XENOTRANSPLANTATION

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.

Xenotransplantation Defined

While consensus is not universal, xenotransplantation is defined as "any procedure that involves the transplantation, implantation, or infusion into a human recipient of either

TABLE 1

(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.

Scientific and Clinical State of the Art: Continuing Challenges

Tables 1 and 2 summarize the attempts at clinical xenotransplantation since the 1960s. 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.

HYPERACUTE REJECTION. 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

TABLE 2

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.

OTHER IMMUNOLOGICAL CHALLENGES. 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.

Related research focuses on attempts to manipulate the immune system of higher animals in ways that would make it "tolerate" one, or a few, foreign antigens without paralyzing the whole immune system. Should immunological tolerance be achieved in humans, it would become possible to transplant organs without administering the large doses of powerful immunosuppressive drugs that leave the recipients vulnerable to dangerous infections.

PHYSIOLOGICAL BARRIERS. Physiological barriers may also stand in the way of successful xenotransplantation. For example, there is serious doubt that a pig liver will be able to sustain a human being for long. The liver is not only a detoxifying and storage organ, it is the main factory in the body for the manufacture of a large number of crucial molecules, including proteins such as albumin and clotting factors. Many of these are species-specific and will function inadequately in humans (Hammer and Thein), and some may also evoke immune reactions. In contrast, porcine insulin has successfully treated human diabetics; thus porcine pancreatic islet transplantation may offer human diabetics hope for a cure.

Xenogeneic Infections

Another reason for caution is that infections not normally encountered in humans might be transmitted from source animals to human recipients. In addition to the risk to the recipient, there is a theoretical risk that an infected recipient could transmit the infection to others. Of particular concern in this regard are infectious agents such as retroviruses that result in persistent infections and remain clinically quiescent for long periods before causing identifiable disease. During that "silent" period they can be transmitted from person to person, infecting many people before the danger is recognized.

In the past, animal viruses, such as Nipah virus and avian influenza, have been known to infect humans, resulting in outbreaks of disease of limited scope and duration (CDC, 1998, 1999). Of even greater concern is evidence that viruses once restricted to a nonhuman host species may infect and adapt to humans as a host species, as is theorized to have occurred with the HIV/AIDS pandemic (Hahn et al.). There is some controversy about whether nonhuman primates are more likely than other species to transmit dangerous infections to humans (Chapman et al). In response to widespread concern, the U.S. Food and Drug Administration produced an advisory in April 1999 against the use of primates as source animals pending adequate demonstration of safety.

Exogenous infection (infections from agents passed among animals by contagion) can theoretically be controlled by eliminating them from the source animals. More uncertainty exists about the significance of endogenous retroviruses, which exist as part of the genetic material of humans, nonhuman primates, pigs, mice, and perhaps all animals. Endogenous retroviruses are passed from one animal to another through inheritance. Unable to cause active infection in the host animal, many can produce a virus capable of causing infection in cells from other species in the laboratory. Thus, living biological material devoid of recognized microbes has an innate infectious potential of uncertain significance for xenotransplantation. Specifically, both pigs and nonhuman primates have been shown to have endogenous retroviruses that can infect human cells in the laboratory.

Since the pig is the most likely source animal for human clinical xenotransplants, endogenous retroviruses of pigs have become a major focus of research. Porcine endogenous retroviruses (PERV) exist in the genomes of all pigs. Several variants of PERV have been characterized that vary in their infectivity. It would be difficult, but perhaps possible, to eliminate PERV through breeding or genetic manipulations (Patience et al.; Stoye).

In animal experiments, short-lived (but nonclinically obvious) replicative infections have been documented (van der Laan et al.), and PERV can be transmitted from pig cells to human cells when they are cultured together in the laboratory (Patience et al.; Wilson et al.), but there is currently no convincing evidence that PERV can cause infections leading to disease in humans. This does not, of course, exclude the possibility that it may be capable of doing so given the right circumstances.

HUMAN PATIENTS PREVIOUSLY EXPOSED TO PIG TIS SUE. In the past decade or so a small but significant number of patients have been exposed to various experimental forms of xenotransplantation. Several studies of these patients have found no evidence of PERV infection, despite evidence that many of those exposed exhibited "microchimerism" (they had small numbers of pig cells in their bodies which provided ongoing exposure to PERV). While many scientists do not consider that these studies conclusively establish the absence of infectious disease risk associated with xenotransplantation, they are reassuring to some extent.

Ethical, Social and Economic Issues

Research and development costs for any major new technology, including xenotransplantation, can be high. If xenotransplantation progresses from experimentation into clinical practice, the final cost is uncertain. Even beyond the development costs, many factors will contribute to the expense of a clinical xenotransplantation program, including rearing specific infection-free source animals, laboratory tests for early diagnosis of infection, specialized staff, and maintaining monitoring and surveillance regimes. Costs will also be determined by companies owning intellectual property rights to the technologies employed, the size of the market, and so on. Whether this cost will exceed the current costs of medication and extended hospital care for patients awaiting allotransplants is uncertain. It seems likely, however, that xenotransplantation, like allotransplantation, would initially benefit only a privileged few.

It has been argued that xenotransplantation efforts could be justified only if large numbers of patients could benefit at reasonable cost and with no significant diversion of resources from the healthcare system. In this light, efforts to develop applications of porcine pancreatic islets for functional cure of type I diabetes mellitus are the most easily justified. While many applications of xenotransplantation research would benefit relatively few patients, diabetes mellitus affects a large number of people and poses substantial costs to society, both in terms of economics and in years of productive life lost.

PRECAUTIONARY PRINCIPLE VERSUS RISK-BENEFIT ANALYSIS. It is possible that the public may eventually benefit indirectly from successful widespread xenotransplantation due to a decrease in the societal burdens of healthcare costs and years of productive lives lost due to chronic diseases. The public may, however, also be put at risk of infections. As a result, although the extent of the risk is not clear, many nations have regulations that would allow xenotransplant clinical trials only when using husbandry methods that eliminate exogenous infectious agents from source animals prior to transplantation, and ensuring ongoing monitoring of receipients.

As long as uncertainty about the risk to society exists, different constituencies will perceive the same scientific data on public risk in different ways. Those basing their publicpolicy decisions on traditional risk-benefit analysis would tend to favor patients, perhaps at the expense of the public. Many clinicians and scientists in the transplant community do this instinctively, emphasizing the benefits in terms of a moral imperative to ameliorate suffering and save lives. This attitude is reflected by the Institute of Medicine's statement that "our own humanity is diminished if, in order to protect ourselves, we turn away from others whose suffering is both clearly visible … and … devastating in … impact … we are morally obliged, not only as individuals but as a community, to accept some risk to ourselves to save our fellow human beings from more certain harm" (Institute of Medicine, p.71). On the other hand, those who would base decisions on the "precautionary principle" (of which there are several versions) would tend to pay more attention to the public interest, perhaps at the expense of needy patients (Daar; 2001).

The precautionary principle originated in environmental risk discourse, but has been adopted into health-policy discussions partly because of the history of infections with agents that cause AIDS, mad cow disease, and so on. It is easy to misunderstand, misquote, and misuse this concept, as there is no single definition. There are two well-known formulations. The first, from Article 15 of the United Nation's 1992 Rio Declaration on Environment and Development, states: "In order to protect the environment, the precautionary approach shall be widely applied by States according to their capabilities. Where there are threats of serious or irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation." The second, the so-called Wingspread Declaration, states: "When an activity raises threats of harm to human health or the environment, precautionary measures should be taken, even if some cause-and-effect relationships are not established scientifically."

As can be expected, the precautionary principle has become a subject of intense scholarly debate and ethical analysis (Saner). Some have argued that to be true to itself the precautionary approach requires risk-risk analysis, which would suggest an alternative formulation for the principle along the lines that "Public health and environmental policies should attempt to minimize net risks to public health and the environment based on the best available scientific information and their net anticipated cost to society" (Goklany, p. 1075).

ANIMAL ISSUES. The great British reformer Jeremy Bentham, a key figure in the development of utilitarian ethics, was also one of the earliest advocates for the humane treatment of animals. In 1780 he asked two fundamental questions: (1) "The question is not can they reason? nor can they talk? but can they suffer?" and (2) "What insuperable line prevents us from extending moral regard to animals?"

Since Bentham's time, it has become widely recognized that all vertebrates essentially perceive pain in the same way. Some argue that animals can also suffer. Animals reared in stressful conditions in captivity experience fear, boredom, isolation, and separation anxiety. Recent evidence indicates that the great apes are capable of using language, including human words (BBC), and also exhibit forms of culture. The emotional repertoire of nonhuman primates, according to ethologists Jane Goodall and Dian Fossey, includes love, sorrow and jealousy. These attributes have led some to argue that such animals are more than just sentient beings, and that they possess intrinsic value. If so, then they must have rights. To some, ignoring these rights is a form of speciesism, a term analogous to racism, and a growing minority are embracing this view.

The awareness of such qualities of animal life raises serious questions: What is it in humans that bestows on us the right of killing an animal for our own self interest? Is it our complex use of language and tools? Is it our rationality, intentionality, consciousness, conscience, or empathy? Immanuel Kant argued that all nonhuman animals can be regarded as means to ends, and that only humans, who are "rational beings," have the intrinsic right to be considered as ends in themselves. If capacity for rational thought is the basis of intrinsic rights, some have questioned whether we are justified in using organs taken from a nonhuman primate but not those taken from an anencephalic, or severely retarded, human. Philosophic justifications for the prohibition against killing incapacitated humans for such purposes have referenced their memories, if any, their potential to grow and form lasting relationships, their capacity to be mourned for long periods, and the effect that using their organs would have on relationships between humans. Others justify this distinction based on religious or metaphysical notions of the inherent elevation of humans above other creatures. These views are not convincing to many animal rights advocates, however.

NONHUMAN PRIMATES AND PIGS. Nonhuman primates are biologically close to humans, and many humans feel an emotional attachment to them. They are a concordant species, and would therefore be easier to use as sources for xenotransplantation (from an immunological and physiological perspective) than pigs, which are a discordant species. However, there are several arguments against using them for such purposes. First, the microorganisms they harbor may more easily infect and be pathogenic in humans than would be the case with pigs. Humans have a long history of contact with the pig, and the resultant physical proximity has only rarely led to the acquisition of serious infections. Second, it is not possible to raise primates under the husbandry conditions that currently allow for the production of pig herds from which exogenous infectious agents of concern have been excluded (specific-pathogen-free pigs). Third, some primate species (e.g. the chimpanzee) are endangered. While the baboon exists in large numbers and is considered a pest in some parts of the world, it breeds slowly (and it is currently impossible to rear specific-pathogen-free baboons). Thus, a consensus to exclude nonhuman primates as source animals for xenotransplantation has emerged.

There are laws to protect research animals in many countries. Sensible guidelines include the 3 Rs of Russell and Burch (1959); namely to "reduce, replace, and refine"—to which we might now add "respect and reconsider." There are increased efforts underway to look for alternatives to animal use.

GENETIC MANIPULATION OF ANIMALS FOR HUMAN PUR POSES. The recently acquired power to manipulate the genomes of animals, including the ability to produce "double knockouts" and to clone these over several generations raises an important ethical question: Where do we draw the line? The Kennedy Report (1997) and other similar reports have concluded that the current extent of manipulating the pig's genome to incorporate human genes or other manipulations of the same magnitude raise little ethical concern provided the pig "recognizably remains a pig." Today, on balance, a case has been made that it is ethically acceptable to use pig organs, but not organs from nonhuman primates, for human xenotransplantation. At this stage of development a larger consensus exists on the importance of attending to "animal welfare" than to "animal rights."

RELIGIOUS PERSPECTIVES ON XENOTRANSPLANTATION. The views of different religions concerning xenotransplantation largely depend on the manner in which these religions consider animals and how they should be treated. From the religious perspective, it would be important that a xenotransplant not tamper with the human personality or the individual's freedom, and ability, and eligibility to bear responsibility. Minimally, all religions consider that humans have stewardship responsibilities to minimize the pain and suffering of animals being used for the benefit of humans.

Within the three major monotheistic religions (Judaism, Christianity and Islam), human beings have canonically been considered unique, with the rest of creation existing to serve humankind. The Old Testament, the first five chapters of which are canonical to both Jews and Christians, declares: "Man was made in God's image and has dominion over all other creatures and all the earth" (Genesis 1:26). In both Judaism and Islam the imperative to preserve human life overcomes many religious prohibitions.

The pig is considered to be ritually unclean in both Islam and Judaism, and it is not surprising that authorities in these two religions have been asked if the pig can be used as a source animal for organs. In Islam, the conclusion of the majority seems to be that this would not be a barrier to xenotransplantation, based on the Shariah principle that need and necessity can allow that which is forbidden—and that, in any case, the prohibition is only to eating pig tissue. F. Rosner, a physician and scholar of Jewish medical ethics, has come to the same conclusion with regard to Judaism. There is, however, a minority opinion in Islam that pigs, because they are ritually unclean, cannot be used as source animals.

A number of thoughtful Christian commentators have written about xenotransplantation. On the whole, these are generally accepting, while emphasizing that animal suffering should be minimized. The Catholic Church addressed xenotransplantation as far back as 1956, and in 2000 Pope John Paul II restated its permissive position:

It is not my intention to explore in detail the problems connected with this form of intervention. I would merely recall that already in 1956 Pope Pius XII raised the question of their legitimacy. He did so when commenting on the scientific possibility, then being presaged, of transplanting animal corneas to humans. His response in still enlightening for us today: in principle, he stated, for a xenotransplant to be licit, the transplanted organ must not impair the integrity of the psychological or genetic identity of the person receiving it; and there must also be a proven biological possibility that the transplant will be successful and will not expose the recipient to inordinate risk. (Transplantation Society)

Some Christian arguments against xenotransplantation have focused on the themes of "playing God" and "interfering with creation." These arguments have less emphasis in Judaism and Islam.

Hinduism, Buddhism, and some Animist traditions have not drawn such a sharp theological distinction between humans and other animals, seeing all as part of a hierarchy of creatures, with indistinct borders between them. Other religions supportive of xenotransplantation include Baha'i and Sikhism. Those that have religious concerns about xenotransplantation include Buddhism, Hinduism and Native American faiths (Council of Europe).

REGULATORY CHALLENGES. The uncertain potential for introducing xenogeneic pathogens has influenced many countries to develop specific policies that incorporate very stringent safety standards for clinical xenotransplantation. Some countries have initiated moratoria, while others have allowed limited and tightly monitored clinical trials. Several countries have developed policies that advocate caution with xenotransplantation clinical trials, requiring that they occur only with regulatory oversight and involve stringent standards for animal husbandry, particularly for screening and surveillance for infectious diseases. (Bloom; Tibbel; OECD).

The Council of Europe, the European Agency for Evaluation of Medicinal Products, and the United Kingdom Xenotransplantation Interim Regulatory Authority (UKXIRA, 2003) are developing specific policies on at least certain kinds of xenotransplants that incorporate the concepts of safety built around pre-xenotransplantation screening to prevent transmission of infection and post-transplantation surveillance to maximize the probability of early recognition and containment of any infections introduced through xenotransplantation. Further, the European Union has advocated multinational efforts toward consensus development and collaborative work to minimize threats from emerging infections in general.

Multinational organizations have recognized infectious disease issues associated with xenotransplantation as policy issues that transcend national boundaries. The World Health Organization (WHO) has produced recommendations for addressing and harmonizing issues related to infection control, monitoring, sharing of scientific information, consent, and human rights. Both the WHO and the Organization for Economic Co-operation and Development (OECD) have recommended that member states develop regulatory frameworks for xenotransplantation clinical trials, and they have taken leadership roles that encourage international collaborative efforts to minimize infectious risks and actively discourage expatriate xenotransplantation experiments in countries with poor regulatory environments.

Some professional societies were early critics of efforts to bring xenotransplantation clinical trials under special regulatory oversight. In recent years, however, most professional societies have been active advocates for clinical trials under regulatory oversight with stringent husbandry and infection surveillance standards. Many professionals working in xenotransplantation are concerned about "xENOTOURISM" (the migration of patients across geopolitical boundaries to obtain unregulated xenotransplantation "therapies"). These patients may undergo risky procedures without adequate understanding, and they may bring unrecognized infections back to their home communities. Further, professionals who conduct expatriate xenotransplantation clinical trials potentially endanger the ability of the field to move forward in a systematic way. In an effort to discourage such practices, the International Xenotransplantation Society has adopted a rule that reports of such experiments will not be accepted for presentation at its meetings or for publication in its journals.

MANAGING POTENTIAL CONFLICTS OF INTEREST. The increasing participation of private interests in biomedical research is an important trend. One of the key catalysts of this change in the United States was the passage in 1980 of the Bayh-Dole act, which transferred intellectual property rights to researchers funded by federal research monies. In addition, universities in many countries must now attract more private funding to function in a very competitive environment. As a result, companies and investigators with potential conflicts of interest (COI) are testing increasingly powerful experimental therapeutic interventions.

Identifying ways to deal with potential COI while introducing innovative therapies is a complex issue and a constant source of ethical tension. Many would argue that full disclosure of financial and other COI by both institutions and investigators is adequate to manage such COI. Others have argued that disclosure alone may not suffice, and that even a pilot trial should not be conducted if an institution has a major financial interest in the outcome (Emanuel and Steiner). The Institute of Medicine has observed that "Clinical trials with cellular xenotransplants are already under way, and a real danger exists that the commercial applications of xenotransplant technology will outstrip both the research base and the national capacity to address special issues raised by xenotransplantation, including the risk of disease transmission" (Executive Summary, p. 4).

TIMING OF CLINICAL INTRODUCTION OF XENOTRANS-PLANTATION OF WHOLE ORGANS. Although small-scale experimental clinical xenotransplantation of cells and xenotransplantation involving ex vivo contact of human living cells with living nonhuman animal cells is underway in some countries, the question of when it would be prudent to translate laboratory successes into clinical trials remains open. The accepted standard is that before clinical trials are attempted in humans, preclinical research should provide proof of the principle hypothesis adequate to anticipate that humans may benefit from the experiment. lec. However, no consensus has been reached on what would constitute adequate graft survival in animal experiments to justify clinical trials. Attempts to define this crucial criterion have ranged from a median survival time of a minimum of three months to the suggestion that, although it is likely that hyperacute rejection can be prevented, xenotransplants should be delayed until there is a better understanding of acute vascular and cellular responses (Cooper et al.).

EPIDEMIOLOGICAL SURVEILLANCE AND POST-TRANSPLANT PATIENT MONITORING. In the past, infections transferred across species boundaries (e.g. HIV-AIDS, parvoviruses, SARS coronavirus) have spread globally. The development of international surveillance for xenotransplantation-associated infections has been proposed as a way to assist countries to manage risks associated with infections introduced through xenotransplantation performed within and beyond their borders (Rhonchi). Such recommendations raise concerns for many people. The concept of lifelong international surveillance of xenotransplant recipients is fraught with ethical complexities. International consensus has not been achieved on the definition of xenotransplantation, on what constitutes a xenogeneic infection or disease, on what events should be reported and by what methods, or on which individuals should constitute the population under surveillance. Whether a surveillance system should only report transmission of xenogeneic infections from recipients to their contacts, or should go further to collect information on the contacts themselves, is a source of controversy. All proposed national policies for monitoring xenotransplantation recipients are intrusive. Most advise against unprotected sex, donation of blood or other biological materials, and for education of intimate contacts. Some go further to require the consent of intimate partners for xenotransplantation, active surveillance of intimate contacts as well as xenotransplant recipients, and pre-transplantation agreements to avoid procreation post-xenotransplantation.

PATIENT-PHYSICIAN RELATIONSHIPS AND CONSENT. The perceived potential for xenotransplantation to benefit an individual while putting the larger community at risk complicates both the patient-physician relationship and the issue of informed consent. The Helsinki Declaration on Ethical Principles for Medical Research Involving Human Subjects states that, in medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society. Xenotransplantation clinical trials present situations that may place the interests of recipients and the greater good of society at odds. If a doctor is required to think of the public interest rather than merely the interests of the immediate patient, the traditional role of the physician as patient advocate is altered. At best, this will create confusion, since the physicians must weigh the responsibility to individual patients against the public good. At worst, the doctor-patient relationship itself could become one of antagonism rather than of trust (Daar, 1997).

The current informed-consent requirements for patients who might receive xenotransplants exceed those required in most other research settings. A major question on which there is no consensus at present is the problem of what to do if a patient changes her or his mind about intrusive follow-up monitoring and the waiver or curtailment of confidentiality rights previously agreed to. Informed consent is not usually legally binding on the patient, who retains a right to withdraw participation at any point in the investigational process.

Given the expectations of lifelong follow-up for initial xenotransplant recipients, a different kind of consent has been discussed (Daar 1999). A specific legal contract might provide enforceability of pre-transplant agreements for lifelong monitoring. Unlike the traditional consent form, such a contract would allow specific curtailment of the patient's rights (the traditional consent procedure does not, in all cases, require that a document be signed; more often than not, the signed form protects the doctor more than the patient). Such a legal contract would be a radical departure from current accepted norms, since it would directly conflict with the present emphasis on the primacy of respect for the autonomy of the research subject. Thus, these issues are fraught with controversy.

MODELS TO BUILD ON. Are there any precedents in which a patient can decide in advance what medical treatment she or he would want to receive in the future? Both "advance directives" and the so-called "Ulysses contract" fall into this category.

Advance directives are used in medicine as a means by which patients declare their wishes in anticipation of a future day when they may not be competent to make decisions. Such an instrument has been used, for example, to establish the point at which a patient desires a "do not resuscitate" status. It could be adapted to allow a mentally competent xenotransplantation recipient to make provision for intrusive post-transplant medical monitoring (with its attendant curtailment of certain rights), to continue if the recipient changes her or his mind-a situation that might occur, if, for example, the graft fails but monitoring must continue in order to protect public health.

This would be more akin to a "Ulysses contract." In Greek, mythology Ulysses was a strong, good man. He knew he would sail near the Sirens, whose enchanting songs would overcome him and cause his ship to be destroyed. He ordered his sailors to plug their ears, and, wanting to hear the songs, had himself tied to the mast of the ship, ordering his companions not to release him regardless of his subsequent demands. A Ulysses contract, then, is used for patients who are likely to experience periods of incompetence in the future, such as patients with psychiatric disorders characterized by alternating periods of therapy-induced competence and incompetence. While they are in a competent state, they can specify treatment decisions for future occasions. In the xenotransplant setting, such a binding advance directive signed by the recipient prior to the xenotransplantation could, theoretically, be used to forcibly investigate, treat, or even confine a recipient who fails to meet responsibilities to the public agreed to prior to the procedure (Daar 1999). A Ulysses contract usually assumes that the subject is so affected as to have their true judgment subordinated by some other pressure, while in this instance the xenotransplantation recipient may merely have changed her or his mind about cooperating with intrusive surveillance. Discussion of these options has raised concerns about the possibility of unacceptably eroding the human rights of research participants on the basis of hypothesis and fear rather than established or proximate risk.

PUBLIC ENGAGEMENT AND PUBLIC CONSENT. Some people have argued that since the public is going to be exposed to some level of risk of xenogeneic infections, the public must be consulted, and must consent, before xenotransplantation clinical trials proceed. Many national reports recommend that the public must in some way be consulted before proceeding with xenotransplantation. It is, however, difficult to define what would constitute public consent. Further, efforts at public education can easily merge over into propaganda, since the opinions formed by non-experts are completely dependent on the nature and presentation of the information they receive.

While some have advocated a moratorium pending public consent (Bach et al.) there are significant problems with adopting a moratorium. The majority of researchers and clinicians appear to be opposed to this position, mainly because moratoria remove from public discourse the very issues that ought to be addressed. Most researchers and clinicians would encourage increased capacity to evaluate the potential social consequences as the technology develops. Significantly, there have been no serious calls for reduction in xenotransplantation research.

Canada has undertaken a major public engagement exercise consisting of a series of forums involving education, discussion, and citizen juries. A subsequent report of the Canadian Public Health Association has recommended that Canada not proceed with xenotransplantation involving humans until several critical issues are addressed. It recommends, among other steps, that further efforts be made to inform and educate the public; that additional preclinical research be carried out; and that the risks and probability of benefit from clinical trials be more fully defined. It also calls for the development of legislation and regulations to cover all aspects of xenotransplantation clinical trials, concluding that there is a continuing need to involve the public in discussions about the future of xenotransplantation. This approach, however, has been criticized as being vulnerable to biases introduced by the information presented to the public (Wright). Nevertheless, this particular exercise reflects the current uncertainties surrounding xenotransplantation.

Conclusion

Xenotransplantation currently describes a multifaceted array of experimental biotechnological approaches to disease amelioration, some of which have progressed to small-scale clinical trials. The theoretical risk of infections spreading from source animal to recipient and then to contacts and the public has triggered debates on issues of science and on how biomedical technology should be developed, regulated and implemented. The specific ethical dilemmas discussed in the context of xenotransplantation reflect areas of ethical conflict and uncertainty relevant to other aspects of community life. These include the rights of the minority in the face of concern by the majority; conflicting values around decision making in the face of uncertain collective risk; the relative rights of humans and nonhuman animals; the relative value of safety versus of hope for progress; and the rights of, and appropriate protections afforded to, human subjects of research.

abdallah s. daar

louisa e. chapman

SEE ALSO: Animal Research: Law and Policy; Organ and Tissue Procurement; Organ Transplants; Tissue Banking and Transplantation, Ethical Issues in; Transhumanism and Posthumanism

BIBLIOGRAPHY

Advisory Group on the Ethics of Xenotransplantation. 1997. Kennedy Report: Advisory Group on the Ethics of Xenotransplantation: Animal Tissues into Humans. London, HM Stationery Office.

Auchincloss, H., Jr. 2001. "In Search of the Elusive Holy Grail: The Mechanisms and Prospects for Achieving Clinical Transplantation Tolerance." American Journal of Transplantation 1(1): 6–12.

Bach F. H.; Fishman, J. A.; Daniels, N.; Proimos, J.; et al. 1998. "Uncertainty in Xenotransplantation: Individual Benefit versus Collective Risk." Nature Medicine 4(2): 141–144.

Bentham, Jeremy. 1789. An Introduction to the Principles of Morals and Legislation. Reissued by Prometheus Books, Amherst, New York.

Bloom, Eda T. 2001. "Regulating Xenotransplantation in the United States." Graft 4(2): 160–162.

Centers for Disease Control and Prevention.1998. "Update: Isolation of Avian Influenza A (H5N1) Viruses from Humans— Hong Kong, 1997–1998." Morbidity and Mortality Weekly Report 46(52): 1245–1247.

Centers for Disease Control and Prevention. 1999. "Update: Outbreak of Nipah Virus—Malaysia and Singapore, 1999." Morbidity and Mortality Weekly Report 48(16): 325–348.

Centers for Disease Control and Prevention. 2001. "U.S. Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation." MMWR Recommendations and Reports, August 24, 2001/50(RR15): 1–46.

Chapman, L.E.; Folks, T. M.; Salomon, D. R.; Patterson, A.P.; et al. 1995. "XENOTRANSPLANTATION and Xenogeneic Infections." New England Journal of Medicine 333(22): 1498–1501.

Chari, R. S. et al. 1994. "Treatment of Hepatic Failure with Ex Vivo Pig-Liver Perfusion followed by Liver Transplantation." New England Journal of Medicine 331(4): 234–237.

Cooper, D. K.; Keogh, A. M.; Brink, J.; Corris, P. A.; et al. 2000. "Report of the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation: The Present Status of Xenotransplantation and Its Potential Role in the Treatment of End-Stage Cardiac and Pulmonary Diseases." Journal of Heart and Lung Transplantation 19(12): 1125–1165.

Collins, B. H.; Parker, W. R.; and Platt, J. L. 1994. "Characterization of Porcine Endothelial Cell Determinants Recognized by Human Natural Antibodies." Xenotransplantation 1: 36.

Cozzi, E.; Tucker, A. W.; Langford, G. A.; Pino-Chavez, G.; et al. 1997. "Characterization of Pigs Transgenic for Human Decay-Accelerating Factor." Transplantation 64(10): 1383–1392.

Daar, A. S. 1994. "XENOTRANSPLANTATION and Religion: The Major Monotheistic Religions." Xeno 2: 61–64.

Daar, A. S. 1997. "Ethics of Xenotransplantation: Animal Issues, Consent, and Likely Transformation of Transplant Ethics." World Journal of Surgery 21: 975–982.

Daar, A. S. 1999. "XENOTRANSPLANTATION: Informed Consent/ Contract and Patient Surveillance." Biomedical Ethics 4(3): 87–91.

Daar, A. S. 2001. "Choosing Risk-Benefit Analysis or Precautionary Principle as Our Approach to Clinical Xenotransplantation." Graft 4(2): 164–166.

Diamond, L.E.; McCurry, K. R.; Martin, M. J.; McClellan, S. B.; et al. 1996. "Characterization of Transgenic Pigs Expressing Functionally Active Human CD59 on Cardiac Endothelium." Transplantation 61: 1241–1249.

Diamond, L. E.; Quinn, C. M.; Martin, M. J.; Lawson, J.; et al. 2001. "A Human CD46 Transgenic Pig Model System for the Study of Discordant Xenotransplantation." Transplantation 71: 132–142.

Dossetor, J. B., and Daar, A. S. 2001. "Ethics of Transplantation: Allotransplantation and Xenotransplantation." In Kidney Transplantation:Principles and Practice, 5th edition, ed. P. J. Morris. Philadelphia: W. B. Saunders.

Emanuel, E. J., and Steiner, D. 1995. "Sounding Board: Institutional Conflict of Interest." New England Journal of Medicine 332(4): 262–268.

Fink, J. S., et al. 2000. "Porcine Xenografts in Parkinson's Disease and Huntington's Disease Patients: Preliminary Results." Cell Transplantation 9: 273–278.

Fishman, J. A. 2001. "Infection in Xenotransplantation." Journal of Cardiac Surgery 16(5): 363–373.

Goklany, I. M. 2002. "From Precautionary Principle to Risk-Risk Analysis." Nature Biotechnology 20(11): 1075.

Hahn, B.H.; Shaw, G.M.; De Cock, K. M.; and Sharp, P. M. 2000. "AIDS as a Zoonosis: Scientific and Public Health Implications." Science 287(5453): 607–614.

Hammer, C., and Thein, E. 2001. "Physiological Aspects of Xenotransplantation." Xenotransplantation 9: 303–305.

Heneine, W.; Tibell, A; Switzer, W. M.; et al. 1998. "No Evidence of Infection with Porcine Endogenous Retrovirus in Recipients of Porcine Islet-Cell Xenografts." Lancet 352: 695–699.

Ivinson, A. J. 1998. "Does Biomedical Research Need Another Moratorium?" Nature Medicine 4(2): 131.

Institute of Medicine. 1996. Xenotransplantation: Science, Ethics, and Public Policy. Washington, D.C.: National Academy Press.

Levinsky, N. G. 2002. "Nonfinancial Conflicts of Interest in Research." New England Journal of Medicine 347(10): 759–761

Michaels, Marian G. 2001. "Determining the Risk of Xenozoonoses." Graft 4(2): 129–130.

Moosa, M. R.; Walele, A. A.; Daar, A. S. 2001. "Renal Transplantation in Developing Countries." In Kidney Transplantation: Principles and Practice, 5th edition, ed. P. J. Morris. Philadelphia: W. B. Saunders.

Nuffield Council on Bioethics. 1996. Animal-to-Human Transplants: The Ethics of Xenotransplantation. London.

O'Riordan, T., and Jordan, A. 1995. "The Precautionary Principle in Contemporary Environmental Politics." Environmental Values 4: 191.

Paradis, K.; Langford, G.; Long, Z.; Heneine, W.; et al. 1999. "Search for Cross-Species Transmission of Porcine Endogenous Retrovirus in Patients Treated with Living Pig Tissue." Science 285: 1236–1241.

Patience, C.; Patton, G. S.; Takeuchi, Y.; Weiss, R. A.; et al. 1998. "No Evidence of Pig DNA or Retroviral Infection in Patients with Short-Term Extracorporeal Connection to Pig Kidneys." Lancet 352: 699–701.

Patience, C.; Takeuchi, Y.; and Weiss, R. A. 1997. "Infection of Human Cells By an Endogenous Retrovirus of Pigs." Nature Medicine 3: 276–282.

Phelps, C. J.; Koike, C.; Vaught, T. D.; Boone, J.; et al. 2003. "Production of Alpha1, 3-Galactosyltransferase-Deficient Pigs." Science 299: 411–414.

Pitkin Z., and Mullon, C. 1999. "Evidence of Absence of Porcine Endogenous Retrovirus (PERV) Infection in Patients Treated with a Bioartificial Liver System." Artificial Organs 23(9): 829–833.

Regan T. 1983. The Case for Animal Rights. Los Angeles: University of California Press.

Rosner F. 1999. "Pig Organs for Transplantation into Humans: A Jewish View."Mount Sinai Journal of Medicine 66(5–6): 314–319.

Russel, W. M. S., and Burch, R. L. 1959. The Principles of Humane Experimental Technique. London: Methuen.

Sandrin, M. S.; Fodor, W. L.; Mouhtouris, E.; Osman, N.; et al. 1995. "Enzymatic Remodeling of the Carbohydrate Surface of a Xenogenic Cell Substantially Reduces Human Antibody Binding and Complement-Mediated Cytolysis." Nature Medicine 1: 1261–1267.

Sandrin, M. S.; Vaughan, H. A.; Dabkowski, P. L.; and McKenzie, I. F. C. 1993. "Anti-Pig IgM Antibodies in Human Serum React Predominatly with Gala (1,3) Gal Epitopes." Proceedings of the National Academy of Science USA 90: 11391.

Saner, M. A. 2002. "An Ethical Analysis of the Precautionary Principle." International Journal of Biotechnology 4(1): 81–95.

Schumacher, J. M., Ellias, S. A.. et al. 2000. "Transplantation of Embryonic Porcine Mesencephalic Tissue in Patients with PD." Neurology 54(5): 1042–1050.

Sharma, A.; Okabe, J.; Birch, P.; McClellan, S. B.; et al.1996. "Reduction in the Level of Galalpha (1,3) Gal in Transgenic Mice and Pigs by the Expression of an alpha(1,2) Fucosyltransferase." Proceedings of the National Academy of Sciences USA 93: 7190–7195.

Shiraishi, M.; Oshiro, T.; Nozato, E.; Nagahama, M.; et al. 2002. "Adenovirus-Mediated Gene Transfer of Triple Human Complement Regulating Proteins (DAF, MCP and CD59) in the Xenogeneic Porcine-to-Human Transplantation Model." Transplant International 15(5): 212–219.

Singer, P. 1975. Animal Liberation. New York: Random House.

Soares, M. P.; Brouard, S.; Smith, R. N.; and Bach F. H. 2001. "Heme Oxygenase-1, a Protective Gene That Prevents the Rejection of Transplanted Organs." Immunological Reviews 184: 275–285

Stoye, J. P. 1998. "No Clear Answers on Safety of Pigs As Tissue Donor Source." Lancet 352(9129): 666–668.

Swedish Committee on Xenotransplantation. 1999. From One Species to Another: Transplantation from Animals to Humans. Swedish Government Official Report No. 1999: 120.

Tearle, R. G.; Tange, M. J.; Zanettino, Z. L.; et al. 1996 "The a-1,3-Galactosyltransferase Knockout Mouse: Implications for Xenotransplantation." Transplantation 61: 13.

Tibbel, Anika. 2001. "Regulating Xenotransplantation in Europe." Graft 4(2): 157–159.

van der Laan, J. W.; Lockey, C.; Griffeth, B. C.; Frasier, F. S.; et al. 2000. "Infection by Porcine Endogenous Retrovirus after Islet Xenotransplantation in SCID Mice." Nature 407: 90–94.

White, D., and Wallwork, J. 1993. "XENOGRAFTING: Probability, Possibility, or Pipe Dream?" Lancet 342: 879.

Wilson, C. A.; Wong, S.; Muller, J.; Davidson, C. E.; et al. 1998. "Type C Retrovirus Released from Porcine Primary Peripheral Blood Mononuclear Cells Infects Human Cells." Journal of Virology 72: 3082–3087.

World Health Organization. 1997. Report of the WHO Consultation on Xenotransplantation. Doc. No. WHO/EMC/ZOO/98.2. Geneva: WHO.

Wright, J. R., Jr. 2002. "Alternative Interpretations of the Same Data: Flaws in the Process of Consulting the Canadian Public about Xenotransplantation Issues." Canadian Medical Association Journal 167: 40–42.

Wu, A.; Yamada, K.; Neville, D. M.; Awwad, M.; et al. 2003. "XENOGENEIC Thymus Transplantation in a Pig-to-Baboon Model." Transplantation 75(3): 282–291.

INTERNET RESOURCES

BBC News. 2003. "Ape 'Learns to Talk.'" Available from <http://news.bbc.co.uk/1/hi/sci/tech/2617063.stm>.

Canadian Public Health Association. 2001. "Animal-to-Human Transplantation: Should Canada Proceed?" Available from <http://www.xeno.cpha.ca>

Centers for Disease Control and Prevention. 1998. "CDC Update: Isolation of Avian Influenza A (H5N1) Viruses from Humans—Hong Kong, 1997–1998. Morbidity and Mortality Weekly Report 46(52): 1245–1247." Available from <http://www.cdc.gov/mmwr/PDF/wk/mm4652.pdf>.

Centers for Disease Control and Prevention. 1999. "CDC Update: Outbreak of Nipah Virus—Malaysia and Singapore, 1999." Morbidity and Mortality Weekly Report 48(16): 325–348. Available from <http://www.cdc.gov/mmwr/PDF/wk/mm4816.pdf>.

Centers for Disease Control and Prevention. 2001. "U.S. Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation." MMWR Recommendations and Reports, August 24, 2001/50(RR15): 1–46. Available from <http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5015a1.htm>.

Church of Scotland, Society, Religion and Technology Project. 1995. "The Ethics of Xenotransplantation." Available from <http://dspace.dial.pipex.com/srtscot/xennuf03.shtml#Contents>.

Council of Europe Working Party on Xenotransplantation. 2003. "Report on the State of the Art in the Field of Xenotransplantation." Available from <http://www.coe.int7>.

Nuffield Council on Bioethics. 1996. "Animal-to-Human Transplants: The Ethics of Xenotransplantation." London. Available from <http://www.nuffieldbioethics.org>.

Organization of Economic Co-operation and Development (OECD). Joint WHO/OECD Consultation on Xenotransplantation Surveillance, 4–6 October 2000. Available from <http://www.oecd.org>.

Rhonchi, Elettra. 2001. "OECD/WHO Consultation on Xenotransplantation Surveillance: Summary Report." Directorate for Science, Technology and Industry—Committee for Scientific and Technological Policy, Working Party on Biotechnology. Available from <http://www.olis.oecd.org/olis/2001doc.nsf>.

Transplantation Society. "Address of John Paul II to the 18th International Congress of the Transplantation Society." Available from <http://cnserver0.nkf.med.ualberta.ca/misc/Rome/Encyclical.htm>.

United Kingdom Xenotransplantation Interim Regulatory Authority (UKXIRA). Draft guidance notes on biosecurity considerations in relation to xenotransplantation. Available from <http://www.doh.gov.uk/ukxira/publications.htm>.

U.S. Food and Drug Administration. 1999. "Guidance for Industry; Public Health Issues Posed by the Use of Nonhuman Primate Xenografts in Humans." Available from <http://www.fda.gov/cber/gdlns/xenoprim.pdf>.

World Health Organization. 1997. Report of the WHO Consultation on Xenotransplantation. Doc. No. WHO/EMC/ZOO/98.2. Geneva: WHO. Available from <http://www.who.int/emc-documents/zoonoses/docs/whoemczoo982.pdf>.

Xenotransplantation

Xenotransplantation is transplanting an organ or tissue from one species to another. A shortage of human body parts available for allotransplantation (transplantation to other humans) has increased interest in this alternative. Since the 1960s, attempts at xenotransplantation have been made using chimpanzee kidneys, baboon hearts and livers, and pig hearts and livers. Present efforts focus on pigs rather than primates, as pigs reach maturity and reproduce quicker than primates, and pigs are not an endangered species. While pig heart valves are used successfully to repair human hearts, xenotransplantation remains in limited clinical trials. The genetic modification of animals has the potential for reducing human rejection and the danger of transmitting dangerous pathogenic agents. Some researchers have suggested that the transplantation of pig organs to humans may be possible within five years.

How religions evaluate the morality of xenotransplantation hinges on views of animals in the created order. For example, Christianity, particularly Roman Catholicism, believes that xenotransplantation can be justified in certain circumstances since humans have a higher dignity than the animals that serve them. Moral limits, however, preclude transplantation of the encephalon and gonads that are linked indissolubly by their function with the personal identity of humans.

See also Animal Rights; Biotechnology; Christianity, Roman Catholic, Issues in Science and Religion; Cloning

Bibliography

clark, m. a. "this little piggy went to market: the xenotransplantation and xenozoonose debate." journal of law, medicine, and ethics 27 (1999): 137–152.

cooper, david k. c., and lanza, robert p. xeno: thepromise of transplanting animal organs into humans. new york: oxford university press, 2000.

hanson, m. j. "the seductive sirens of medical transplantation: the case of xenotransplantation." hastings center report 25 (1995): 5–6.

international xenotransplantation society. available from http://www.ixa2001chicago.com.

mccarthy, charles r. "a new look at animal-to-humanorgan transplantation." kennedy institute of ethics journal 6, no. 2 (1996): 183–188.

pontifical academy for life. "prospects for xenotransplantation: scientific aspects and ethical considerations." september 26, 2001. available from http://www.vatican.va/roman_curia/pontifical_academies/acdlife/.

who electronic discussion group (edg) on internationalxenotranplantation policy considerations. available from http://www.who.int/emc/diseases/zoo/meetings/xenodg.html.

donna m. mckenzie

xenotransplantation (zen-oh-trans-plahn-tay-shŏn) n. the transplantation of organs from one species into another.