Ann R Coll Surg Engl 1996; 78: 92-96

Xenotransplantation: benefits, risks and regulation

D K C Cooper MA PhD MD MS FRCS FACC FACS Cardiothoracic Transplant Surgeon, Director of Research and Education, Scientist-in-Residence Oklahoma Transplantation Institute, Baptist Medical Center, Oklahoma City, Oklahoma, USA

Between 25 and 27 June 1995, I was privileged to under review, I have drawn up a brief report on the participate in a workshop on the future of xenotransplan- workshop as I saw it. I would emphasise that I am not a tation organised by the Institute of Medicine (IOM) of member of the IOM committee and my comments in no the National Academy of Sciences in Bethesda, Maryland. way represent the opinions of the committee. Further- The conference, entitled 'Xenograft Transplantation: more, my interpretation of the discussion at the workshop Science, Ethics and Public Policy,' consisted of presenta- is purely personal and others might have interpreted it tions and discussions with regard to the immunological rather differently. progress being made in this field and to the potential infectious issues that successful xenotransplantation might raise. In addition, the ethics of the topic were Organ donor shortage discussed and consideration given to public policy towards xenotransplantation as it edges closer to the There was general agreement that the demand for organs clinical arena. Presentations and discussion were also and cells for transplantation purposes would not be met made on such topics as the potential health care costs, the from the use of human tissues. Although comments were question of the use of animals for this purpose, and what, made, mainly by those not personally involved in clinical if any, government regulation was required. Attendees transplantation, that increased efforts should be expen- covered a broad spectrum, from scientists and surgeons to ded to maximise cadaveric organ donation by further human and animal infectious disease experts, from both education of the public, etc, there was a consensus that, government facilities as well as academia, through even if these educational efforts were successful, there ethicists, lawyers, and patients. would never be enough human organs to satisfy the The Institute of Medicine has set up a committee to demand. consider and make recommendations for future public policy with regard to xenograft transplantation. The committee members participated in the forum, but were to meet subsequently to draw up a formal official report Immunobiology with recommendations for public comment. As there was fairly strong participation in the workshop from staff from The immunobiology of xenograft rejection, particularly various govemment agencies, including the Food and that relating to the hyperacute rejection of discordant Drug Administration (FDA), Center for Disease Control grafts, was reviewed, as was the experience of those few (CDC), and National Institutes of Health (NIH), it can groups who have participated in clinical concordant organ reasonably be anticipated that the recommendations ofthe xenotransplantation. Techniques of genetically engineer- committee will carry considerable weight. ing pigs, both with regard to the presentation of human In the belief that the discussions that took place at this complement-inhibiting proteins and to modifying the conference would be of interest to the medical community expression of the ocl-3galactose epitopes on their tissues, in the United Kingdom, where this topic is also currently were outlined. Methods of attempting to induce tolerance and/or chimerism in the potential recipient were dis- cussed. Attention was paid to the problems relating to Report of a Workshop organised by the Institute of Medicine of cellular xenotransplantation, including the transplanta- the National Academy of Sciences in Bethesda, Maryland, 25-27 tion of pig islet cells as a therapy for diabetes, and the June 1995 potential treatment of AIDS utilising baboon bone Correspondence to: D K C Cooper MD PhD FRCS, Oklahoma marrow. Transplantation Institute, Baptist Medical Centre, 3300 NW The AIDS trial was of particular interest, even though Expressway, Oklahoma City, Oklahoma 73112, USA it does not fall strictly into our general concept of organ Xenotransplantation 93 transplantation. A clinical protocol has been drawn up hazards could be divided into those that are already through collaboration between groups in Pittsburgh and known and those that remain unknown at the present San Francisco to treat a very small number of AIDS time. The unknown risks, eg of a hitherto unrecognised patients by partial ablation of the recipient's bone marrow virus being transferred from a non-human primate to a and replacement with baboon bone marrow cells. The human, were of particular concern. Attention was drawn basis for this trial, which at the time of the workshop had to the fact that in recent years several viruses that have not yet been sanctioned, is that baboon T cells appear to become of clinical importance, most notably the HIV, are be resistant to the HIV. (The trial has subsequently been believed to have originated in non-human primates, given FDA approval.) particularly in Africa. Although causing no or little As a 'primer' for the members ofthe committee who are morbidity in the original non-human host, there are not immunologists, nor even scientists or physicians, the many examples of viruses that can be lethal when review of the immunobiological aspects of xenotransplan- transferred to another non-human primate or human tation was, in my opinion, too complex. I suspect that the host. 'uneducated' participants were left with a confused Furthermore, the incubation period of such viruses may impression of the present state of our knowledge. For be greatly prolonged, as can be the case with the AIDS example, insufficient attention was drawn to the difference virus, extending to several years. It would therefore be in response of the recipient to a concordant graft in impossible to 'quarantine' the xenotransplant recipient as contrast to a discordant graft. It was not sufficiently we have no idea of the period of isolation that would be emphasised that experimental work has demonstrated that required. Although the risk of transferring a 'hidden' closely related monkey organs can survive in baboons for virus was considered to be significantly less with regard to periods of several months or even a year or longer, albeit 'domesticated' non-primate mammals than with wild- at a relatively high risk of over-immunosuppression with caught or even captivity-bred non-human primates, resultant infection hazards. In contrast, clinical attempts nevertheless the risk of viral recombination was present at pig organ xenografting have all failed within minutes or even with the use of the pig. The transferred virus might hours, and experimental results to date have been not necessarily cause infection but, particularly in the case successful for periods of less than 1 month. It is of endogenous retroviruses, might result in the develop- important that the members of the committee are able to ment of neoplasia in the host in the distant future. make the distinction between the relative success of The potential health hazard of the development of such experimental concordant xenografting and the major 'xenozoonoses' or 'xenoses' was greatly magnified by the problems that still exist with regard to discordant suggestion that not only would the patient become infec- xenografting. ted (eg with an AIDS-like condition) but all contacts of Perhaps insufficient emphasis was also placed on the the patient, or at least those exposed to body fluids, might fact that, because of logistic and other reasons, the baboon also become infected. This might include not only family will probably never be bred in numbers sufficient to members and members of the surgical and nursing teams, supply the needs of the transplanters, whereas the pig but also casual sexual partners or others who came into could meet these needs fairly rapidly if the immunological transient but close contact with the carrier of the agent. problems could be overcome. The potential of an epidemic, or even a pandemic, result- During the course of the discussion it became clear that ing from relatively few xenotransplants using non-human the xenotransplantation of cells provided rather different primates as donors was put forward. As this potential risk consideration by the committee than did the xenotrans- related to the transfer of agents that had as yet not even plantation of organs. For example, techniques of been identified, no conclusive rebuttal of this argument encapsulating pig islet cells so that they can be protected was possible. from rejection might allow more rapid progress in this Relatively long lists of potential agents that could field than is likely in pig organ transplantation. possibly be transferred with baboon or pig tissues to Furthermore, cellular transplants in general would be humans have been drawn up, and the consensus was that expected to be associated with an insignificant mortality at the very least all ofthese known infectious agents should when compared with organ transplantation. Public policy be eradicated from the donor animal before xenotrans- with regard to these two issues, therefore, might well need plantation took place. This could be achieved by selective to be different. However, both organ and cell transplants breeding of animals free of known pathogens. This would posed a potential risk of infection, perhaps particularly so be relatively easy to do with regard to the pig, with the if baboon bone marrow was to be infused into human possible exception of eradication of endogenous retro- recipients. viruses, although expert opinion was that even this would be possible within the foreseeable future. In view of the small number of offspring born to non-human primates Infectious issues and their slow growth to puberty, attempts to do this in these species would be very expensive and would take It was generally agreed that the transplantation of cells or many years. Even if the known infectious hazards were organs from animals to humans constituted an infection avoided, however, the unknown remain. risk, particularly when the human recipient was likely to In view of the fact that man and pigs have been living be heavily immunosuppressed. Furthermore, infectious together for hundreds of years, that 90 million pigs are 94 D K C Cooper slaughtered in the USA alone each year for food purposes, would accept an organ from an animal, such as a pig or and that no specific serious infection (or neoplasia) baboon, if no human organ was available. It would seem appears to have arisen in those who breed, farm, likely that if the survey had been carried out among slaughter, or eat pigs, the point was made that even this patients awaiting organ transplantation, rather than in benign history was not sufficient to guarantee that the healthy members of the public, the number willing to deliberate transfer of pig tissues to humans might not lead accept a xenograft might have been significantly higher, as to recombination of endogenous retroviruses that might long as they could be assured of a reasonable prospect of have a serious effect on the health of the recipient and, of success. much greater concern, on that of the community at large. Possibly some of this concern, particularly with regard Use of animals for xenotransplantation to the pig, was overstated. We have been administering fluids derived from animals to humans for many years, for A discussion on the value and use of animals formed part example, antilymphocyte globulin prepared in horses or of this section of the workshop. Whereas the majority of rabbits, porcine or bovine insulin, and the controversial speakers in the ethics forum had appeared rather more 'rejuvenating' injections using sheep tissues. Further- negative than I had anticipated, the speakers in this part of more, in 10 or 20 years time, when the pandemic might the forum were rather more positive. hit, we would probably have far more advanced drugs for The concept of replacing 'speciesism' with 'person- the treatment of viral and other infectious diseases than hood' was put forward. By this, it was suggested that we we have at present. As a comparison, AIDS would not should not differentiate purely on the basis of species but perhaps be a major problem today if, when its cause had on the intelligence and quality of life of individuals within first been elucidated, we already had a drug to which the that species. For example, virtually all of us would agree virus was susceptible. However, even after acknowledging that if an organ were required urgently for a human, be it the advances that will inevitably take place during the an adult or a child, and donation would result in the death next 10 or 20 years, the argument that the transfer of an of the donor, a baboon would be a more acceptable donor unknown virus, particularly a retrovirus, might lead to an than another living human. However, if the choice of epidemic of either infection or malignant disease, cannot donor was between a healthy baboon, who was a valued successfully be refuted. member of a family of baboons (or even more so, if the proposed donor was a chimpanzee), and a human who had been in a permanent vegetative state for 10 years, who was Ethics and public policy being maintained by intravenous or nasogastric tube feeding and who was clearly unaware of his or her sur- The opinions of the 'ethicists' present were variable and roundings, with presumably an exceedingly poor quality were not always strictly related to the questions raised by of life (if any), then the choice of donor might for many xenotransplantation. For example, the view was put prove less clear. forward that transplant teams were already on the Similarly, the anencephalic neonate, who would never 'slippery slope' of ethical decline, examples of this being be able to love or be aware that he or she was loved, might the use of non-heart-beating donors, sometimes allegedly prove to some to be a more acceptable donor of organs under circumstances where the family members were not than a healthy non-human primate infant. In other words, given sufficient time to consider donation fully, and the higher brain function and quality of life, rather than recent report from the American Medical Association pro- species alone, should be considered as part of the equation posing that anencephalic neonates should be considered in the selection of the donor. as potential organ donors. Further examples included Despite the above consideration, there did not appear to payment for organs from living donors in some countries, be any clear opposition to the use of animals as organ and the presumed consent law in others. The fact that donors, particularly in the case of the pig or other successful xenotransplantation might obviate the need for domesticated animal. The fact that domesticated animals human donors was either not clear enough in the mind of were already being slaughtered in such large numbers for the ethicist or, as appeared more likely, was thought to be human use was acknowledged, and it was suggested that yet one more step down the slippery slope. the use of a relatively small number to directly save the The view was also put forward that transplant scientists lives of humans by donation of organs was, in fact, a more and surgeons should 'slow down' their efforts as it was 'noble' use of the animal. intimated that the public was becoming concemed with the rate of scientific progress, which could be illustrated Potential health care costs by concerns over gene transfer therapy and the genetic engineering of animals. However, it was pointed out by Some attempt was made to estimate the potential financial others that this perception of the public's attitude was in cost to the health care system of the USA if clinical contrast to the survey carried out by the Partnership for xenotransplantation became possible. An attempt was Organ Donation in the USA in 1993, which documented made to compare the potential expenditure on xenotrans- that approximately 80% of the more than 6000 members plantation with that on allografting today, and to put it in ofthe population surveyed would accept an organ allograft perspective with the overall national costs of health care. if it would save their lives and, perhaps surprisingly, 50% In the event of an unlimited supply of organ donors, Xenotransplantation 95 considerably more would be spent on transplantation than Institutes of Health that has been overseeing trials at present, where the major limiting factor was the donor relating to human gene therapy. supply. However, against this had to be weighed the cost I was particularly impressed by the case made for a to the system of poorly functioning patients awaiting national peer review board, although it would seem that allotransplantation who might be highly dependent on two such review boards would be required, one con- expensive medical technology and resources to keep them centrating its attention on cellular xenotransplantation alive. Furthermore, such patients were non- or poorly and the other on organ xenotransplantation. Those productive members of society during this period of time. involved in islet cell or bone marrow transplantation are The costs involved with transplantation today still form not necessarily experts in the clinical aspects of organ a surprisingly small proportion (approximately 0.3%) of transplantation and vice versa and, therefore, for the peer the total health care burden in the USA, accounting for review body to be fully effective, two such bodies would less than $3 billion per year. If xenotransplantation probably be required. The advantages of such bodies proved a successful alternative, it has been estimated would appear to be numerous. They would be able to that this would probably rise to approximately $20 billion ensure that clinical trials were not duplicated in various per year. In relation to the overall health care bill for the parts of the country and that the group proposing the nation, now approaching $1 trillion per year, this is a protocol had the necessary background and expertise to major but perhaps not overwhelming item. However, with perform the trial in a satisfactory manner. Furthermore, the high and rapidly increasing costs of health care and the board would be able to ensure that all alternatives to the increasing emphasis on reducing both federal and state xenotransplantation had been explored thoroughly, that budgets, it was suggested that this was not an opportune sufficient attention had been paid to minimising any time for the introduction of any new form of expensive infectious risks, and that the subjects of the trial had given medical therapy, whether it be organ transplantation or their fully informed consent. otherwise. Perhaps surprisingly, the few patients and spokes- persons for patient organisations who participated in the workshop were more inclined to accept a local IRB Informed consent decision rather than feel there was a need for a national Concern was expressed as to whether a patient entering a peer review board. Perhaps they, more than others, were clinical trial of xenotransplantation would be sufficiently suspicious that a national level of overview would lead to well informed of the experimental nature of the trial. unnecessary bureaucracy and delays in progressing with Methods of obtaining informed consent from the patient, novel, potentially life-saving forms of therapy. and possibly also from his or her family, were considered As all of the patients present were either organ to be inadequate, and past examples of such inadequate transplant recipients or candidates, it was perhaps not informed consent were presented. Too commonly, it was surprising that they all spoke in favour of advancing as suggested, the medical team had put forward organ xeno- rapidly as possible with both experimental and clinical transplantation as a potential therapeutic option with a research in the field. They did emphasise, however, that reasonable possibility of long-term success, whereas in physicians planning clinical trials should be absolutely reality this was not the case. The patient should have honest and open with candidates being approached to been made more fully aware that he or she would be par- participate in such trials, and should not hold out false ticipating in an experiment from which he or she was un- hopes for the success of a procedure that was clearly likely to benefit personally, but which might prove of experimental. value to the advancement ofmedical science and therefore be of benefit to future generations. 'Regulation' of xenotransplantation As xenotransplantation involves a number of controversial Investigational review boards areas, such as the genetic engineering of animals, the risk Concern was also raised that local Investigational Review of introducing serious infection into the community, the Boards (IRBs) did not have the background information, possibility of experimenting on patients without their expertise, or time to assess protocols for such clinical trials fully informed consent, etc, there was some consensus that adequately. Not only were the members of local IRBs xenotransplantation would have to be overseen (if not frequently ignorant of the field being considered and of actually regulated) by some form of national body. If this the potential for success or failure of the experiment, but were not done, it was suggested that there was a very real they were at times unduly influenced in their decision- risk that if poorly conceived and poorly performed clinical making by powerful personalities who were members of trials took place, with resulting failure and/or ethical the clinical research team. It was suggested that at the questions being asked (all of which were likely to gain very least the local IRBs should have access to a team of overwhelming media attention and publicity), transplan- national experts to provide guidance in their decisions, or tation, and those involved in it, would rapidly fall into even that clinical trials in such controversial and complex disrepute. fields as xenotransplantation should be considered by a A comparison was drawn with the early days of clinical national peer review board similar to the Recombinant heart transplantation where a large number of inade- DNA Advisory Committee (RAC) of the National quately prepared surgical groups embarked on this 96 D K C Cooper operation without the necessary immunological expertise this potential magnitude until it has become a clinical and experience. The overwhelmingly poor results that reality and problems have already developed. The were obtained in the initial 1-2 years of clinical heart regulators then step in and progress is impeded. Rather transplantation led to an almost total moratorium on the the present approach, where all involved in this field, from procedure until further advances in immunosuppression research scientists to patients, will hopefully have the had taken place. It should not be forgotten, however, that opportunity of sharing in its development during future the stimulus generated by these initial heart transplants to years. explore further methods of immunosuppression was Frequent mention, particularly by the ethicists, was considerable. made ofthe wishes or attitudes of 'society', yet no one was If it were agreed that some form of regulation was able to adequately define who or what 'society' was. required, and this point was not resolved at the forum, Everyone agreed, however, that the patient is clearly an who would do the regulating? It was acknowledged that important member of society, particularly when it comes the FDA would of necessity be involved in such matters to the subject of medical advances, and therefore much as the introduction of genetically engineered pigs and new attention needs to be directed towards the patient's immunosuppressive agents, etc, and had wide powers that viewpoint. The small number of patients and patient could easily be utilised to assume overall regulation of advocates who attended the meeting, however, drew xenotransplantation. Was the FDA, however, the right attention to the fact that no patient or patient advocate organisation to oversee the general development of this had been invited to be a member of the committee that field? Should medical organisations and societies be asked would make recommendations on the future of xeno- to oversee their own fields of interest, or should some new transplantation. They pointed out that it was not organisation be set up to guide clinical development of necessary to have several letters after one's name to have xenotransplantation? a viewpoint on a topic that might affect one so intimately. No conclusions were forthcoming but, if abuses are to However, as one of the patient advocates himself pointed be avoided, the case for a national body to review all out, a dying person is a desperate person, whose opinion clinical protocols and to advise, encourage, and even may be greatly influenced by the overwhelming desire for deny-at least, for the forseeable future until clinical survival. The dying patient may not necessarily, there- xenotransplantation is well-established-is relatively fore, advocate an approach that is in the best interests of strong. 'society' at large. This unhappy fact, along with myriad others) will have to be carefully considered by the Institute of Medicine Comment committee charged with making recommendations for public consideration. A sensible balance has to be sought In summary, the IOM workshop was a valuable step in between facilitating medical advancement that may be of our advance towards clinical xenotransplantation. It was enormous benefit to future generations and safeguarding timely in that topics were discussed prospectively rather the individual patient and the community at large from than retrospectively, as is so often the case. National the potentially adverse effects of such progress. The IOM bodies frequently do not turn their attention to a topic of committee's report will be awaited with great interest.