.S. Public Health Services, and the Council of Europe has a similar one. This definition would include transplantation of an animal heart into a patient with heart failure, implantation of pancreatic islets for people with diabetes, circulation of blood from a patient with acute liver failure through a nonhuman liver or a device containing nonhuman liver cells, or the treatment of burn patients using human skin cells that have been grown ex vivo (outside the body) over a layer of mouse feeder cells. The transplantation of inert animal tissue (such as pig heart valves) does not fall under this definition.
With the exception of the inexplicable survival for nine months of a kidney transplanted from a chimpanzee into a human recipient in the 1960s, all whole-organ xenotransplants have failed rapidly, despite massive immunosuppression of the human recipients. In contrast, a number of preclinical trials of cellular therapies have shown enough promise to justify progressing to clinical trials. These include neural-cell transplants to treat disorders such as Parkinson’s disease, intractable epilepsy, and other degenerative neurologic diseases (Fink et al.). There have also been attempts at perfusing the blood of patients in acute liver failure ex vivo through nonhuman animal livers until a human liver becomes available or the patient recovers (Chari et al). However, as of April 2003, no xenotransplantation application has demonstrated a high enough level of efficacy in clinical trials to allow progression to general clinical adoption.
The initial technical obstacle to xenotransplantation is the phenomenon of hyperacute rejection, which occurs when tissue is transplanted between two distant (discordant) species, for example between pigs and humans. Hyperacute rejection is swifter and more severe than the acute rejection response usually seen in transplants between individuals of the same species. Xenotransplant rejection responses are, however, also less severe in transplants between members of closely related (concordant) species, such as between rats and mice. A carbohydrate molecule known as Gal alpha-1, 3 Gal (alpha-gal) is present on all cells of most mammalian species, including pigs, which at present are considered the most likely sourceanimal species. Humans and closely related old-world primates such as chimpanzees lack alpha-gal, but have naturally occurring antibodies that recognize it as foreign. In hyperacute rejection these antibodies would react against the alpha-gal on pig cells, causing the blood to clot (thrombosis) and the transplanted organ to die within minutes.
Activation of complement, a substance found in blood, is part of normal defense mechanism against foreign tissue or microbes. The presence of chemical substances that inactivate complement when its work is done normally prevents thrombosis. These complement factor regulatory proteins (CRPs) are species-specific. Thus one of the scientific responses to the challenge of hyperacute rejection has been to create transgenic pigs in which the genes for various human CRPs have been incorporated into the pig’s genome, and thus prevent thrombosis. Experiments in which tissue from these transgenic pigs was transplanted into nonhuman primates have shown better graft survival rates than using tissue from unmodified pigs, raising hopes that similar improved results would be reproduced in human recipients.
Another genetic approach to dealing with hyperacute rejection has aimed to alter the expression of the alpha-gal molecule on pig tissue either by inserting genes that result in carbohydrate remodeling (Sandrin et al.,1995); by a reduction in expression of alpha-gal (Sharma et al.); or by “knocking out” (removing) the gene for the enzyme that is involved in making alpha-gal (Tearle et al). A double knockout pig, (a pig in which both copies of the gene have been deleted from its genome) was announced in 2002 (Phelps et al.). Others have focused on reducing the massive inflammatory responses.
Hyperacute rejection is only one challenge facing xenotransplantation. Even if hyperacute rejection can be avoided, progressive phases of rejection would follow, including acute vascular rejection, cellular rejection, and chronic rejection.
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