Animal-to-human organ transplants--a solution or a new problem?

54 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Animal-to-human organ transplants – a solution or a new problem? A.S. Daar1 1 Professor and Chairman, Department of Surgery, College of Medicine, Sultan Qaboos University, Sultanate of Oman; and Visiting Professor in Health Policy and Society, Faculty of Law and Joint Center for Bioethics, University of Toronto. The current definition of xenotransplantation in- cludes the grafting of cells, tissues or organs from non-human animal species into humans (although technically it can be the other way round or between any two species). It is obviously a subject that has fascinated people for a long time because we find examples of this kind of organ grafting in the mythologies of many religions. Perhaps the one best known is the grafting of the head of an elephant onto the body of the boy who went on to become the very popular Hindu god, Ganesha. The fascina- tion seems now to have reached fever pitch, with high stakes for those concerned, particularly patients, scientists, the biotechnology industry, and infectious disease specialists. We seem to be poised on the brink of clinical success, but with advocates on opposite sides of the argument about whether we are ready to embark on large-scale clinical trials of vascularized whole organs or not. In this presentation I will try to capture the main elements that have brought us to this pass, where we have a division between “those who want to get it right” and “those who want to get it right now” (1). Short history In modern biomedicine there have been efforts at xenotransplantation dating back to the early part of this century, well before we knew anything about the immunological principles underlying transplan- tation in general. Most of these efforts have failed, although in one of Keith Reemtsma’s patients in the 1960s a chimpanzee kidney did survive and work for about nine months (2); we do not know why this success occurred, as there were no powerful im- munosuppressive agents in the 1960s, and no so- phisticated immunological or genetic manipulations of donor or recipient. Table 1 is a summary of these transplants. In the very modern era, which I will define as anything after 1980, we have had a number of well- publicized whole-organ (vascularized) xenotrans- plant attempts, as well as several less-publicized cellular and tissue transplants. These provide us with an opportunity to examine and define the issues of current concern in xenotransplantation. Sources of discomfort There are many issues that make people uncomfort- able about xenotransplantation. At a very fundamen- tal level it seems to transgress those boundaries which define us as human, and so challenge and threaten our identity and sense of order; the sense of order and disorder, according to some anthropologists, is the very basis of our entire cognitive world. In some Eastern mythologies we do have a certain amount of fluidity between the human and animal categories, with movement in both directions. It may be tempting to speculate on this basis that these cultures would easily assimilate xenotrans- plantation, but it can also be argued that this very fluidity might make people anxious to maintain clearly distinct categories in the physical world. In the Islamic and Judaeo-Christian traditions the concerns are easy to identify, and fundamental amongst them is the question of morality: man is held accountable because he has choice and respon- sibility. Is this responsibility as a moral agent reduced if one’s functioning depends on a foreign organ? Will the characteristics of the animal be incorporated into the consciousness of the human recipient? Of course, at present, there is no scientific evidence with which to answer such questions, but as we begin to trans- plant pig neural tissue into the human brain and demonstrate neuronal connection between the two © World Health Organization 1999 Xenotransplantation is seen by some mainly as an opportunity and by others mainly as a danger. It could help overcome the shortage of organs from human donors, but it raises a number of questions, particularly about safety, ethics and human nature. This article reviews the progress of research, debate and decision-making in this area. Voir page 59 le résumé en français. En la página 59 figura un resumen en español. Bulletin of the World Health Organization, 1999, 77 (1) 55 powerful than ciclosporin A on a weight-for-weight basis. Powerful immunosuppression means greater predisposition to lethal and generalized infections, and so both of the first two patients succumbed. Interestingly enough, after the death of the second patient, Dr Starzl’s team decided not to go ahead with any more transplants; in 1995, in an in- terview with a reporter from the Scientist, Dr Starzl indicated that he thought there was not enough sci- entific knowledge to do any more xenotransplants, and that, although they had permission to perform two more, they would have been “nuts” to have done them (4). At about this time, the field was progressing very rapidly in terms of accumulation of relevant scientific knowledge. The Pittsburgh team docu- mented microchimaerism in transplant recipients, especially those who had had a (human) liver trans- plant, and there was speculation about whether this phenomenon, by setting up a subclinical level of graft-versus-host disease, somehow blinded the re- cipient’s immune systems to the graft (5); in some instances this active biological accommodation was so effective that chemical immunosuppression could be stopped without graft rejection. From the same scientific milieu in Pittsburgh came the discovery by Dr Suzanne Ildstad of puta- tive “facilitator” cells – a distinct subpopulation of cells that facilitates the engraftment of bone mar- row transplants (6). Subsequent evidence seems to (as has already actually been done), and as the pur- pose of the transplant is to restore biochemical ac- tivity and neural transmitters, surely it is time to raise them. At the psychological level we have very little information about the possible effects of the xenotransplant on the recipient. Will someone who harbours the heart of a pig begin to worry about this? In allotransplantation, partly because of the neurotoxic effects of drugs such as the cortico- steroids, ciclosporin, and FK506, we do see psycho- logical problems (3) and there certainly are examples of recipients beginning to identify with im- agined or real qualities of the donors. The drugs used in allotransplantation, some of which are very likely to be used in xenotransplantation as well, lead to bodily changes such as hirsutism, rounded facies, obesity and hypertrophied gums. In fact, in their extreme forms these dramatic changes can make the recipient look a little simian - and one can imagine the kind of comments from schoolchildren if they suddenly learn that their odd-looking classmate has recently received the liver of a baboon. Xenotransplantation after 1980 In 1982, in Loma Linda, California, a team of sur- geons led by Dr Leonard Bailey transplanted the heart of a baboon into Baby Fae, an infant born with hypoplastic left heart syndrome. Dr Bailey’s team proceeded because it had some laboratory evidence that xenotransplants would work, but also because the powerful new immunosuppressive drug, ciclosporin A, became widely available to transplantologists in the United States at about this time. The operation was technically successful, and the child lived for about three weeks before the heart was rejected. In the early days after the transplant the media were full of praise for the operation and its success, but this soon turned sour when the child died. Questions were asked about the adequacy of the information given to the parents. The surgeons were faulted for not looking hard enough for a hu- man heart to transplant, and for being too optimis- tic. The scientific evidence, in retrospect, was inadequate and many have come to view the Baby Fae episode as having had an overall negative effect in the field of xenotransplantation. In 1992, the team that was most advanced in the quest for success in xenotransplantation was the one led by Dr Thomas Starzl in Pittsburgh. In the 1960s Starzl had performed about half a dozen baboon-to-human kidney transplants, all of which subsequently failed. This time his team had permis- sion to perform four baboon-to-human liver trans- plants. The experimental nature of these attempts naturally leads to the selection of very sick persons; thus the first recipient was a patient with advanced AIDS and near-terminal hepatitis. This time, too, there was an extremely powerful new immunosup- pressive drug called FK506, which is 100 times more Table 1. Animal organs transplanted into humans, 1906–1995 Donors Organ Transplants Survival time Author Year Pig Kidney 1 3 days Jaboulay 1906 Goat Kidney 1 3 days Jaboulay 1906 Macaque Kidney 1 32 hours Unger 1910 Sheep Kidney 1 9 days Neuhof 1923 Baboon Kidney 1 4 days Hitchcock 1963 Macaque Kidney 1 12 days Reemtsma 1963 Chimpanzee Kidney 3 9 months Reemtsma 1963 Baboon Kidney 6 60 days Starzl 1963 Chimpanzee Kidney 1 - Hardy 1964 Chimpanzee Kidney 1 1 day Hume 1964 Chimpanzee Kidney 6 one 9 mths Reemtsma 1964 Baboon Kidney 6 max 60 days Starzl 1964 Chimpanzee Kidney 31 49 days Traeger 1964 Chimpanzee Kidney 2 4 months Goldsmith 1965 Chimpanzee Kidney 1 31 days Cortesini 1966 Pig Heart 1 0 days . 1968 Baboon Heart 1 - Barnard 1977 Baboon Heart 1 20 days Bailey 1985 Pig Heart 1 < 1 day - 1992 Baboon Liver 1 70 days Starzl 1993 Baboon Liver 1 26 days Starzl 1993 Baboon Bone 1 - Gorman 1995 marrow Source: Mohacsi, Thompson and Quine (21) Other sources indicate that in fact there have been eight xenogeneic heart transplants and 11 xenogeneic liver transplants, of which one was with a pig liver (C.G. Groth, personal communication, August 1998). Animal-to-human organ transplants 56 Bulletin of the World Health Organization, 1999, 77 (1) Round Table have borne out its existence in animal models. Dr Ildstad suggested in 1995 that a baboon-to-human bone marrow transplant could be used to cure a pa- tient with advanced HIV infection. She did not per- form this experiment in Pittsburgh, but was able to collaborate with clinicians and scientists at the Uni- versity of California, San Francisco. The recipient was a 38 year-old AIDS activist from Oakland, Cali- fornia, called Jeff Getty, who was himself suffering from AIDS and was not expected to live long; the theory was that if his marrow was partly reconsti- tuted by that of a baboon (to develop chimaerism), he would be much improved because baboon lymphocytes are not infectable with HIV. This is a very instructive episode in the annals of xenotransplantation from a number of different perspectives which illustrate the current issues of concern in the field. From the regulatory point of view in the United States, the freewheeling days when any surgeon could transplant an organ from an ani- mal with the permission only of the local Institu- tional Review Board were over. All such experiments now required a specific Initial Notification of Drug application to the US Food and Drugs Administra- tion (FDA). The field was new, and so the FDA set up a panel to review the application. Arguments in favour of proceeding were that this was a valid ex- periment, that the scientific justification was ad- equate, and that if the experiment was not done in the United States it would be done elsewhere, and the United States would lose out. The opposing ar- guments were that the risk of infection from known and unknown viruses in the baboon bone marrow was just too high to ignore, and that contacts and the public might be exposed to a risk whose extent was unquantifiable. Two things influenced the decision to proceed: one was the powerful lobbying from Getty’s family, and of course from the scientists and clinicians who were advocating the transplant. The other was the persuasive argument that the patient was likely to die anyway, and so the risk of spread of infection would be minimal. The transplant went ahead, and although it did not succeed in terms of engraftment of the bone marrow, it did succeed in terms of mak- ing the patient better (higher T-cell count, general well-being in the months after the transplant). Three years later he is alive, apparently in fairly good health, and writing and speaking on behalf of experiments using animals, especially in HIV infection (7). Increased awareness of risk of infection The emphasis in discussion of xenotransplantation has changed from concern about the rights and wel- fare of potential non-human source animals to con- cern about the risk of xenozoonoses. One of several things that brought this change about was a letter published by Dr Jonathan Allan and about 40 other scientists, including a number of virologists, who pointed out the real dangers of infection from non- human primates (8). The authors of the letter and others again reminded us that, almost certainly, HIV came from simian sources, and that the incubation period of retroviruses can be many years before any clinical symptoms are manifest. We were also re- minded that if these infections were transmitted to the recipient, they could be rapidly lethal because of the heavy immunosuppression, and could also be transmitted, theoretically, to immediate contacts and even to the public. This widely publicized letter was written in response to the draft guidelines for reduction of the risk of xenozoonoses published by the Public Health Services (9), a federal umbrella body which encom- passes both the FDA and the Centers for Disease Control and Prevention (CDC) in the United States. The main point of the Allan letter was that these guidelines were not strict enough, that the risk of infection from non-human primates was real enough, and that we should therefore embargo the use of primates completely. The Public Health Service draft guidelines were also criticized by other organizations, includ- ing the American Society of Transplant Physicians. The criticisms included the vagueness of the docu- ment regarding the funding of the regulatory instru- ments and, again, its failure to exclude the use of primates. Guidelines In 1994 and 1995 something stirred those concerned with ethics and public policy in both Europe and the United States. In January 1995 in the United Kingdom the Nuffield Council on Bioethics set up a Working Party to look at many xenotransplant is- sues and it produced a report, which came out in 1996 (10). Subsequently the United Kingdom Government’s Advisory Group on the Ethics of Xenotransplantation examined a similar range of is- sues and came up in 1997 with the definitive Kennedy Report (11), named after its admirably capable chairman, Professor Ian Kennedy. The essence of the Kennedy Report was that it was worth pursuing xenotransplantation research, and that using pigs, but not non-human primates, as source animals would be ethically acceptable. Furthermore, it was ethically acceptable to alter the pig’s genome to the extent foreseen so as to facilitate the transplant, provided the pig remained recogniz- ably a pig. Primates could ethically be used only as recipients, in small numbers, in animal-to-animal experiments. Non-human primates were not ethically ac- ceptable as source animals partly because of the emotional attachment that human beings have to them, and partly because their being phylogenetically closer to man increases the risk of infection. In com- parison to the pig, there were other disadvantages such as their depletability, slow breeding, small lit- Bulletin of the World Health Organization, 1999, 77 (1) 57 ters, and the fact that there are no specified-patho- gen-free (SPF) colonies of primates, while there are such SPF colonies of pigs. These factors also mean that the cost of breeding non-human primates for xenotransplantation would be prohibitive. Further- more, the organs of primates are often too small for humans. The pig, on the other hand, has lived close to man for many generations without spreading any serious infections (leaving aside the swine-flu epi- demic); its physiology is quite similar to man’s; its organs are roughly the same size; it breeds very quickly, has large litters, and in any case is eaten by millions of people throughout the world. The mat- ter of physiology, however, is not yet really resolved – particularly for major synthesizing organs such as the liver, which would be pouring out pig molecules into the human recipient’s circulation. Also, not much is known about the response of these organs to normal homoeostatic signals. This is a subject that has not received the attention that it really deserves (12). The most significant conclusion of the Kennedy Report was that the base of scientific knowledge was inadequate in 1997 to proceed to clinical trials, and that there should be an effective embargo until a formal regulatory authority was es- tablished, with an opportunity to review the evidence at the time of submission of any applications to it. The Government of the United Kingdom rapidly responded by setting up the Xenotransplant Interim Regulatory Authority under the Chairmanship of Lord Habgood. In the United States the consultation process was initiated by the Institute of Medicine, which held a workshop in June 1995, and its report was published in 1996 (13). Its conclusions differed from the Kennedy Report’s in that non-human primates were not excluded as source animals, and the scien- tific base was considered to be adequate to “proceed with caution” to clinical trials. The American ap- proach was emphatically to have an advisory, not a regulatory, body to deal with xenotransplantation. International consultation By 1997 it was obvious that there was a risk to the public’s health, that the magnitude of this risk was not really known and was perceived differently by different countries, and that there were a number of ethical, social and cultural ramifications to xenotransplantation. There was a distinct need for an international and interdisciplinary dialogue. The World Health Organization responded to this glo- bal challenge by convening a consultation in Ge- neva in October 1997. Participants included experts from several countries in Europe, as well as from Canada, Cameroon, Japan, Oman, the Philippines, Sri Lanka and the United States. The main tasks given to the consultation were to work out techni- cal and ethical guidelines to minimize the risk of infection, safeguard human dignity and human rights, and ensure animal welfare. Despite the apparent differences of approach and perceptions amongst the participants, the con- sultation was very successful, and formulated a uni- fied set of recommendations. One of the points that became clear was that if xenotransplantation did succeed, developing countries might well be among the main beneficiaries. This is because in most of the developing world organ replacement therapies such as haemodialysis are beyond the means of gov- ernments or individuals, and organ transplantation, especially through cadaveric donation of organs, has not really taken off. For many of these countries, at the current level of expenditure, allotransplantation necessarily has lower priority than basic public health needs. Here, xenotransplantation holds out the hope that one day, when the ethical, technical, infectious disease and cost problems have been resolved, de- veloping countries will be able to embark on this type of transplantation without having to divert too much of their scarce resources to it. The fundamen- tal need for international cooperation in research, communication and standardization was recognized. The report of the WHO Consultation was issued in February 1998 (14). Cellular and tissue xenotransplants In 1993 a Swedish team transplanted 10 diabetic patients with pig islets of Langerhans. None of them succeeded in producing pig insulin in the long term, but the experiment is nevertheless important because the future of xenotransplantation may well lie in such cellular transplants for very common conditions such as diabetes mellitus. The other significant outcome of this experiment was important data on the pres- ence or absence of risk of viral infection. All 10 of the patients have developed antibodies to pig viruses, some to the influenza virus and some to picorna- virus. According to the Swedish team, none of the patients has actually become sick with any pig vi- ruses, and they believe that there is a possibility that the antibodies may simply be cross-reactive (Anne Tibell, personal communication, 1998). Neural tissue transplants have been performed from pig to man to alleviate Parkinson disease and more recently for intractable epilepsy. One of the patients treated for Parkinson disease died of other causes; a post mortem examination showed connec- tions had developed between the pig neural tissue and his brain — answering a critically important biological question, but at the same time raising philosophical and theological questions about the brain, identity and responsibility. Summary of current status The field is moving very rapidly. There are a number of important stakeholders, and the stakes are high for some of them. Major research is now being Animal-to-human organ transplants 58 Bulletin of the World Health Organization, 1999, 77 (1) Round Table funded and carried out by venture-capitalized bio- technology companies, and one of the considera- tions in the current discussions is the part played by these companies in determining the timing, the tech- nology and the development of xenotransplantation as a whole. There is a distinct difference in the approaches to xenotransplantation in Europe and the United States. In Europe the feeling is that the scientific base is inadequate to proceed to clinical trials and so there is at present an effective embargo. In the United States the consensus seems to be that further labora- tory and animal-to-animal experiments will not an- swer the key questions, and that the only way to advance the scientific base is to “proceed with cau- tion” (15) to clinical trials. In the United States, therefore, while the Public Health Services draft guidelines are becoming more strict in response to comments, criticisms and consultations, the Food and Drug Administration has been receiving appli- cations. It has already authorized a number of clini- cal trials, most of which at present involve cells and tissues rather than whole vascularized organs, al- though a number of researchers are preparing for the latter. Furthermore, rather than completely ex- cluding the use of non-human primates, the ap- proach in the United States is to set the requirements for their use at levels that are virtually impossible to achieve. This effectively embargoes their use with- out actually using the dreaded term. The question of consent to the clinical trials, especially in the early patients, is likely to be a vexed one. We have argued (16) that some of the funda- mental traditional principles of consent would need to be violated, and that because of the continuing need to monitor the patient and perform invasive investigations even if the graft failed, the agreement may need to be more of a contract, with specifically binding requirements, than the traditional consent whereby the patient has the right to withdraw at any time from the experiment. Since the community is in a sense being put at risk, there is a real argument for considering some form of community consent as well – but at present, with our inability to quan- tify the xenozoonotic risk (to calculate the risk–ben- efit ratio), it is not clear how far we should push this point. In any case, there is little experience in ob- taining such community consent. On the purely scientific side, the evidence has accumulated rapidly on both sides of the divide. On the one hand, our understanding of the hyperacute rejection phenomenon is increasing, and scientific enquiry is already being directed to the subsequent “delayed xenotransplant reaction”. More and more animal models are being developed; and immuno- logical manipulations are becoming more sophisti- cated. Animal models have been developed which no longer express on their endothelium the alpha- gal molecule, which is the main target of the anti- bodies mediating the hyperacute rejection response. Also, transgenic animals have been developed which express on their endothelium human molecules such as the decay-accelerating factor, which helps to in- activate complement components in a species- specific manner. At the same time, however, we have growing evidence of viruses, in pigs and in primates, which can theoretically cause xenozoonotic infection. New pig endogenous retroviruses, which would be very difficult to eradicate and which have been shown to infect human cell lines in vitro have been described (17). While it is fair to say that there is little evi- dence that such viruses will be pathogenic in man, it cannot be assumed that they will not become so, especially if introduced into an immunocompro- mised host. Evidence has also accumulated of trans- species transmission of viruses from pig to man, causing infection, for example, with paramyxovirus in Australia (18), and in the case of primates we now know that the simian foamy virus (and other viruses) can be transmitted via scratches and bites to animal handlers (19). The effect of xenotransplantation on the do- nation of cadaveric and living-donor human organs needs to be taken into account. Xenotransplantation itself can be seen as serving one of several purposes: to be a complete substitute for human organs; to supplement human organs, thus alleviating short- age; or to be “bridging” rather than “destination” organs. Whatever the purpose, it would be a set- back if the effect was to reduce the supply of human organs because the public now perceives a lack of need since pigs are plentiful, or for whatever other speculative reasons (20). We think that xenotrans- plants will be very expensive in the first decade of their application, and so, for at least this reason, they will not be an adequate substitute for allotransplan- tation for at least a decade after xenotransplanatation is truly established. One major issue for developing countries is the phenomenon of “expatriate” experiments: it is possible that, because of restrictions imposed in in- dustrialized countries, researchers may bring these experiments to be done in developing countries, with potentially disastrous results in terms both of safety and of human rights. This is only one of the reasons for which developing countries need to be repre- sented in formulating guidelines for this exciting, challenging and potentially useful new technology. Attempts are now being made to predict factors that would affect the response of the public to xenotransplantation (20), but surveys of public atti- tudes are beset by deficiencies and are cumulatively contradictory at present (21). n Bulletin of the World Health Organization, 1999, 77 (1) 59 Résumé Les xénogreffes : solution ou problème ? déjà suffisantes pour «procéder avec prudence» à des essais cliniques. Il était également recommandé de créer un organe consultatif (et non de réglementation) afin de veiller à ce que soient prises toutes les précautions nécessaires. En 1997, l’OMS a organisé une consulta- tion internationale à l’issue de laquelle un certain nom- bre de recommandations ont été formulées, qui soulignaient, entre autres, le besoin d’une coopération internationale aux fins de la recherche, de la communi- cation et de la standardisation des principes directeurs visant à réduire le risque de transmission des xénozoonoses non pas simplement chez les receveurs mais aussi chez leurs contacts et dans la population en général. Des greffes de cellules et de tissus hétérologues pour le traitement de maladies courantes comme le dia- bète, la maladie de Parkinson et l’épilepsie ont déjà été réalisées. Ce type d’opérations a permis de compren- dre certains aspects des xénogreffes, encore que sur le plan clinique, elles n’aient pas donné de résultats pro- bants. En règle générale, lorsque les enjeux sont impor- tants, par exemple, quand des recherches sont financées par des entreprises de biotechnologie à capital à ris- que, le désir est grand de se hâter pour développer cette technologie et procéder à des essais cliniques. Aux Etats- Unis d’Amérique, la Food and Drug Administration a déjà autorisé un certain nombre d’essais cliniques qui, jusqu’ici, concernent des cellules et des tissus et non des organes vascularisés entiers. Dans la mesure où le risque d’infection n’inté- resse pas seulement l’individu mais en un sens l’en- semble de la communauté, il serait fondé d’envisager une forme de consentement de la communauté. A ce jour, les enquêtes d’opinion sur les xénogreffes ont été peu concluantes, voire contradictoires. Des études récentes ont montré que sur les dix malades qui avaient reçu il y a quelques années en Suède des îlots de Langerhans de porc, aucun n’a pré- senté de signe d’infection par des rétrovirus endogè- nes porcins. Toutefois, il convient de se rappeler que des études in vitro ont fait apparaître une infectiosité intercellulaire et que, en tout état de cause, l’absence de preuve d’infection n’est pas une preuve d’absence de risque. Nous devons poursuivre, mais avec une grande prudence, notamment parce que le coût des xénogreffes sera très élevé au début et que seuls quelques rece- veurs pourront en bénéficier dans les premiers temps. Animal-to-human organ transplants Ces dernières années ont été marquées par un regain d’intérêt pour les xénogreffes. Cliniciens, scientifiques, spécialistes de l’éthique, analystes politiques et cher- cheurs ont aujourd’hui des opinions divergentes sur le risque de transmission des xénozoonoses. Certains veu- lent dès à présent passer à l’acte et procéder à des essais cliniques alors que d’autres, partisans d’une ap- proche prudente, souhaitent d’abord évaluer les risques. Mais presque tous sont d’accord pour que la science progresse dans ce domaine. Le battage médiatique suscité en 1982 par la transplantation d’un coeur de babouin chez une petite fille «Baby Fae» en Californie, favorable dans un pre- mier temps, s’est rapidement mué en critiques lorsque l’enfant est décédée. Le Dr Thomas Starzl, qui a effec- tué deux transplantations de foie de babouin chez l’homme à Pittsburgh au début des années 90, a dé- cidé après le décès du deuxième patient que des re- cherches supplémentaires s’imposaient avant que d’autres essais cliniques puissent être réalisés. La trans- plantation de la moelle osseuse d’un babouin sur Jeff Getty, un patient atteint du SIDA, a échoué du point de vue de la greffe mais a été un succès en ce que l’état du malade s’est amélioré. L’inquiétude suscitée par le risque de transmis- sion des xénozoonoses a conduit à exiger que les xénogreffes fassent l’objet de contrôles d’autant plus rigoureux que le VIH, par exemple, est probablement d’origine simienne et que plusieurs années peuvent s’écouler avant que la maladie ne se déclare chez l’homme : un argument venant renforcer le sentiment largement répandu que les organes de primates non humains ne devraient pas être transplantés chez l’homme. Au Royaume-Uni, le rapport Kennedy indiquait en 1996 que les xénogreffes pourraient être éthiquement acceptables si le donneur animal était le porc. Mais le rapport appelait à un moratoire jusqu’à ce que soit créé un organe national de réglementation des xénogreffes qui serait chargé de fixer des normes, d’examiner les demandes d’autorisation d’essais clini- ques et d’étudier au fur et à mesure les données scien- tifiques. Actuellement, tout essai clinique doit faire l’objet d’une demande d’autorisation adressée à l’Or- gane intérimaire de Réglementation des Xénogreffes (Royaume-Uni) qui indiquera au Secrétaire d’Etat à la Santé s’il convient ou non d’accorder cette autorisa- tion. A l’inverse, aux Etats-Unis d’Amérique, le rapport de l’Institut de Médecine, qui date aussi de 1996, a conclu que les données scientifiques disponibles étaient Resumen Trasplantes de órganos de animales: ¿solución o nuevo problema? En los últimos años se ha reavivado el interés por los xenotrasplantes. La opinión de los clínicos, especialistas científicos, expertos en ética, analistas de las políticas públicas e investigadores está actualmente dividida en lo que respecta al tema del riesgo de xenozoonosis. Algunos desean pasar a la acción y empezar ya los ensayos clínicos, mientras que otros prefieren poner primero en marcha estructuras de evaluación y de minimización de los riesgos. Casi todos, sin embargo, desean ser testigos de avances científicos en ese terreno. 60 Bulletin of the World Health Organization, 1999, 77 (1) Round Table A raíz del trasplante de un corazón de babuino a Baby Fae en California, en 1982, la alternativa del xe- notrasplante tuvo gran repercusión pública, al princi- pio positiva, pero más tarde, cuando la niña falleció, negativa. El Dr. Thomas Starzl, quien llevó a cabo dos trasplantes de hígado de babuino a receptores huma- nos en Pittsburgh a principios de los años noventa, lle- gó a la conclusión, tras la muerte de su segundo paciente, de que había que llevar a cabo nuevas inves- tigaciones antes de realizar más ensayos clínicos. El tras- plante de médula ósea de babuino a Jeff Getty, un enfermo de SIDA, fracasó, pero benefició en cierta me- dida al paciente. La preocupación suscitada por las xenozoonosis ha llevado a exigir que se apliquen controles más rigu- rosos a los xenotrasplantes, sobre todo teniendo en cuenta la sospecha de que el VIH procede de simios y el hecho de que los retrovirus humanos pueden tardar muchos años en manifestarse. Ello ha conducido además a un amplio acuerdo en el sentido de que no debe uti- lizarse a primates no humanos como fuente de órga- nos para el hombre. En el Reino Unido, el informe Kennedy (1996) sostenía que el xenotrasplante a partir del cerdo podía ser éticamente aceptable. En el infor- me, no obstante, se recomendaba aplicar una morato- ria efectiva mientras no se constituyera una autoridad nacional de regulación de los xenotrasplantes que es- tableciera normas, aceptara solicitudes y analizase los progresos en ese campo de la ciencia. Actualmente, para realizar cualquier ensayo clínico se debe presentar una solicitud a la Autoridad Provisional de Regulación de los Xenotrasplantes del Reino Unido, que aconsejará al Ministro de Salud si debe o no dar su autorización. En los Estados Unidos, por el contrario, en el Informe del Instituto de Medicina (también de 1996) se resolvía que había base científica suficiente para justificar que se pasara «con las debidas precauciones» a realizar en- sayos clínicos. Se recomendaba la creación de un órga- no asesor, más que de un órgano regulador, para velar por que se observaran las precauciones necesarias. En una reunión consultiva internacional organizada por la OMS en 1997 se formularon diversas recomenda-cio- nes que resaltan la necesidad de cooperación técnica en materia de investigación, comunicación y normali- zación de directrices a fin de reducir al mínimo el riesgo de xenozoonosis, no sólo entre los receptores sino tam- bién entre sus contactos y el público en general. Ya se han realizado xenotrasplantes de células y tejidos contra enfermedades comunes como la diabe- tes mellitus, la enfermedad de Parkinson y la epilepsia. Esas operaciones han ayudado a profundizar en el cono- cimiento de determinados aspectos de los xenotrasplan- tes, pero aún no han tenido gran trascendencia clínica. En general, cuando es mucho lo que está en juego, por ejemplo en las investigaciones financiadas por empre- sas de biotecnología de capital de riesgo, hay gran in- terés en potenciar el desarrollo de esas técnicas y en pasar a realizar ensayos clínicos. En los Estados Uni- dos, la Administración de Alimentos y Medicamentos ha autorizado ya varios ensayos de ese tipo, que sin embargo hasta ahora se han realizado sólo con células y tejidos, no con órganos enteros vascularizados. Dado que el riesgo de infección afecta no sólo a los pacien- tes sino, teóricamente, al conjunto de la comunidad, parece lógico que deba preverse algún tipo de consen- timiento informado por parte del público. Los resulta- dos de las encuestas de opinión pública sobre los xenotrasplantes han sido hasta ahora contradictorios y no permiten extraer conclusiones. Estudios recientes han mostrado que los diez pacientes que recibieron islotes pancreáticos porcinos en Suecia hace unos años no presentan signos de in- fección por retrovirus endógenos porcinos, según los análisis realizados con las actuales técnicas diagnósti- cas. Sin embargo, debemos recordar que los estudios in vitro realizados han revelado signos de infectividad in- tercelular, y que en cualquier caso la inexistencia de pruebas no demuestra la inexistencia de riesgos aso- ciados a esos u otros agentes infecciosos. 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