New problems beget new solutions.

62 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Discussion Nonhuman primates as organ donors? Jonathan S. Allan1 Baboons and pigs are potential source animals for human xenotransplantation. For practical reasons, baboons have been proposed by only a handful of US surgeons to demonstrate “proof of concept”. The Loma Linda paediatric heart transplant performed by Leonard Bailey in 1986 received a lot of negative publicity because of ethical concerns about “experi- menting” on a newborn baby. Nevertheless, further paediatric xenografts using baboon hearts are being planned (1). Two baboon liver transplants were per- formed in 1993 and they also failed for unknown reasons. This has precluded further liver transplant studies (2). AIDS activists helped to accelerate human xenograft trials in the case of an AIDS patient who received a baboon bone marrow in a high risk at- tempt at immune constitution (3). The monkey bone marrow failed to grow but the patient derived some benefit from the conditioning regimen used in pre- paring him for the procedure. This was not an abla- tive bone marrow procedure, so the patient’s own marrow remained fully functional. Strong criticism of the experiment, based on a lack of significant sci- entific merit and the potential infectious disease risks, was voiced by many researchers, but in this case pub- lic health policy was determined by pressure from special interests. Some of these pioneering studies have done more harm than good to the xenotransplantation field because of negative pub- licity. On the other hand, they have made the trans- plant community more aware of the problems, and steered them towards using nonprimate species. There will always be a handful of individuals who want to be the first to succeed using primates, how- ever, and this is where strict regulations can prevent new pandemics caused by cross-species infections. Widespread use of nonhuman primates is no longer foreseen, mainly because of serious risks caused by infectious diseases naturally carried by baboons (4). It is also unlikely that sufficient num- bers of baboons could be made available even with tremendous commitments of time and money. Cur- rently, the largest breeding colony of baboons is at the Southwest Foundation for Biomedical Research, where there are over 3200 baboons bred for use in research. Unfortunately, breeding practices there have not been developed with zoonotic infections in mind. For example, virtually all adult baboons in this colony carry simian foamy virus (SFV) a per- sistent retroviral infection that has recently been found in humans who work with primates (5,6). A novel retroviral infection that can be transmitted to humans via wounds or needlesticks is not a good sign. Transplantation of tissues along with a cock- tail of immunosuppressive agents would be an ideal way of transferring simian viruses to humans. Most baboons also harbour simian T-cell lymphotropic virus (STLV), another retroviral in- fection that causes leukaemia and T-cell lymphomas in baboons (7). The human form (HTLV) probably arose from cross-species transmission from non- human primates (8). Higher rates of infection for both retroviruses and herpesviruses are found in cap- tive colonies than in the wild, indicating that inten- sive breeding may adversely affect the pool of nonhuman primates. Given the breadth of persist- ent infections, selecting baboons in this milieu would not be good public health practice. In addition, wild- caught baboons are occasionally introduced into the breeding programme, which could seed the estab- lished colony with new infections. Furthermore, many viral infections remain nonpathogenic in their existing hosts only to become pandemics when transmitted to new ones, as was the case with AIDS. We are currently unable to pre- dict the outcome of such zoonotic infections in xe- nograft recipients, or to predict in vivo pathogenicity on the basis of in vitro studies. Most problemati- cally, novel agents transmitted by xenotransplan- tation might circulate into the population for some time before evidence of new clinical syndromes comes to light through changes in disease prevalence. For retroviruses the time between infection and dis- ease can span decades, and many thousands of peo- ple could be infected before a change in disease patterns is detected. Preventing even some of the known infections can be expensive. The cost of developing a specific- pathogen-free (SPF) baboon colony, for instance, has been estimated at US$ 20 million, with the first 50 animals ready for donation in five to ten years. Infectious disease risks are not equal Most of the effort and enthusiasm for xenotrans- plantation has centred on pig cells and tissues for use in humans. Attempts are being made to over- come hyperacute and later rejection, but the ulti- mate goal of such efforts has not yet been defined. Injection of cells or tissues as a temporary measure or for use in bridging studies represents a significant risk: if the patient survives, the viral passenger can survive too, and thus transmission can occur later on. As has been the case with most whole organ 1 Scientist, Department of Virology and Immunology, Southwest Foundation for Biomedical Research, 7620 N.W. Loop 410 at Military Drive, San Antonio, Texas 78228, USA. E-mail: jallan@icarus.sfbr.org; tel.1(210) 670-3275, fax 1(210) 670-3332. Bulletin of the World Health Organization, 1999, 77 (1) 63 xenografts, human patients rarely survive for long enough to get back to a way of life that would en- hance transmission. With the advent of cellular therapies, however, such as those used to treat pa- tients with Parkinson disease, comes the prospect of long-term survival. Still, here the risk is to some ex- tent limited by the fact that these patients are usu- ally elderly and thus less likely than others to have a lifestyle that fosters the spread of sexually transmit- ted pathogens. Also, the infusion of only several million fetal porcine cells reduces the risk of viral transmission to the patient and the establishment of infection. Increasing the “dose” of foreign cells in- creases viral load and might result in a persistent infection. Studies are in progress on the risk to the population from pig endogenous viruses, and there is some evidence that these may not be expressed in the peripheral blood of human recipients of porcine cells (9,10). The same may not be true for immuno- suppressed recipients of whole organs, however. Are we creating chimeric humans? The possibility that xenotransplantation could change human evolution in some profound way has received little attention. The interplay of species genomes through recombinational events stemming from xenotransplantation is a theoretical reality. Retroviruses are in vogue as vectors for shuttling genes into patients to treat a variety of genetic dis- eases. More than 200 gene transfer human clinical protocols have been registered by the Office of Recombinant DNA Activities and approved by the Food and Drug Administration. The admixture of porcine cells and retroviruses produces a favourable environment for the transduction of porcine genes by a pig endogenous retrovirus. Several studies sup- port the notion that this retrovirus is infectious in human cells (9,10). Theoretically, transduced por- cine cell genes might then be spliced into the hu- man genome when the xenograft recipient is infected with a porcine endogenous retrovirus. If thousands of xenotransplants were to be carried out, this might favour the evolution of porcine-human chimeras. Science fiction may meet reality if a selective advantage arises from some porcine gene such as a chemokine, enzyme, oncogene, or chaperone. The issue of chimerism has been discussed in the con- text of transferring donor lymphoid cells either as part of the xenograft (leukocyte passengers) or by bone marrow transplantation in an attempt at toler- ance induction (11). Several proposed xenotrans- plants have been designed specifically to incorporate microchimerism as an adjunct to the induction of tolerance (12). The use of bone marrow may help xenotransplantation to succeed, but long-lived for- eign lymphocytes derived from the donor marrow are likely to harbour long-lived viruses, increasing the chances of cross-species infection (13). If public health is to be protected, these concerns must be at the forefront of any discussions on animal species and therapeutic modality. History has taught us that we should restrict animal transplants to lower nonprimate animals. Even if one were to screen baboons for the known pathogens, emotionally charged situations, such as the one that led to the Getty baboon transplant, would be sure to arise. For these reasons, and to avoid the danger of rogue transplanters dumping primate organs into humans, we should restrict our efforts in xenotransplantation to safer and more economi- cal donor resources. At a recent meeting sponsored by the Organisation for Economic Co-operation and Development (OECD) in conjunction with the New York Academy of Sciences, there was a clear inter- national consensus in favour of the use of porcine tissues and cells (14). From everyone except a few United States officials, there was strong opposition to the use of primates for transplants. Since viruses do not respect national borders, we must hope that the US will decide to take a leadership role in plac- ing public health first in this burgeoning field. n 1. Bailey LL, Gundry SR. Survival following orthotopic cardiac xenotransplantation between juvenile baboon recipients and concordant and discordant donor species: foundation for clinical trials. World journal of surgery, 1997, 21:943–950. 2. Starzl TE et al. Baboon-to-human liver transplantation. Lancet, 1993, 341: 65–71. 3. Exner BG, Neipp M, Edstad ST. Baboon bone marrow transplantation in humans: application of cross-species disease resistance. World journal of surgery, 1997, 21:962–967. 4. Allan LS. Xenotransplantation and possible emerging infectious diseases. Molecular diagnosis, 1996, 1(3): 1–8. 5. Broussard SK et al. Characterization of new simian foamy viruses (SFV) from African nonhuman primates. Virology, 1997, 237:349–359. 6. Heneine W et al. (1998). Identification of a human population infected with simian foamy viruses. Nature medicine, 1998, 4:403–407. 7. Moné J et al. (1992) Simian T-cell leukemia virus type 1 infection in captive baboons. AIDS research and human retroviruses, 1992, 8(9): 1667–1675. 8. Koralnik LL et al. A wide spectrum of simian T-cell leukemia/lymphotropic virus type 1 variants in nature: evidence for interspecies transmission in Equatorial Africa. Journal of virology. , 1994, 68:2693–2707. 9. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nature medicine, 1997, 3:282–286. 10. Wilson CA et al. Type C retrovirus released from porcine primary peripheral blood mononuclear cells infects human cells. Journal of virology, 1998, 72:3082–3087. 11. Starzl TE et al. Chimerism and donor-specific nonreactivity 27 to 29 years after kidney allotransplantation. Transplantation, 1993, 55:1272–1277. 12. Greenstein JL, Sachs DH. The use of tolerance for transplantation across xenogeneic barriers. Nature biotechnology, 1997, 15:235–238. 13. Allan JS et al. Amplification of simian retroviral sequences from human recipients of baboon liver transplants. AIDS research and human retroviruses, 1998, 14:821–824. 14. Allan JS. The risk of using baboons as transplant donors: exogenous and endogenous viruses. Annals of the New York Academy of Sciences, 1998 (in press). Animal-to-human organ transplants 64 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Discussion New problems beget new solutions A.P.R.Aluwihare1 Professor Daar has made an excellent survey of the various issues that arise. Acceptability of the con- cept of xenotransplantation and the sources used in different cultural and religious systems is an impor- tant part of the discussion. The right of recipients to proper information about the risks and the op- portunity involved does not overrule the right of communities to information on the risks involved for them, and to the security of knowing that rea- sonable precautions have been taken. The animals used also must be treated in a humane manner. The other ethical problems of priorities surrounding transplantation in general also apply. Now that rapid progress is being achieved in dealing with the im- mune system problems associated with xenotrans- plantation, and that assurance of the functional capability of suitable organs is closer, the many other issues need continuing and urgent consideration in a pragmatic manner. Source of organs The patient has a right to know where an organ was obtained. However, this might cease to be a religious or moral issue after a time. Although catgut is of animal intestine origin and requires the death of the animal for its production, it is so ubiquitous that no one objects to its use, and the matter does not even come up for discussion with patients. Heart valves of porcine origin, tissues of nonhuman origin stored in tissue banks for use in humans, and hormones and enzymes of porcine origin are acceptable in many societies. In others they are still not acceptable on religious grounds, but if no alternative were avail- able the reaction might be different. A potential jus- tification for acceptance may be that the complex preparatory process would “elevate” the material into the domain of a therapeutic device, and it would cease to be porcine. It would have been interesting to know Professor Daar’s views on whether the reac- tions to transplants other than those of whole or- gans might indicate less long-term opposition to xenotransplantation than one might have antici- pated. “Pseudo-rationalization” by societies is not new. Even where organs are concerned, especially those whose antigenic potential is altered by genetic manipulation, an argument could develop to facili- tate their use on the lines that the organ is no longer porcine but human as it will “take” in a human. A strong middle-class demand could both facilitate and necessitate the use of such rationalizations. It is ap- posite to mention that there are now many patents for transgenic animals and animal materials. The major religions Professor Daar has mentioned some issues arising out of religious beliefs; my comments are aimed at supplementing his. • In Buddhism where there is belief in reincarna- tion, there could be conflicting views on whether the use of a nonhuman organ confers disadvan- tage on the human or advantage on the animal as regards the next birth. This matter has not come up for discussion, and it is unlikely that any de- bate would have an adverse effect on the use of animal organs. • In Hinduism also, the pantheistic philosophies do not have any direct comment on the concept of xenotransplantation; the use of organs of bovine origin could raise a problem similar to the use of porcine organs in Islam and Judaism. However, here again demand from the middle class is likely to lead to a rationalization of use in the absence of other alternatives. • In the philosophies and religious systems of other societies such as China and Japan, where the ex- traction of organs from the brain-dead may be thought by some to be dehumanizing, it is possi- ble that implantation of a nonhuman organ may be viewed similarly. Basic ethics The basic principles of biomedical ethics such as beneficence, non-maleficence, autonomy and jus- tice (among others) must apply in this field, both to the individual and to the community. There is a potential conflict, for example, between the right of a dying patient to the only available treatment and the right of the community to avoid being exposed to an unknown and possibly nonexistent threat of infection. Such arguments arose in the case of the Getty marrow transplant described by Professor Daar. Infection It is not necessary to debate here the whole vitally important issue of the possibility of infection and its avoidance, prevention, monitoring, diagnosis, and control in the individual or community. Suffice it to point out that host-to-donor infection or disease transmission has to be and is considered even when blood transfusion is done and homografts of any kind used. Individual patients and the community have a right to expect that all reasonable precautions are taken to ensure that such risks are lower than the risks of the illnesses for which the xenotransplants are being done. That is to say, it is choice of the lesser risk that is required here, rather than absence of risk. The non-maleficence principle when applied to individuals and communities does call for rigour in looking for possible infections. The exposure of the widest possible range of human tissue and cell cultures to the cells and extracts from the donor animal would seem an essential step in such an evalu- 1 Professor of Surgery, Faculty of Medicine, University of Peradeniya, Sri Lanka, and Human Rights Commissioner of Sri Lanka. Bulletin of the World Health Organization, 1999, 77 (1) 65 ation. It might be argued that if no infection or in- festation in such tissue or cell culture (neither of which has any immune competence) occurs, then infection of the general population, whose immune systems are normal, is much less likely than infec- tion in a host whose immune system is suppressed. The xenotransplant also has to be protected from infection by the host’s organisms; in this respect grafts from gnotobiotic animals may be more susceptible (as the whole animals are) to such infection than grafts from normal animals. Issues of rights and resources The question of priority of rights arises when deter- mining how health resources are used, and weigh- ing the need for community services against that of expensive therapeutic procedures. Xenotransplant- ation would be very expensive, and involve the di- version of resources from activities with a much higher cost–benefit ratio. Diversion even from ef- forts at increasing the availability of cadaver organs might occur. It would be appropriate for the work to be done only in a few centres until reduction of costs as a result of better methodology or economies of scale is anticipated. In the transplant field the choice of patients in a situation of donor shortage is done by various methods, including the ability to pay for the organ or for the procedure. The choice may be between xenotransplantation or nothing ini- tially. The category of treatment a patient would be offered would require the same kind of ethical bal- ancing act doctors face at present. It would be un- fortunate if xenotransplants were regarded as available only to “the poor” (who would ironically also be the least able to afford them) and the alter- native of live donor or cadaver organs were reserved for the rich because it was perceived as “better”. Restrictions The restrictions imposed on a patient fall into two categories. In the first they would be to protect the patient. The ethics and rights of this are no differ- ent from those that apply in the case of, say, patients who need total body radiotherapy or have had mas- sive chemotherapy or immune suppression. In the second they would be to protect the community. Such restrictions might be justified, or they may be terribly wrong – as was the way in which those with leprosy were ostracized in the recent past. In the event of an unforeseen epidemic it is conceivable that quar- antine of a community could be required. Action of this kind is not new, but has not been used for dec- ades. It would have to be taken at government level. In the matter of transplant ethics it is imperative that each country be allowed to make its own ethi- cal decisions – guided by other countries’ experi- ence. In the case of organ procurement from other animals, international codes regarding some aspects of preventing the risk of infection would have to apply. The “mad cow” problem provides a good il- lustration of the need for thoughtfully and imagi- natively formulated stringent controls. Rights of disadvantaged patients From historical precedent we can expect that termi- nally ill prisoners or poor people, who need trans- plantation but have no hope of access to the best currently available, may be asked to be guinea pigs for xenotransplantation. However, the quantity and types of drugs needed, the kinds of suffering that may occur, the kinds of restrictions it may be neces- sary to impose on patients, as well as many other parameters, remain unknown. The rewards for the patient, even if health were restored, may be small. Are the rights of the community to have access to new treatments such that the rights of these indi- viduals can be overlooked? Or should such experi- ments be seen rather as fulfilling the individual’s right to any treatment that might offer some hope? n Putting the public at risk Fritz H. Bach1 Of the many important points discussed by Daar, I shall address only one: the ethical issues raised by the fact that xenotransplantation will put the public at risk of an infectious epidemic. My emphasis on this one point should not detract from other ethical concerns related to xenotransplantation. I have been and continue to be in general agreement with Daar’s writings and comments regarding xenotransplant- ation. This one area I shall discuss from my own perspective. The possibility that xenotransplantation, such as from pigs to humans, could lead to an infection that spreads to the human population, possibly not unlike the AIDS epidemic, is generally accepted. Earlier in 1998, we wrote an article suggesting that a moratorium be declared on clinical trials involv- ing xenogeneic organs, tissues and cells that involve such a risk (1). That moratorium, we felt, should be in place until the public has been informed about the risk to which it will be exposed if xenotransplan- tation proceeds, and has had an opportunity to par- ticipate in a meaningful way in making the decision on whether and how to proceed. This is not different from Daar’s view. He states “Since the community is in a sense being put at risk, there is a real argument to consider some form of community consent.” The suggestion for public in- volvement in the decision-making process is analo- gous to “informed consent” as it is obtained from individual patients undergoing an experimental pro- cedure. We urged that research on xenotransplant- ation should continue actively (1). In that article, we discussed the question of how the “public” might be involved in the decision-making. I return to that topic below. 1 Lewis Thomas Professor, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Avenue RM 370, Boston, MA 02215, USA. Animal-to-human organ transplants 66 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Discussion While supporting the desirability of commu- nity consent, Daar wonders whether we should “push this point”, in view of two factors: first, “our inabil- ity to quantify the…risk”, and second, the fact that “there is little experience in obtaining such commu- nity consent”. I would like to take up both of these points. Our lack of knowledge about the quantitative aspects of the risk of xenotransplantation does not detract from the pressing ethical need to involve the public now. One of the most important steps in our progress regarding the ethics of medical experimen- tation was to insist that informed consent be ob- tained from the patient undergoing a procedure. Our proposal that the public must have a voice in decid- ing under which conditions one could proceed with xenotransplantation essentially extends this concept of informed consent. Such an approach attempts to ensure that the public is truly represented on this ethical issue. Daar’s argument that we should not push pub- lic discussion now, given our uncertainty about the risk, will achieve the same result as the approach proposed by some who are against a moratorium. They have argued that since we do not know the extent of the risk of xenotransplantation, we must do a number of xenotransplants so that it can be assessed. This argument repudiates one of the most sacred tenets of informed consent: that consent must be obtained before any part of the procedure is per- formed. We often do not know how much risk we impose on an individual patient when asking for informed consent, and we make that fact clear to the patient in the process of obtaining informed consent. We do not say to the first patients under- going a new procedure that we have to go ahead without informed consent so that we can assess the degree of the risk. By that logic, we would only ask patients undergoing the new procedure for informed consent after we had performed the procedure on a sufficient number of patients without such consent, in order to understand the extent of the risk. The fact that the magnitude of the risk is not known does not justify proceeding in order to find out. The decision by the individual patient, and in the case of xenotransplantation by the public, must be made while realizing that the risk exists, even though we cannot quantify it. The argument that we must proceed with xenotransplantation in order to assess the risk has profound implications. If an infection related to xenotransplantation occurs in the human popula- tion, we will have determined that there is a risk, and we will also have created a potentially devastatingly dangerous scenario. If there is no in- fection in the first several years, it still does not mean that there will be no problems later. Thus, the argu- ment that we should proceed to assess the risk in this way is proposing a potential fait accompli, an approach that some criticize as the general insensi- tivity of medicine to the public (2). Ethically, can we put the public at risk in or- der to help individual patients? If it is not the public that decides, who should? The individuals who make such a decision cannot be those who are stakeholders in xenotransplantation, in the sense that they have a conflict of interests in this regard. As we have previ- ously discussed (1), they must be involved in the decision-making but the decision should not rest with them. Nor should others who come under pres- sure from the stakeholders make the decision. The Food and Drug Administration (FDA) properly deals, and has dealt, with the technical issues of safety. However, that body too is under pressure from many interests. I would thus reject arguments that our lack of knowledge about the extent of risk should reduce our insistence that there be public involvement in the decision-making prior to putting the public at risk. There is a logical inconsistency in the rules currently governing xenotransplantation. As Daar points out, the FDA has issued guidelines that es- sentially exclude the baboon as a donor. This has been done on the basis, at least in part, of the per- ceived higher risk of infection if baboons rather than pigs are used as donors. The baboon as a donor may well pose a higher infectious risk than the pig, but in fact we do not know the extent of the risk pre- sented by either animal. Given this ignorance, is it not somewhat incongruous to conclude that the risk of using baboons is too great while the risk of using the pig is acceptable? From the ethical point of view, both pose a risk to society and it must be society that decides under which conditions it is willing to accept that risk. Daar’s second point is that there is little expe- rience in obtaining public opinion or consent. It is correct that public consultation is a difficult task. However, in some countries such as Switzerland, the public is consulted by referendum. There was such a referendum in Switzerland on the use of genetic engineering very recently. Many expected the pub- lic to forbid the use of such techniques. However, probably because of the excellent effort that was made to educate the public, the referendum resulted in a solid endorsement of continued use of genetic techniques. In the United States it is hard to imag- ine holding a national referendum, although doing it at the local level is not inconceivable. For this rea- son we proposed that for the United States there should be a national committee composed of indi- viduals from a variety of disciplines, including eth- ics, who would try to reach a consensus on how to proceed, on behalf of the public. We have previously discussed such a national committee in detail (1). In fact, there is a committee not unlike the one we suggested now functioning: the President’s Ethics Committee, which recently issued a report dealing with human cloning. As discussed above, the deci- sions of the committee should not be made by indi- viduals with conflicts of interest or by those who are under pressure from interest groups. Bulletin of the World Health Organization, 1999, 77 (1) 67 The fact that we do not have much experience with polling the public in such situations should not dissuade us from developing appropriate procedures in this regard, or from proceeding in the best possi- ble way. We face a time in which there will be in- creasing numbers of technologies that offer great benefit in medicine while having potential dangers that might affect the public. We will need mecha- nisms for handling such situations from the ethical standpoint. Xenotransplantation is a clear example of such a problem; we should use this opportunity to develop an approach to decision-making that is both responsible and ethical. The suggestion of a moratorium to allow us to inform the public and gauge the response of soci- ety is not anti-xenotransplantation. As we wrote in a letter answering a critique of our suggestion for a moratorium: “our call for a moratorium on clinical work is not anti-science; rather it is a way of respect- ing the rights of the public, thus preserving the trust of the public in science” (3). n 1. Bach FH et al. Uncertainty in xenotransplantation: individual benefit versus collective risk. Nature medicine, 1998, 4: 141–144 . 2. Beck U. Risk society. London, Sage Publications, 1992. 3. Bach FH, Daniels N, Fineberg HV. Letter. Nature medicine, 1998, 4: 372–3. The case for using pigs Arthur Caplan1 The question of whether or not to use pigs, geneti- cally altered to minimize the likelihood of organ re- jection, as sources for transplantable organs seems to hinge only on whether xenografting poses an in- tolerable danger to public health. As Dr Daar accu- rately notes in his comprehensive review of the state of xenografting, recent debates about the morality of xenografting in the United States and Europe, especially the United Kingdom, have arrived at dif- ferent answers to the question based on their assess- ment of the public health risk posed. The decision in Europe has been that the threat to public health of disease transmission is too great, given the lim- ited knowledge available, to justify clinical trials of any xenografts at the present time. Expert panels in the US are not so convinced of the dangers, and see the science as more promising. In one way the differences between the Ameri- can and European assessment of the morality of xenografting reflect deep cultural differences in atti- tudes toward biomedicine and science. Americans tend to be more positive toward the promise of sci- ence then do Europeans, who tend toward caution in their assessment of risk when it derives from sci- entific activities. Strangely, it is also the case that for all the dif- ficulty that surrounds the computation of the risks posed by transmission of viruses and microorgan- isms to people from animals, questions of safety pro- vide a framework within which scientists and policy-makers are comfortable. Attitudes and an- swers may differ from country to country, but there are no sticky, complex or ineffable ethical issues to tackle if the debate about xenografting can be re- duced to a question of safety. Public safety surely must be a primary consid- eration in deciding whether or not genetically modi- fied animals ought be used as sources of organs for people in need of transplants. The threat of a public health catastrophe caused by a lethal virus transmit- ted from a pig or primate to a human transplant recipient and thence to a large segment of the hu- man population is small but real. It is a risk that cannot be justified simply by the possibility of sav- ing a comparatively small number of lives by means of transplants. But, as Daar correctly and insightfully perceives, the ethics of xenografting involves more than an analysis of the safety question. Equally important questions in assessing the morality of xenografting are whether it is ethical to breed and kill pigs or other animals for this pur- pose; whether it is ethical to ask a human subject to face the risks, emotional as well as physical, that will attend any attempt to xenograft; or whether the psy- chosocial issues raised for recipients are too great to bear. Each of these issues must be answered in a way that the public finds convincing. I suspect this will require clinical research in xenografting to follow very specific protocols if it is to be an option for solving the problem of scarce supply in the field of organ transplantation. There should be no doubt that serious risks are posed when organs from any animal are placed inside a human body. It is a well-established fact that many viral and prion agents are capable of moving from animal vectors to humans. The natural defences of the human body against viruses and other micro- organisms that can be carried along in an animal organ may well be compromised when that organ comes into direct contact with the body’s own in- ternal organs and fluids. It might be supposed that the danger posed is greatest with the earliest experiments, but this is not true. It may well be easier to manage the danger of transmission and infection by animal-borne viruses and microorganisms in the earliest stages of xenografting than later in the development of the technology. The f irst experiments can be done under very carefully controlled conditions. Those involved in the first xenografts can be closely monitored. Recipients can be rigorously isolated and those who come into close contact with them can be required to wear appropriate protective clothing and equipment. Animal organ recipients must under- stand that they will have to be under biological surveillance, undergo restrictions in living and hu- 1 Trustee Professor and Director, Center for Bioethics, University of Pennsylvania, 3401 Market Street, PA 19104, USA. Animal-to-human organ transplants 68 Bulletin of the World Health Organization, 1999, 77 (1) 1 Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, USA. Round Table Discussion man contact possibly for the rest of their lives and that a postmortem will be required when they die. It will be very difficult for the first recipients to endure the safety precautions that must accom- pany this surgery. Still, the safety measures needed are not unprecedented, having been used in a number of other situations in which infection from human to human with dangerous agents is a real possibility. The isolation of David the so-called “bub- ble boy”, the carefully controlled environments in which persons live after bone marrow transplants, and the special facilities used to handle persons be- lieved to be carrying tuberculosis and other highly infectious agents all provide examples. It is only if xenografting should prove clini- cally feasible that the real question of public health safety will loom large as a possible stumbling block. The same exacting monitoring and environmental control standards used for a small series of experi- mental subjects, chosen in part for their capacity to deal with them, will be difficult, costly and far more prone to failure when put to use in larger numbers of patients. The need for safety is not a barrier to the conduct of a small number of clinical experi- ments to show the feasibility of using genetically modified animals as sources of organs. If safety can be reasonably assured for an ini- tial series of experiments, the ethical focus on the use of animals as sources of organs shifts to the ques- tion of whether it is ethical to raise and kill them for this purpose. For many, including some prospective recipients, xenografting will only be morally accept- able if the animals do not suffer, are not rare or on the verge of extinction, and are as distant as possible phylogenetically from human beings, so that con- cerns about the moral standing of the animal to be sacrificed are minimized. In addition, there would need to be no other plausible alternative source of transplantable organs. Happily, the animals to be used for xeno- grafting at present are pigs, not primates. The fact that hundreds of millions of these animals are killed for food each year makes it difficult to muster moral outrage over their sacrifice to save lives. True, pigs are capable of suffering, and it might be argued that if pigs are genetically altered to improve the chances of transplantation success some wrong or harm is being done to them. But changes to the immune system of a small number of pigs hardly threaten to undermine the dignity or individuality of that spe- cies. To serve as sources of healthy organs, the pigs that will be sacrificed must be very carefully raised in safe and clean environments. So although pigs will be killed, the standard of their treatment and the quality of their lives will be very high prior to their deaths. Unless one believes that a human life and a pig life have absolutely equal value – a moral position that is exceedingly implausible – and once it is understood that the pigs will be very well treated and killed in a humane manner, concerns about the welfare of these animals are not sufficient grounds for prohibiting their sacrifice (1). In examining the ethics of xenografting it is easy to overlook the issue of how much a subject can be asked to do. Since prospective subjects face death without a transplant and since there will be competition to gain access to a clinical trial of xenografting, there is a danger of overlooking the burden that xenografting can place upon subjects in such research. Subjects in proposed xenografting trials will face death, but there is a real danger that the surgery could lead to more suffering and an earlier death than they would have had if they had not received an organ from a pig. In addition, the conditions re- quired for ensuring public safety will require great sacrifice from subjects, who would not be able to preserve their confidentiality or the privacy of their loved ones in an experiment of this nature. Subjects would need to understand that in becoming sub- jects they may suffer more if the research fails or find themselves treated as subjects for the rest of their lives if it succeeds. This is not to say that the risks of pig xenografting are so onerous that the experiment ought not be done, but the psychosocial issues of living with an animal organ may prove too burden- some for some to bear. Extraordinary care must be taken in subject selection, informed consent must be thorough, independent sources of information must be available to those considering serving as subjects, and persons who wish to be candidates must understand that the experiment is likely to fail. Public health can best be protected if only a small number of experiments are conducted, and those in a rigorous manner. The ethical case against xenografting, while compelling and worthy of more public and expert debate and discussion, is not per- suasive. Genetically altered pigs may not be able to save human lives but the time has come to take a tentative step to see whether they can. n 1. Caplan AL. Am I my brother’s keeper? Indianapolis, Indiana University Press, 1998. Speculation, stringent reasoning, and science Louisa Chapman1 Dr Daar has provided a cogent review of recent de- velopments in xenotransplantation that have at- tracted public concern. In 1993, the US Centers for Disease Control and Prevention (CDC) began to assess such concerns in response to requests for lead- ership in developing a national consensus on xenotransplantation. Those chairing academic hu- man subject review committees, struggling to adopt responsible local positions on xenotransplantation Bulletin of the World Health Organization, 1999, 77 (1) 69 clinical trials, were foremost among the petitioners. By 1995, at the initiative of the US Food and Drug Administration (FDA), the agencies of the US Pub- lic Health Service (USPHS) were working together to draw up national guidelines. An initial assessment of the issues, published in 1995 (1), can be summa- rized as follows. Infectious agents already endemic in human populations have been transmitted from donors to recipients through allotransplantation. Xenotrans- plantation carries a risk of transmitting infectious agents not recognized as classic zoonoses (and per- haps not capable of infecting humans under normal circumstances) from source animals to human re- cipients. The unusual circumstances of xenotrans- plantation, in which normally intact barriers are breached and the living xenograft serves as a persist- ent source of exposure to infectious agents, may per- mit transmission of xenogeneic infectious agents that do not pose a threat under normal circumstances. Once infected, the xenograft recipient may become a source patient, introducing new infections into the larger human community. Historic pandemics of zoonotic human disease, including the 1918 influ- enza pandemic attributed to swine influenza and the current HIV/AIDS pandemic, are precedents for these concerns. By September 1996 a draft USPHS guideline on infectious disease issues in xenotransplantation had been jointly drawn up by the FDA, the CDC, the National Institutes of Health (NIH) and the Health Resources Service Administrations, and published for public comment (2). As noted by Dr Daar, this draft provoked an extensive critical response. A re- vision of the guideline, based on this public response and the interim advances in science and public policy development, should be published in the near fu- ture. Foremost among the significant changes be- tween the draft and the revised document is the requirement that all clinical xenotransplantation tri- als in the United States proceed under FDA regula- tion. Plans have also been made for forming a National Xenotransplantation Advisory Committee, which will have, among other responsibilities, that of providing a forum for the consideration of per- sistently contentious issues (such as concerns about the use of nonhuman primates as sources of xenografts). In the absence of hard data, attempts to assess risks and develop a rational policy are exercises in reasoned speculation. Prudence requires that one neither understate nor exaggerate risk when attempt- ing to generate public discussion of these issues. As long as hypotheses remain untested, there will be a wide divergence of opinion among responsible sci- entists. These conditions provide an open field for sensationalism or unrealistically imaginative con- cerns by less responsible or less knowledgeable discussants. Responsible dialogue requires stringent reasoning with the available information. In this re- gard, Dr Daar has done an admirable job of walking a cautious line while attempting to facilitate public discussion of this topic. Dr Daar refers to the assumption that xenografts procured from nonhuman primates pose more risk of transmitting infections to humans than do those procured from pigs. This issue has gener- ated much concern among both scientists and lay people and is an area in which science at present offers inexact guidance. While the simplest solution is to call for an absolute moratorium on the use of nonhuman primates, the wisdom of imposing one on the basis of fear rather than science is question- able. A moratorium would prevent the reckless use of nonhuman primate xenografts when alternative solutions are available, but it would also prevent the use of such xenografts for selected “niche” applica- tions that may become desirable in the future. The assumptions implicit in the statement that “xenografts procured from nonhuman primates are more dangerous than porcine xenografts” become clearer if the statement is reversed. Can we confi- dently base public policy on the assumption that xenografts procured from pigs are safer (pose less risk of transmitting infection) than xenografts pro- cured form nonhuman primates? Familiarity can lead to complacency. Prudence again argues that we rec- ognize the limitations in our knowledge in this area. It is true that domesticated pigs have coexisted with humans for centuries while captive nonhuman pri- mates are only a generation or two removed from the wild. It seems reasonable to deduce that the mi- crobial flora of pigs, whose husbandry has been the subject of industrial development, is more throughly explored than that of nonhuman primates. How- ever, the description of a newly recognized persist- ent hepatitis E virus infection of pigs suggests that our knowledge in this area is less than comprehen- sive (3). Likewise, it seems reasonable to argue that the phylogenetic proximity of human and nonhuman primates increases the probability that cross-species infections will be facilitated by shared cellular machinery, and epitopes retained despite evolutionary divergence. However, available data from which one may infer the evolutionary history of existing retroviruses suggest a more complex real- ity. Despite the phylogenetic divergence of primates, cats, and mice, gibbon ape leukaemia virus and fe- line leukaemia virus both appear to have evolved through the cross-species transmission of an ances- tral C-type murine retrovirus (4). The Swedish diabetic recipients of porcine pancreatic islet xenografts, to whom Dr Daar refers, have been carefully investigated for evidence of in- fection with porcine endogenous virus. No evidence of infection was found in these patients or in an additional two who underwent short-term extracor- poreal connection to pig kidneys (5, 6). This initial investigation is a promising first step, but only the first step in what must be a laboriously developed multiphase process. The risk of xenogeneic infec- tion will be influenced by the species from which Animal-to-human organ transplants 70 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Discussion the xenograft is procured, the lifelong exposure his- tory of the individual animal, the tissue used in the xenograft, and the specific application employed. The development of clinical trials employing immunoprotected cellular xenotransplants can be expected to result in longer post-hospital survival of larger numbers of xenograft recipients. These survi- vors are likely to have retained functioning xenograft tissue for months or years rather than days or weeks. The presence or absence of endogenous retrovirus infection in larger numbers of these recipients must be explored to develop a database with which to quantify the risk of xenogeneic infections. Existing public policies can then be refined in light of new knowledge. We often have to choose an initial course of action based on reasoned assumptions. There is a danger, in the face of laboriously established policy, of becoming intellectually bound by early precedents. The comfort of having established policy can ob- scure the need to test the hypotheses and assump- tions underlying that policy. For this reason, adversaries who push us to refine our reasoning, ex- amine our prejudices, and be uncomfortable with conclusions not yet supported by science may be more valuable than allies. Dr Daar’s closing paragraph discusses the risk of expatriate experiments and introduces another important caveat. We cannot protect communities in the industrialized world by driving renegade ex- periments into the developing world where fewer regulatory protections may exist. Infectious diseases intermittently remind us that we are all citizens of an increasingly global community. Many recent events warn us against the illusion of being protected by geopolitical boundaries. They include: • the importation of Lassa fever from Nigeria to Chicago in 1988 by an infected person (6); • the importation of Ebola Reston fever from the Philippines to Reston, Virginia, in 1989 and 1990 by infected nonhuman primates (7); • the importation of malaria into the United King- dom and the United States with subsequent sec- ondary transmission (8, 9); • the establishment of endemicity after the intro- duction of HIV/AIDS initially in Africa, subse- quently in the United States and Europe, and most recently in Asia (10). For residents of industrialized countries, the preven- tion of renegade experiments in the developing world is as much enlightened self-interest as benevolent regard for our fellow residents on this planet. n 1. Chapman LE et al. Xenotransplantation and xenogeneic infections. New England journal of medicine, 1995, 333: 1498–1501. 2. United States Public Health Service. Draft Public Health Service guideline on infectious disease issues in xenotrans- plantation. Federal register. 23 September, 1996, 61: 49920-49932. 3. Meng XJ et al. A novel virus in swine is closely related to the human hepatitis E virus. Proceedings of the National Academy of Science, USA, 1997, 94: 9860–9865. 4. Brown J et al. Xenotransplantation and the risk of retroviral zoonosis. Trends in microbiology, 1998, 6:411–415. 5. Heneine W et al. No evidence of infection with the porcine endogenous retrovirus in human recipients of porcine islet cell xenografts. Lancet, 1998, 352:695–699. 6. Patience C et al. No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys. Lancet, 1998, 352: 699–701. 7. Holmes GP et al. Lassa fever in the United States. Investigation of a case and new guidelines for management. New England journal of medicine. 1990, 323: 1120–1123. 8. Jahrling PB et al. Preliminary report: isolation of Ebola virus from monkeys imported to USA. Lancet. 1990, 335:502–505. 9. Brabin BJ, Ganley Y. Imported malaria in children in the UK. Archives of disease in childhood. 1997, 77: 76–81. 10. Zucker JR. Changing patterns of autochthonous malaria transmission in the United States: a review of recent outbreaks. Emerging infectious diseases. 1996, 2: 37–43. 11. Mann JM, Tarantola DJ. HIV 1998: the global picture. Scientific American. 1998, 279: 82–83. Legal and regulatory issues Bernard M. Dickens1 The review of developments and key issues so admi- rably presented by Professor Daar raises concerns of appropriate legal and regulatory responses at three levels, namely governmental, clinical and social. Governmental approaches Developments in medical technology need not nec- essarily induce a legislative or regulatory response. Professor Daar notes that the field of xenotrans- plantation is moving very rapidly. This may caution governments against rushing to legislation that risks being overtaken by events, thus denying benefits to those whose interests governments claim to serve. Such a rush could, for instance, freeze governments into ill-considered positions, shaped perhaps by misguided stereotypes or imaginary horrors that are irrational and become increasingly indefensible. We have recently seen how moral panic over prospects of human cloning has resulted in demands for pro- hibitive laws that would endanger respect for values such as the right to freedom of therapeutic and aca- demic enquiry, the right to reproductive choice and the right to benefit from scientific advances. Nevertheless, the concerns Professor Daar raises include risks to recipients of animal organs and cells, as well as to their companions and the public at large, that justify governmental scrutiny. The contrast is presented between the regulatory approach recommended in the United Kingdom by the Kennedy Report (1) and the advisory approach favoured by the United States Institute of Medicine (2). The regulatory approach depends on legislation that empowers a regulatory agency to approve or reject prospective xenotransplants. It protects poten- tial recipients against their own and others’ disre- 1 Professor of Law, Faculty of Law, Faculty of Medicine and Joint Centre for Bioethics, University of Toronto, Canada. Bulletin of the World Health Organization, 1999, 77 (1) 71 gard of dangers arising from xenotransplantation, and it protects family members and others whom patients might expose to animal-derived infections, and the wider public. This approach may be criti- cized for being paternalistic, but people who in other regards are competent adults may feel that they have only an infantile understanding of the scientific im- plications of xenotransplantation, and appreciate in- formed regulation of this technology. This is particularly so if they see the technology as being promoted by commercial rather than therapeutic interests. The advisory approach favours informed, au- tonomous choice rather than governmental direc- tion. An advisory council can often be legally constituted under existing governmental powers, but legislation may be required for payment of council members and administrators. If public health au- thorities or public clinics incorporate advisory coun- cil recommendations into their practices, principles of administrative law may apply. If their decisions affect patients’ or staff members’ legal rights or le- gitimate expectations, for instance to receive or render appropriate treatment, the persons concerned may be entitled to contradict advice and oppose rec- ommendations before final decisions are made. Public authorities whose decisions affect others’ legal interests cannot voluntarily surrender their duty of judgement to another agency like an advi- sory council. Though not directly legally binding, advisory council recommendations can have legal effects through the professional licensing of health care pro- viders, and through private service contracts. Pro- fessional licensing authorities may consider disregard of such advice to constitute professional misconduct, and impose disciplinary sanctions such as the with- drawal or suspension of a licence. Similarly, it may be a written or implied term of a service contract that performance will follow such advice, and disre- gard may amount to breach of contract and justify its termination. Accordingly, advisory council rec- ommendations on xenotransplantation can have serious but indirect legal consequences. Clinical approaches Professor Daar refers to the controversy over whether we are ready to embark on large-scale clinical trials of vascularized whole organs. It has become com- mon to expect that new medical technologies will be introduced through “clinical trials”, and proceed only with caution and due ethical reflection. In the United Kingdom, for instance, the Clothier Com- mittee on gene therapy recommended that, at least initially, somatic cell therapy should be regarded not as ordinary medical practice but as clinical research (3). Many procedures that are undertaken only for research purposes are performed in clinical settings. So also, however, are many innovative therapies designed primarily to offer seriously ill patients per- haps their only chance of survival. Xenotransplant- ation itself will probably initially be offered only to patients close to death. Professor Daar describes Dr Thomas Starzl’s 1992 baboon-to-human kidney transplants, and observes that “the experimental nature of these attempts naturally leads to the selec- tion of very sick persons; thus the first recipient was a patient with advanced AIDS and near-terminal hepatitis.” A legal and regulatory concern is whether clini- cal trials of proposed life-saving innovations are gov- erned as research or as therapy. A proposed distinction between “therapeutic research” and “nontherapeutic research” has been condemned as illogical and harmfully confusing (4). Research and therapy are usually distinguishable in law and in regulatory provisions. Research is undertaken for development of generalizable knowledge on people rather than for people who may be patients. It re- quires preliminary approval by committees that re- view proposals on ethical grounds (5). Some procedures may require additional approval. For in- stance, Professor Daar describes the detailed review undertaken in 1995 by the US Food and Drug Ad- ministration (FDA) before an experimental baboon- to-human bone marrow transplant was performed, with apparent success. In contrast, therapy, including innovative therapy, is practised upon adequately informed pa- tients for their personal benefit. Its outcome, whether successful or not, may be of considerable interest to other therapists and the research and wider scien- tific communities, but its primary purpose is to ad- vance the health interests of the sick patient whose attending clinician judges it to be clinically appro- priate. The proposal and performance of procedures intended as therapy constitute the practice of medi- cine. Those legally unqualified for this within a ju- risdiction, including lay members of research ethics review committees, are entitled neither to practise medicine nor to veto the proposals made to their patients by those who are qualified. Innovative proposals to desperately ill patients do indeed often require ethical review, and this is what the FDA may have accomplished in 1995 in the baboon bone marrow case. There is a tendency to describe proposed innovations such as gene therapy, as “research” in order to bring them before research ethics review committees, in the absence of alternative means of ethical review. However, such committees have no authority over therapy. Where laws or regulations govern therapeutic procedures, for instance because they are innovative or contro- versial, health care providers are expected to com- ply. However, when patients are facing death with no alternative means of relief, disregard of such laws or regulations may be found legally excusable. There is a long history, for instance, of physicians being acquitted of serious criminal charges for disregard- ing the legal prohibition of abortion on the grounds that their procedures were necessary to save their patients’ lives (6). In this context excusable conduct is unlawful even when held not to warrant judicial sanction. Animal-to-human organ transplants 72 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Discussion Professional licensing authorities may therefore im- pose disciplinary sanctions, since their mandate is not to punish but to protect the public against un- ethical conduct. Performing xenotransplantation in breach of the law and without prior ethical consid- eration may be classed as medical professional mis- conduct. Lawyers cannot advise unlawful conduct, and must inform clients of its illegality. They may also inform clients, however, that a court of law might find a certain action excusable although li- censing authorities might not. Accordingly, whether initial instances of xenotransplantation are charac- terized as research or as attempts at life-preserving therapy is a matter of legal and regulatory concern. Social approaches Xenotransplantation may be presented as a means to reduce the serious gap between the supply of trans- plantable organs of human origin and the demand for them. Some legal or regulatory oversight of this biotechnology may be required, however, to ensure that use of animal organs does not cause prejudice to patients on waiting lists for human organs, and that the potential benefits of xenotransplantation are fairly assessed. Prejudice may arise when patients who agree to receive xenotransplants as therapy suffer organ rejection, and thereby move into a category of need that affords them priority over other patients on the same waiting list. Rules governing assignment of patients to priority status on the list should be developed to counter strategies by a patient or phy- sician that prejudice the patients who are pre-empted on the waiting list for therapeutic transplantation by one who has accepted xenotransplantation. It has been seen that more experimental pro- cedures, such as Dr Starzl’s baboon kidney trans- plants, may be considered acceptable and natural only for patients close to death. The modern history of transplantations of artificial hearts and human hearts, for instance, shows their justification as means of last resort offered to patients nearing death (7). Necessity may explain resort to desperate and un- proven medical interventions. However, there is a risk of inadequate assessment of new medical tech- nologies when their initial use in research is limited to patients in whom alternative means have failed, and whose health is so compromised that they are liable to succumb even if the novel intervention were otherwise able to succeed. “Last chance” interven- tions limited to treatment only of the most severe or hopeless cases, involving patients least likely to be helped, do not test a research intervention ad- equately. Social interests in acquisition of scientific knowledge about the potential of xenotransplant- ation require that the procedure should not risk be- ing discredited by regulations or practices that confine its use to patients at the most advanced stage of deterioration. Laws or regulations should allow patients to approve xenotransplantation research at earlier stages in their illness. Professor Daar discusses the risk of infection that explains why organs from non-human primates such as baboons and chimpanzees may be contra- indicated for transplantation into humans, but elsewhere he has also reviewed the cultural consid- erations that underlie discomfort with use of organs from sources so close to the human species (8). He writes of the part played by “the emotional attach- ment that human beings have to them” that leads to rejection of non-human primates as sources of or- gans for human recipients. This emotional attach- ment may be parallelled by a need for detachment. We can perhaps accept transplantation of pigs’ or- gans into humans because we know we are not pigs, but the prospect of non-human primates as organ sources raises the issue of uncomfortable similarities between all of the walking apes (9). Sigmund Freud once explained that the smaller the real difference between two peoples, the larger it looms in their imagination. This may explain why a group’s capac- ity to esteem itself is dependent on an ability to emphasize trivial distinctions from others (10), which Freud described as the narcissism of minor difference (11). In Canada, research ethics boards constituted under a new joint policy statement of the three fed- eral research councils concerned will increase the number of representatives of social sciences partici- pating in the ethical review of medical research (10). Further, the Industrial Biotechnology Association has established an ethics committee (11) to examine ethi- cal aspects of biotechnology in a broad context. Ex- posing xenotransplantation to widely reflective review offers a prospect of biomedical advance that is consistent with social values and conscience. n 1. Advisory Committee on the Ethics of Xenotrans- plantation. Animal tissues into humans. London, Stationery Office, 1997. 2. Institute of Medicine. Xenotransplantation: science, ethics and public policy. Washington, DC, National Academic Press, 1996. 3. Committee on the Ethics of Gene Therapy. Report: development of health. London, Stationery Office, 1992. 4. Levine RJ. Clarifying the concepts of research ethics. Hastings Center report, 1979, 9(3), 21–26. 5. Council for International Organizations of Medical Sciences, International ethical guidelines for biomedical research involving human subjects. Geneva, CIOMS / World Health Organization, 1993. 6. Cook RJ, Dickens BM. Abortion laws in commonwealth countries. Geneva, World Health Organization, 1979. 7. Annas GJ. Death and the magic machine: informed consent to the artificial heart. Western New England law review, 1987, 9(1):198–210. 8. Daar AS and Marshall P. Culture and psychology in organ transplantation. World health forum, 1998, 19(2): 124–132. 9. Morris D. The naked ape. London, Jonathan Cape, 1967. 10. Ignatieff M. Blood and belonging: journeys into the new nationalism. Toronto, Penguin Books Canada, 1994: 21–28. 11. Freud S. Group psychology and the analysis of ego, 1921. In: Pelican Freud library, Vol.21. London, 1961: 131. 12. Medical Research Council of Canada. Tri-Council policy statement on ethical conduct for research involving humans. Ottawa, MRC, 1998. 13. National Biotechnology Advisory Committee. Leading in the next millennium: sixth report. Ottawa, Industry Canada, Ottawa, 1998: 67. Bulletin of the World Health Organization, 1999, 77 (1) 73 The process of discovery Jay A. Fishman1 Questions about xenotransplantation are often posed philosophically, in terms of right and wrong. This approach contrasts with the rest of evidence-based biomedicine, which rarely provides absolute answers to questions of merit. Should xenotransplants be performed? Do the potential benefits outweigh the theoretical risks? In general, such questions are ex- amined in the light of current biological knowledge, and are subject to revision over time. As our data- base develops, hypotheses are reformulated. Cer- tainty does not exist. Thus, when allotransplantation was introduced, knowledge of the infectious risks associated with immune suppression was rudimen- tary. Data about infection in allotransplantation has grown rapidly with basic science and clinical experi- ence (1). This relatively recent information was cen- tral to the discussions on the risk to the individual (potentially great) and to society (thought to be small) when the transplantation of baboon marrow into a human with AIDS was reviewed for the Pub- lic Health Service in the United States. Those dis- cussions were coloured by passions about science, AIDS and individual rights, but they resulted in a far safer experiment in terms of risks of infection. They were also of benefit for more general consid- erations of clinical xenotransplantation. The term “xenosis” was coined to reflect not only the experience in allotransplantation, but also the unique epidemiological aspects of interspecies transplantation – the potential transfer into the gen- eral human population of novel or unknown patho- gens derived from animal donors (2–6). In terms of basic science, the search for such novel organisms has already had a beneficial effect on studies of the microbiology of transplantation, for example the iso- lation and sequencing of the first full-length por- cine endogenous retrovirus (7) and to virological studies which suggest the ability of such organisms to infect human cells in vitro (8–10). Such data have been used by the US Public Health Service, and by corporate interests, to develop testing strategies for pigs raised as potential xenograft donors. Such studies and discussions have also made it clearer to most investigators that infection is a critical consideration in the development of clinical xenotransplantation. Further studies are likely to find additional new, and possibly pathogenic, organisms in xenograft donor species, and the potential for human infec- tion can be assessed for each. This discovery process adds to our understanding of the risks of xenotrans- plantation, and of the microbiology of immuno- compromised hosts in general. It is a part of the evolution of the science of xenotransplantation. Microbiological guidelines for xenotransplantation should therefore be devised, to indicate what is cur- rently known about infection for such procedures, and serve as a basis for future scientific investiga- tions. Benefits of xenotransplantation The benefits of xenotransplantation must be seen in the light of the limitations of currently available tech- nologies. Many patients die while awaiting cadaver donor organs. Cadaveric donors provide life-saving opportunities for a small number of fortunate re- cipients, but the organs have often been subjected to hypoperfusion, infectious contamination, or in- jury during surgical procurement. All of these are problems which may be eliminated by the use of planned xenotransplants. Allograft recipients may suffer from chronic infection or debilitation but these problems could be reduced if elective transplanta- tion could be scheduled, as it is currently for living donor transplants. In addition to their potentially unlimited availability and correct size, xenogenic organs may be resistant to infection with viral patho- gens of humans, including HIV (1 and 2), HTLV, hepatitis viruses, and herpes viruses – including hu- man cytomegalovirus (CMV), which has been shown in our laboratory to be unable to infect porcine cells in vitro (11). Further, human hepatitis B virus does not appear to infect baboon in vivo (12). While such protection is unlikely to be observed for all poten- tial pathogens, it may provide a significant advan- tage to patients with organ failure due to viral infection. Assessing the risks The central goal of infectious disease physicians in transplantation is disease prevention, given the poor clinical response of the immunocompromised host to established infections. What types of organisms should we be concerned about in xenotransplanta- tion? As in the case of allotransplantation, the fol- lowing points are fundamental to the assessment of the risks of infection in xenograft recipients. • All organisms are a potential cause of infection in any species, but the organisms most likely to cause infection are the ones that are similar or identical to those that do so in the immunosuppressed human allograft recipient, in addition to species- specific organisms not associated with human tissues. • The risk of infection is a direct function of the overall level of immune suppression needed to maintain allograft function and the nature and intensity of the epidemiological exposure of the recipient. The minimization of immune suppres- sion (for instance by tolerance induction strate- gies such as bone marrow transplantation) may significantly reduce the risk of infection if it does not increase the exposure of the recipient to do- nor-derived organisms or reduce the immune re- sponse to such organisms. • The manifestations of infection in the xenograft recipient will also be modified by the type (such 1 Clinical Director, Transplantation Infectious Disease Program, Infectious Disease Division, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts, USA, 02114. Animal-to-human organ transplants 74 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Discussion as corticosteroids, antilymphocyte therapy or ciclosporin), intensity and duration of the im- mune suppression needed to sustain organ func- tion, and by the clinical status of the recipient following transplantation. A number of additional factors conspire to increase the risk of infection in xenotransplantation: • the xenograft itself serves as a nidus or “culture plate” from which such organisms can spread in the human host without needing a “vector” to achieve disease transmission; • clinical laboratory tests for most organisms de- rived from non-human species (e.g., antibodies, molecular probes, culture systems for species- specific organisms, or serological tests for human antibodies against animal pathogens) are not gen- erally available; • the migration of cells from the graft to other sites in the host may carry cell-associated infection throughout the host; • clinical syndromes caused by new pathogens are not necessarily recognizable; • little is known about the behaviour of potential pathogens from the donor species in humans; • graft rejection and immune suppression are strong stimuli for the activation of many organisms from latency; • genetic recombination, mutation, or interactions between exogenous and/or endogenous organisms may mask or alter the common manifestations of infection; • the absence of pre-existing immunity in the re- cipient to novel, animal-derived organisms may render the host more susceptible to infection; • species disparity of histocompatibility antigens may be associated with diminished cellular im- mune function by the host against organisms within the xenograft (4). Which organisms should we fear? The organisms of greatest concern to the general public are those which spread easily between immu- nocompetent individuals, which can attach to and enter human cells, which can replicate within these cells or tissues, and which can spread with few clini- cal signs or symptoms. The ideal “stealth organism” takes on surface antigens from the host so as to re- duce the capacity of the host’s immune system to attack the pathogen. The organism must also cause disease (injury) directly or must develop pathogenic characteristics in the xenograft recipient so as to jus- tify concern about its spread in the general popula- tion. The endogenous retroviruses, like the beta- herpesviruses, are almost perfect transplantation pathogens. The endogenous retroviruses are carried in the genome of every cell, acquire host antigens while budding off from infected host cells, and re- quire cell-mediated immunity for clearance, which is diminished by immune suppression of the trans- plant recipient. However, there is no clear associa- tion of the porcine retroviruses, as yet, with clinical disease, infection of normal or immunocompro- mised individuals, or spread between individuals. All retroviral assays to date (unfortunately largely based on anecdotal reports) have been negative in terms of infection of humans exposed to porcine tissues (12–14). Preclinical studies of xenotransplantation will be important in defining the risk of spread of infection between species and the factors which con- trol viral replication. However, preclinical models (e.g. pig-to-primate) may not predict the infectivity or all the manifestations of disease which may occur in human xenograft recipients. The available data have not demonstrated risks which should impede measured progress towards further studies of clinical xenotransplantation. How- ever, further microbiological studies of xenograft tis- sues or cells from human recipients may be very revealing, and are of critical importance. To this end, new molecular or antigen detection assays for known organisms of donor species are needed. Each ap- proved clinical trial must also be designed to optimize the possible recovery of novel organisms and should not be limited to searching for previously identified organisms. Therefore, biopsies and blood samples must be collected from xenograft donors and recipi- ents not only for archiving but for use in an active programme of microbiological investigation, includ- ing the search for unknown organisms (for instance by representational difference analysis) and studies of the biology of such potential pathogens. It seems likely that new organisms will be discovered in asso- ciation with the transfer of animal tissues into immunocompromised or otherwise modified human hosts, just as novel infections have been described in association with the immune deficits of AIDS and cancer chemotherapy. Rather than being guided by fear of the unknown, we must not squander a unique opportunity for discovery. n 1. Fishman JA, Rubin RH. Infection in organ transplant recipients. New England journal of medicine, 1998, 338 (June 11):1741–1751. 2. Fishman JA. Miniature swine as organ donors for man: strategies for prevention of xenotransplant-associated infections. Xenotransplantation, 1994, 1:47–57. 3. Fishman JA. Preventing infections in xenotransplantation: xenosis from miniature swine. Xenotransplantation, 1995, 3:72–77. 4. Fishman JA. Xenosis and xenotransplantation: Addressing the infectious risks posed by an emerging technology. Kidney international, 1997, 51 (supplement 58):41–-45. 5. Michaels MG, Simmons RL. Xenotransplant-associated zoonoses: strategies for prevention. Transplantation, 1994, 57:1–7. 6. Ye Y et al. The pig as a potential organ donor for man. A study of potentially transferable disease from donor pig to recipient man. Transplantation,1994, 57:694–703. 7. Akiyoshi DE et al. Identification of a full-length cDNA for an endogenous retrovirus of miniature swine. Journal of virology, 1998, 72:4503–4507. 8. Takeuchi Y et al. Type C retrovirus inactivation by human complement is determined by both the viral genome and the producer cell. Journal of virology, 1994, 68:8001–8007. Bulletin of the World Health Organization, 1999, 77 (1) 75 9. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nature medicine, 1997, 3:276–282. 10. Wilson CA et al. Type C retrovirus released from porcine primary peripheral blood mononuclear cells infects human cells. Journal of virology, 1998, 72:3082–3087. 11. Michaels MG et al. Lack of susceptibility of baboons to infection with hepatitis B virus. Transplantation, 1996, 61:350–351. 12. Heine W et al. No evidence of infection with porcine endogenous retrovirus by primary porcine endothelial cells and infection of human cells. Lancet, 1998, 352:699–701. 13. Martin U et al. Expression of pig endogenous retrovirus by primary porcine endothelial cells and infection of human cells. Lancet, 1998: 352:692–694. 14. Patience C et al. No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys. Lancet, 1998: 352:699–701. Xenotransplantation in Sweden C.G. Groth1 & M. E. Breimer2 Several Swedish research groups are working actively in the field of xenotransplantation. Recently, these efforts have resulted in two clinical pilot trials: 10 diabetic patients have been transplanted with por- cine pancreatic islets, and two patients have had pig kidneys connected to their blood circulation and perfused extracorporeally. Transplantation of porcine islets Transplantation of isolated pancreatic islets offers a simple and safe method to provide the diabetic pa- tient with insulin-producing tissue. If such trans- plantation is to be widely applied, the supply of human pancreases will not suffice. Transplantation of pig islets could then serve as an alternative. Por- cine insulin differs from human insulin only in re- gard to one amino acid, and glucose homoeostasis and the regulation of insulin secretion are similar in pig and man. Furthermore, porcine insulin has been used for decades to treat diabetic patients. Since the transplanted islets will become vascularized by host vessels, hyperacute rejection should not occur. Fetal porcine islets can be prepared in large quantities by tissue digestion and culture. After trans- plantation, the fetal cells mature and differentiate into insulin-producing cells. Microbiological screen- ing revealed no infectious agents in the material, and, when the material was injected intraportally in dogs, no adverse effects were noted. On the basis of the above findings, a clinical pilot trial was conducted in the years 1990–1993 in 10 diabetic renal transplant patients. All patients were given immunsuppressive treatment because of their renal transplant (1). Eight patients who had previously undergone kidney transplantation had the porcine islets injected into the portal vein. Four of the patients excreted small amounts of porcine C-peptide for 100–400 days after transplantation, indicating porcine insulin production. In two pa- tients, the islets were placed under the capsule of their renal graft just after the graft had been revascularized. In one of the patients, a kidney bi- opsy specimen taken three weeks after transplanta- tion revealed morphologically intact epithelial cells under the kidney capsule. These cells stained posi- tively for insulin and glucagon. Ultrastructural and immunocytochemical features were typical of pan- creatic islet cells; the appearance of the cells indi- cated that they were viable (2). All patients had preformed xenoantibodies against the Gal 1,3Gal, an antigen epitope present on porcine but not on human cells. After transplan- tation there was a pronounced increase in the anti- body titres (3). The finding that the porcine islets did not function at all in some patients, and only for a limited time in the others, probably indicates rejection. The role of the xenoantibodies in this pro- cess remains obscure. The patients derived no clinical benefit from the transplantation in that their insulin requirements remained unaffected. A larger and longer-lasting insulin production will be required to accomplish a clinical benefit. Recently, we have isolated adult pig islets which provide immediate function. When such islets were transplanted into unmodified rats, rejec- tion occurred in 4–5 days. However, when the rats were treated with novel immunosuppressive drug regimens, rejection was prevented for several weeks (4). These encouraging findings will provide the basis for further trials with pig-to-human islet transplant- ation. Extracorporeal (ex vivo) perfusion of pig kidneys in two patients Removal of the preformed xenoantibodies by immunoadsorption, or plasmapheresis should facili- tate xenograft survival. In order to test this concept, we performed a clinical trial in 1995 where pig kid- neys were extracorporeally connected to the blood circulation of two volunteer dialysis patients. The procedure was similar to an ordinary dialysis, ex- cept that the dialysis filter was replaced by a pig kid- ney. Prior to the procedure, the patients underwent plasmapheresis with a subsequent reduction in xenoantibody titres. No immunosuppressive drugs were given (5–7). Initially both the pig kidneys perfused well, and produced urine. However, after 65 minutes of perfusion, the first kidney underwent rejection as evidenced by discoloration and a reduction in blood flow, and the experiment was discontinued. The sec- ond patient developed symptoms of anaphylaxis af- ter 15 minutes of perfusion. The pig kidney appeared normal at this time but the perfusion was terminated for safety reasons. Histopathological examination of the first kidney confirmed the diagnosis of rejection, 1 Professor of Transplantation Surgery, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden. 2 Associate Professor of Surgery, Transplantation and Liver Surgery Unit, Department of Surgery, Sahlgrenska University Hospital, Göteborg, Sweden. Animal-to-human organ transplants 76 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Discussion 1 President, Doctors and Lawyers for Responsible Medicine, 104b Weston Park, London N8 9PP, England. while there was no histological evidence of rejection in the second case. In both kidneys, there was a pro- nounced entrapment of platelets. In the second pa- tient, analyses revealed an activation of the complement cascade, this presumably contributing to the symptoms that appeared. Both patients de- veloped a marked increase in their anti-pig antibody titres, the antibodies displayed specific patterns re- garding class and subclass (6). Further pertinent sci- entific questions are currently being examined using material from these two experiments. The aim was to proceed with perfusion experi- ments, using kidneys from transgenic pigs carrying the human complement regulator, h-DAF, which counteracts hyperacute rejection. However, a United Kingdom Government report published in 1996, outlining the possible risks of viral transmission from pig to humans, led to a moratorium on further tri- als with pig organs in Europe. Of particular con- cern was the possibility that porcine endogenous retroviruses (PERV) would be transmitted. In the meantime, blood samples from the 12 Swedish patients who had participated in the clini- cal xenotransplantation trials have been examined for evidence of PERV infection by using polymer- ase chain reaction (PCR) and transcriptase assays. The findings were negative in all patients (8, 9). In conclusion, the two pilot trials conducted in Sweden have provided important information concerning immunological and physiological con- sequences of transplanting porcine tissue to humans. Furthermore, they have provided a unique oppor- tunity to assess the risk for transmission of PERV in the context of xenografting. n 1. Groth CG et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet, 1994, 344:1402–1404. 2. Reinholt F et al. Survival of fetal porcine pancreatic islets tissue transplanted to a diabetic patient: findings by ultrastructural immunocyto-chemistry. Xenotransplantation, 1998, 5:222–225. 3. Satake M et al. Limited specificity of xenoantibodies in diabetic patients transplanted with fetal porcine islet cell clusters. Main antibody reactivity against linked galactose- containing epitopes. Xenotransplantation, 1994, 1:89. 4. Wennberg L et al. Efficacy of immunosuppressive drugs in islet xenotransplantation: leflunomide in combination with cyclosporine and mycophenolate mofetil prevents islet xenograft rejection in the pig-to-rat model. Transplantation, 1997, 63:1234–1242. 5. Breimer ME et al. Extracorporeal (“ex vivo”) connection of pig kidneys to humans I: clinical data and studies of platelet destruction. Xenotransplantation, 1996, 3:328–339. 6. Rydberg L et al. Extracorporeal (“ex vivo”) connection of pig kidneys to humans II: the anti-pig antibody response. Xenotransplantation, 1996, 3:340–353. 7. Bengtsson A et al. Extracorporeal (“ex vivo”) connection of pig kidneys to humans III: studies of plasma complement activation and complement deposition in the kidney tissue. Xenotransplantation, 1998, 5: 176–183. 8. Heneine W et al. No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts. Lancet, 1998, 352:695-699. 9. Patience C et al. No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys. Lancet, 1998, 352:699-701. Stop now before it’s too late André Menache1 Animal-to-human organ transplantation (xeno- transplantation) did not originate in a vacuum. It is the net result of a fundamental assumption by the medical establishment that the solution to most of society’s health problems lies in the development of ever more expensive, complex and sometimes risky technologies. Thus, historically, the first transplant of a human heart in 1967 was widely hailed as mod- ern medicine’s supreme achievement, despite the fact that the patient died not long afterwards. Today, human-to-human organ transplants are becoming more routine but they are far from being a perfect solution to the health problems they are supposed to solve. Many patients still die as a direct result of complications from the transplant, and oth- ers describe their lives as a living hell due to the poly- pharmacy regime and lifestyle restrictions that are forced upon them (C. Ray Greek, personal commu- nication). If human-to-human organ transplants are still fraught with complications, animal-to-human or- gan transplants are taboo, or they should be. Transgenic transplants actually represent one experi- mental technique (the production of transgenic ani- mals) superimposed on another (the transplantation of transgenic animal organs into human beings). At- tempts to analyse the possible outcomes of this situ- ation lead to a statistical nightmare, since there is an exponential increase in unknown risks. Although the consequences of xenotransplan- tion are far from being well understood, the public is being led to believe that the main obstacle – for- eign organ rejection – can be overcome on the basis of earlier experiments in which monkeys receiving transgenic pig hearts survived for 60 days. Modern medicine still has great difficulty matching human tissue types, let alone animal tissue types. However, a more serious public health con- sideration is that of disease transmission from ani- mal to human, and subsequently to the general population. A worst-case scenario could mean an- other AIDS-like epidemic, with little promise of con- tainment, given the difficulty of carrying out environmental impact studies beforehand. Over- whelming scientific evidence is now available to show that xenotransplants represent an unquantifiable risk to the health and well-being of the general public (1). As Murphy put it, “It will not be easy to de- termine which viruses represent a risk to the xeno- graft recipient alone, which represent a risk to society as a whole as a result of species-jumping, and which may be dismissed as representing a minimal risk” (2). Equally disturbing is the well-publicized state- ment made by another US veterinary virologist, Jonathan Allan: “This is a serious mistake…it only Bulletin of the World Health Organization, 1999, 77 (1) 77 takes one transmission from one baboon to a hu- man to start an epidemic. There’s no way you can make it safe” (3). Despite these and other clear warnings not to proceed with xenotransplants, the United Kingdom health authorities have decided, nevertheless, to “pro- ceed with caution” with pig-to-human organ trans- plants (4). It is truly ironic that these health authorities, which go to extremes to protect the pub- lic from importing the rabies virus are now prepared to expose that same public to an “unquantifiable” risk by transplanting known and unknown pig vi- ruses into people (2). The situation in the US is actually far worse, since xenotransplants have already taken place, un- opposed by either the Food and Drug Administra- tion (FDA) or the Centers for Disease Control and Prevention (CDC), the very bodies whose stated policies are to protect the health of the public. De- spite the fact that almost all of the patients who re- ceived animal organs died soon after their operation, and despite the fact that FDA public health policies have always been “risk averse” (i.e. against research methods that are not well understood), the US Gov- ernment continues to allow xenotransplants to pro- ceed. In 1984, Leonard Bailey transplanted a baboon heart into newborn “Baby Fae” at Loma Linda Uni- versity, despite the fact that a proven surgical repair technique could have been used instead of the high- risk baboon heart. In addition, a human heart was available at the time. Also, the majority of medical opinion at the time was against the idea of using a baboon heart at all (5). Should society condone such unethical behav- iour? The public has been presented with a dilemma by the medical establishment: organ transplants can save lives, but there is a shortage of suitable human organs. Clearly, the idea of using animal organs is tempting, but on the basis of its abysmal track record, plus the Pandora’s box of unquantifiable risks in- volved, xenotransplants cannot be the answer. Then there are legal questions which have so far not been answered. For example, who would be responsible for paying compensation to persons who are damaged as a result of the animal organ inside them, or to secondary victims exposed to the viruses xeno-recipients transmit? A further major obstacle, which must be overcome before xenotransplants can proceed, is how to obtain the “informed consent” of the general population, since xenotransplantation puts not only the recipient at risk, but also the gen- eral public. The best long-term solution to organ trans- plants in general is preventive medicine, in the wid- est possible meaning of the term (obviously, this does not apply to those in need of an immediate organ transplant). Several alternatives exist, although none provides a complete solution. There is an urgent need for governments to invest more in preventive meas- ures (such as improved diet and lifestyle patterns, anti-smoking campaigns, and the like) in order to reduce future waiting lists to the point where supply meets demand. Allotransplantation (human-to-human organ transplantation) is still the best that modern medi- cine can offer the end-stage organ failure patient. From a purist medical perspective, however, organ transplants with a few exceptions are an admission of failure, on three counts: • failure to diagnose a disease condition correctly in the early stages; • failure to provide the correct therapeutic regimen despite a correct diagnosis; • failure to implement corrective preventive meas- ures (6). The result of all these failures is a serious shortfall in the number of suitable human organs available for transplantation. Several schemes exist to increase the number of human organs available. For instance, so- called “opt-out” schemes as practised in Austria and Belgium, can increase the availability of human do- nors. However, any organ-donation scheme must be accompanied by strict hospital protocols to fulfil all the criteria of “brainstem” death, and the necessary written informed consent, before a donor’s organs are removed. Even where these schemes are used, the de- mand for organs still far outweighs the supply. How- ever, before rushing for animal organs, there are other options well worth considering. Artificial organs are still in their infancy, but they can provide a tempo- rary substitute, or “bridge”, until a suitable human organ is found. In some cases, artificial organs al- ready provide a permanent solution (e.g. part-hearts). From a public health perspective, artificial organs are far superior to animal organs, because they are essentially disease-free. Indeed, research funding would be better spent on developing these more promising technologies than on xenotransplantation. There are also other alternatives to xenotransplants available today, some of which are already in use, such as the successful transplant of a liver lobe from a mother to her child in need of a total liver trans- plant. Similarly, cells from a particular organ can now be cultured into cell aggregates in the labora- tory, to provide a “part-organ” as a substitute, in some cases, for a conventional organ transplant. Also, cell injection may help some liver diseases, as recently reported in the New England journal of medicine. Viable alternatives to animal organ transplants do exist, but they need to be explored in much greater depth. The present situation, whereby xenotrans- plantation is being allowed to proceed despite alarm bells ringing, is both untenable and intolerable and should be challenged on several fronts: in the me- dia, in court, and in scientific debate. “Seldom, if ever, have we had as much knowledge to prevent a future epidemic. What is lacking is the wisdom to act upon that knowledge” (7). Xenotransplantation is still a dangerous and highly experimental technique, about to be un- leashed on an uninformed, and possibly also misin- formed public, against its will. n Animal-to-human organ transplants 78 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Discussion 1. Animal-to-human transplants: the ethics of xenotransplantation. London, Nuffield Council on Bioethics, 1996. 2. Murphy FA. The public health risk of animal organ and tissue transplantation into humans. Science, 273, 9 August 1996. 3. Allan JS. Time, 15 January 1996, 40. 4. Advisory Group on the Ethics of Transplantation. Animal tissue into humans. Norwich, Stationery Office, 1996. 5. Of pigs, primates and plagues. New York, Medical Research Modernization Committee, 1997. 6. McKeown T. The role of medicine, Oxford, Blackwell, 1979. 7. Allan JS. Xenotransplantation at a crossroads: prevention versus progress. Nature medicine, 2 (1):20. Current obstacles Peter J. Morris1 I read Professor Daar’s article with considerable in- terest. He adopts a conservative stance on the ques- tion of clinical trials of animal organs in humans at this point in time, and I must say that I would join him in this stance. There is no question about the demand for more organ transplants as the numbers of patients with end-stage organ failure awaiting kidney, liver, and heart/lung transplants grow all over the world. Indeed many patients are dying while waiting for liver and intrathoracic transplants. Furthermore, if type 1 diabetes could be cured either by whole organ pancreas transplantation or pancreatic islet transplantation using minimal and safe immunosup- pression, there is no way that the supply of human organs could meet the demand. Hence there is no doubt about the attraction of transplanting organs from animals into man. Nevertheless, there are ma- jor barriers to be overcome before this is possible, and some people would consider some of these bar- riers to be insuperable. The obstacles to successful xenotransplantation are immunological, physiological, infectious, ana- tomical and ethical. The pig, at the moment, is the animal of choice as a donor, for, as Professor Daar points out, anatomically its organs are of a size ap- propriate for the human, physiologically they do not appear too dissimilar, and as much of the world’s population eats pork there are relatively few ethical or cultural objections to the pig as a potential organ donor. Among the immunological problems the first major barrier is the problem of hyperacute rejection mediated by natural cytotoxic antibodies in the pres- ence of complement to a xenoantigen (known sim- ply as the Gal antigen). These cytotoxic antibodies are present in man and in Old World monkeys (from Europe, Asia and Africa), as the Gal antigen is not expressed in these species. Thus a pig organ trans- planted into man would undergo rejection within minutes. Major advances have been made in attempts to overcome hyperacute rejection such as the pro- duction of pigs expressing a human complement inhibitor on endothelial surfaces. Other molecular biological approaches to this problem have also been developed which suggest that the problem of hyperacute rejection of a pig organ may have been essentially resolved. However, less immediate but no less severe degrees of rejection, such as accelerated vascular rejection, conventional cellular rejection, and chronic rejection, will undoubtedly prove to be a problem, which may require heavy immunosup- pression to overcome. On the anatomical and physiological side there is a question of the size of the organ and its work capacity, its behaviour in an upright human com- pared to a quadruped, and of course whether pro- teins produced by the pig organ (e.g. erythropoeitin by the pig kidney) will react with human receptors. These latter problems are likely to make xenotrans- plantation of a pig liver impossible, in view of the fact that the liver produces some 1000 proteins, all of which would be foreign to man. With respect to the transmission of infection, a major concern is the possible transfer of porcine endogenous retroviruses, and although there is no evidence yet that this has occurred in humans ex- posed to pig tissues, such as islets, it is by no means excluded, and indeed transfer of the virus of por- cine endogenous retroviruses to human cells has been demonstrated in vitro. The transfer of potential pathogens represents a danger not only to the immunosuppressed recipient, which might well be justifiable in the case of liver or heart transplants carried out to save life, but also to the public at large if a pathogenic retrovirus is introduced into the human species. Finally, there are ethical problems which cer- tainly apply to the use of higher order primates as donors, bearing in mind their similarity to humans, poor breeding in captivity and their status as endan- gered species. But many people would also see, I suspect, an ethical problem with the use of pigs as organ donors, and recipients might find this to be either an ethical or a cultural issue. Nevertheless there does not appear to be a strong body of opinion rep- resenting this latter view. In conclusion, although we have made very important strides in finding out about the problems that have to be overcome to attempt xenotransplan- tation, and indeed solving some of these problems, there still does not seem to me to be sufficient knowl- edge to advocate clinical trials at this point in time. Nevertheless, if one could be as certain as possible that the risk of introducing a pathogenic virus into man was highly unlikely to occur, one could con- sider trials, in the first place of certain organs as a bridge to transplantation. In this scenario the heart, being the simplest of them all, would be the organ of choice for the initial trials. Needless to say, there would be tremendous potential for the transplanta- tion of tissues, particularly pancreatic islet tissue from 1 Nuffield Professor of Surgery, Nuffield Department of Surgery, University of Oxford, Oxford Radcliffe Hospitals, Oxford OX3 9DU, England. Bulletin of the World Health Organization, 1999, 77 (1) 79 the pig, if this could be achieved successfully with- out risk of infection. Furthermore the transplanta- tion of tissues, in contrast to organs, offers the possibility of transplanting tissues encapsulated so as to allow egress of hormones such as insulin from pancreatic islets, but prevent entry of antibodies and immunologically reactive cells which would destroy the foreign tissue. n The view of the Health Council of the Netherlands Eric van Rongen1 In the past decade, great progress has been made in finding solutions to rejection problems associated with xenotransplantation. In 1995 the first clinical experiment with genetically modified animal organs seemed close at hand. This prompted the Nether- lands Minister of Health, Welfare and Sport to re- quest the Health Council of the Netherlands to summarize the present scientific status of xenotrans- plantation and advise her on the prospects of the technology for the future. The Council was also asked to consider ethical issues in relation to the desirability and acceptability of research on xeno- transplantation, and of its possible clinical applica- tion. An inventory of the relevant legislation in the Netherlands was also requested, together with an evaluation of its applicability in this field. A com- mittee of the Health Council of the Netherlands drafted the report entitled Xenotransplantation, the main conclusions of which are presented here (1). Viability of xenotransplantation Several major biotechnological problems still pre- vent the successful long-term use of xenotransplan- tation. The first is immunological rejection of the transplanted material. Especially when discordant animals such as pigs are used as the source of or- gans, hyperacute rejection is the main obstacle. Since the molecular processes associated with this type of rejection nowadays seem to be quite well understood, the Committee felt that this problem could in due course be solved by using animals made adequately transgenic (2–4). However, for the other forms of rejection, which become manifest within days or weeks after transplantation, the only method of pre- vention is to use immunosuppressive agents in doses which are not acceptable for humans, because of the associated high risk of many serious complications (5,6). There is no obvious solution to this problem at present. Another question that needs to be answered is how the transplanted organ functions in the recipi- ent’s body. Certain considerations and some data indicate that xenotransplants might not always take over the function of the replaced organ properly (7, and C. Hammer, personal communication). At present, a further major obstacle to the use of xenotransplantation is the risk of infection – for the individual recipient and, more importantly, for the human population as a whole. The Committee feels that the use of non-human primates as source animals constitutes a much larger infection risk than that of discordant species and therefore advises against clinical experiments using primate organs. Scientific developments suggest the (transgenic) pig to be currently the most suitable source animal for xenotransplantation. However, since rejection prob- lems with primate organs are much smaller than with pig organs, the use of primates as source animals is not a priori rejected. The technical and ethical problems associated with the necessary breeding of specific-pathogen-free (SPF) primates should not be underestimated, however. Recent research suggests that viruses could make the transition from pig to man, but it is not yet clear whether they would then cause disease (8–10). In any case this means that xenotransplant- ation of pig organs to humans is also not without risks of infection. Much more understanding about the processes involved is required for an assessment of these risks. The Committee felt that it was not possible as yet to reach any conclusion regarding the future vi- ability of xenotransplantation as a clinical technique. Clinical experiments, whether with whole organs, tissues or cells, would not be appropriate until (a) there is a good chance of operative success; (b) the rejection problems have been reduced to a level com- parable to that currently associated with the trans- plantation of organs from human donors; and (c) the risk of infection is reduced to an acceptable level, for the safety of both the recipient and the popula- tion at large. For the same safety reasons, other ap- plications where intimate contact occurs between an animal organ and a human being, such as extracor- poreal pig liver perfusion (11), should also not be performed until the associated infection risks have been better determined. Ethics The Committee agrees with the conclusions of the elaborate ethical considerations of the Nuffield Council of Bioethics and the Advisory Group on the Ethics of Xenotransplantation, both from the United Kingdom (12, 13). If, under the conditions outlined above, xenotransplantation becomes clini- cally viable, the technique will be capable of allevi- ating the suffering of people with certain medical conditions and in many cases of prolonging life. The Committee therefore believes that, from a human point of view, xenotransplantation is ethically ac- ceptable. Furthermore, the Committee feels that the interests of the people who might benefit from the technique are sufficient to justify the possible in- convenience to or infringement upon the integrity 1 Scientific Secretary, Health Council of the Netherlands, P.O. Box 1236, 2280 CE Rijswijk, Netherlands. Animal-to-human organ transplants 80 Bulletin of the World Health Organization, 1999, 77 (1) Round Table Discussion of the animals concerned and that the breeding of genetically modified (SPF) animals for xenotrans- plantation purposes is therefore acceptable. The Committee recognizes that some people may, for cultural, religious or other reasons, disagree with these conclusions. It would consequently like to see more education of the public on xenotrans- plantation and more public debate on these matters. Legislation The use of animals is regulated in the Netherlands by the Animal Health and Welfare Act, which stipu- lates, among other things, that performing biotech- nological procedures, including genetic modification, is subject to licensing based on an ethi- cal judgement of the Biotechnology in Animals Committee. However, the Act does not control ex- perimentation with animals or animal material ge- netically modified in other countries. The Committee therefore proposes to modify the Act in such a way that the use for xenotransplantation pur- poses of organs, tissues and cells from animals ge- netically modified outside the Netherlands should also be licensed and brought before the Biotechnol- ogy in Animals Committee. Organs from genetically modified source ani- mals and the recipients of such organs are covered by the legislation on genetically modified organisms (GMOs). This legislation, based on European regu- lations, is designed to protect the environment and human health from any adverse effects which the production or use of GMOs might have. Any re- cipient of a genetically modified animal organ would be regarded under this legislation as the carrier of a GMO. As such, the recipient would be subject to the requirements of the Environmentally Hazard- ous Substances Act and associated regulations. This is considered undesirable. The Committee recommends strongly that agreement should be sought within the European Union regarding the application of GMO regula- tions in a way which deals specifically with the issues surrounding xenotransplantation. According to the Committee, the government should act before clinical experimentation begins, to protect individual patients and public health against the risks associated with xenotransplantation, particularly the risk of possible pathogen transfer. Requirements for organ quality and for all aspects of treatment associated with transplantation should be introduced, in order to limit the risk of infection from unknown pathogens. As animal organs for xenotransplantation will be supplied on a commercial basis, it is important that quality requirements applicable to such organs are included in product regulations. Given that the trade in organs will in all probability be international, the Committee strongly favours uniform product quality standards, at the least within Europe, but preferably worldwide. In the Committee’s judgement, the Nether- lands’ existing medical product regulations, which are based on European guidelines, are not adequate to regulate the trade in organs for xenotransplan- tation, mainly because they do not contain the de- sired quality standards or quality control requirements. The Committee therefore wishes to see new legislation introduced, covering medical products that consist at least partly of living mate- rial (biologicals). This legislation should include quality standards both for biological products in gen- eral and for particular product types. The quality standards included in any such legislation should be internationally agreed. While recognizing that new legislation of the kind described cannot be introduced in the short term, the Committee would like to see regulations brought in quickly to cover xenotransplantation in- volving human beings. Accordingly, it suggests that, as an interim solution, organs for xenotransplan- tation should be brought within the scope of the legislation on medicines. Until the introduction of European (or global) quality standards, this move should be agreed with other member states of the European Union. The forthcoming Medical Research Involving Human Subjects Act will cover clinical xenotrans- plantation experiments and appears to provide a sound basis for the supervision of such activities. The Act provides for local Medical Ethical Committees that should give permission for clinical experiments. However, it is suggested that only the central ethical review committee, whose establishment is also pro- vided for by the Act, should have the authority to review protocols for research involving human xenotransplantation. As a national body, the central ethical review committee would be well placed to monitor developments in this field. The new Exceptional Medical Procedures Act makes it possible to ban xenotransplantation or to introduce compulsory licensing. The Act could also be used to impose a moratorium. Informed consent Any patient offered an animal organ should be prop- erly informed about the proposed procedure. The possibility of pathogen transfer, and the consequent need for continuous and extensive monitoring fol- lowing the operation, should be clearly explained. Since an infection could be passed on to people with whom the transplant patient has contact, the health of such individuals would also have to be monitored. The voluntary and informed cooperation of these people is therefore needed. Registration of the data collected during the postoperative checks is essen- tial. There may, however, be problems in reconcil- ing public health interests with the individual’s right to privacy. It should be made clear that direct con- tact between the patient and anyone who declines to cooperate in this regard would not be possible. Furthermore, during the clinical experimentation phase at least, it will be necessary to restrict the number of people with whom a patient has contact following a transplant operation, so as to keep the Bulletin of the World Health Organization, 1999, 77 (1) 81 postoperative monitoring programme within toler- able proportions. As a result, the organ recipient’s freedom of movement would need to be restricted. Xenotransplant operations should not be made gen- erally available until these problems become manageable. n 1. Health Council of the Netherlands, Xenotransplant- ation Committee. Xenotransplantation. Rijswijk, Health Council of the Netherlands, 1998 (Publication No. 1998/01E). 2. Cozzi E, White DJG. The generation of transgenic pigs as potential organ donors for humans. Nature medicine, 1995, 1:964–966. 3. Bach FH et al. Modification of vascular responses in xenotransplantation: inflammation and apoptosis. Nature medicine, 1997, 3:944–948. 4. Lawson JH et al. Expression of human complement regulatory proteins CD59 and decay accelerating factor (DAF) prolongs survival and physiologic function in pig-to-baboon kidney transplants. In: The 4th International Congress for Xenotransplantation. Book of abstracts. Nantes, 1997 (No. O–47). 5. Bhatti FNK et al. Life supporting cardiac transplantation in a transgenic pig to primate model. In: The 4th International Congress for Xenotransplantation. Book of abstracts. Nantes, 1997 (No. O–52). Animal-to-human organ transplants 6. Diamond LE et al. Transgenic pig hearts and kidneys expressing human CD59, CD55, or CD46 are protected from hyperacute rejection upon transplantation into baboons. In: The 4th International Congress for Xenotransplantation. Book of abstracts. Nantes, 1997 (No. O–185). 7. Kozlowski TA et al. Clinical outcome of pig kidney transplants in baboons treated with a tolerance inducing regimen. In: The 4th International Congress for Xenotrans- plantation. Book of abstracts. Nantes, 1997 (No. P–285). 8. Le Tissier P et al. Two sets of human-tropic pig retrovirus. Nature, 1997, 389:681–682. 9. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nature medicine, 1997, 3: 282–286. 10. Tibell A et al. Virological and clinical follow-up after xenoislet transplantation. In: The 4th International Congress for Xenotransplantation. Book of abstracts. Nantes, 1997 (No. O–178). 11. Day M. Tainted transplants. New scientist, 1997, 2104:4. 12. Advisory Group on the Ethics of Xenotransplantation. Animal tissue into humans. Norwich, Stationery Office, 1996. 13. Nuffield Council on Bioethics. Animal-to-human transplants. The ethics of xenotransplantation. London, Nuffield Council on Bioethics, 1996.