1
Setting the Stage

Introduction

Successful human-to-human organ transplants (allografts) are considered among the great medical breakthroughs of this century. The full promise of this success, however, has been limited by chronic shortages of donated, transplantable organs and by difficulties in preventing organ rejection. Although sporadic attempts by modern medical practitioners to transplant or graft animal organs into humans date back to the beginning of this century, xenotransplantation has been systematically studied by the medical community only since the 1960s. These first modern clinical trials of xenotransplants were performed in patients with end stage renal disease. Organ transplantation was—and still is for the most part—the only option for these patients, and the need for donated organs far outstripped the supply. In addition, techniques to provide chronic kidney dialysis were just being developed at the time and were not widely available. Thus, interest in animals as a source of organs reemerged.

In late 1963 and early 1964, a team at Tulane University led by Keith Reemtsma transplanted kidneys from chimpanzees into six patients, one of whom lived for nine months. By 1974, including experimental surgeries performed by Thomas Starzl at the University of Pittsburgh, about 20 patients had received xenotransplants. Many of these grafts appeared to function normally at first, but soon the grafts succumbed to immune rejection. Patients later died either from graft rejection, with loss of vital function, or from infections resulting from the use of large doses of immunosuppressive drugs. A voluntary moratorium was established by the transplant community in the United States due to poor survival rates and the advent of renal dialysis.



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--> 1 Setting the Stage Introduction Successful human-to-human organ transplants (allografts) are considered among the great medical breakthroughs of this century. The full promise of this success, however, has been limited by chronic shortages of donated, transplantable organs and by difficulties in preventing organ rejection. Although sporadic attempts by modern medical practitioners to transplant or graft animal organs into humans date back to the beginning of this century, xenotransplantation has been systematically studied by the medical community only since the 1960s. These first modern clinical trials of xenotransplants were performed in patients with end stage renal disease. Organ transplantation was—and still is for the most part—the only option for these patients, and the need for donated organs far outstripped the supply. In addition, techniques to provide chronic kidney dialysis were just being developed at the time and were not widely available. Thus, interest in animals as a source of organs reemerged. In late 1963 and early 1964, a team at Tulane University led by Keith Reemtsma transplanted kidneys from chimpanzees into six patients, one of whom lived for nine months. By 1974, including experimental surgeries performed by Thomas Starzl at the University of Pittsburgh, about 20 patients had received xenotransplants. Many of these grafts appeared to function normally at first, but soon the grafts succumbed to immune rejection. Patients later died either from graft rejection, with loss of vital function, or from infections resulting from the use of large doses of immunosuppressive drugs. A voluntary moratorium was established by the transplant community in the United States due to poor survival rates and the advent of renal dialysis.

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--> Xenotransplant trials, however, continued in the late 1980s and early 1990s in Sweden, China, and Hungary. The introduction of new immunosuppressive drugs (cyclosporine and tacrolimus, in particular), improved understanding of graft rejection, and continuing organ shortages were major factors in more recent xenotransplant trials in the United States. In 1985, at Loma Linda University, Leonard Bailey implanted a baboon heart into Baby Fae, a newborn infant who survived four weeks. This case drew attention to several issues: the plight of neonates, for whom organ shortage is even more dire than for adults; the controversy over the ethics of experimenting on a child; the problem of informed consent for a child; and whether the surgeons might have been able to find a human donor. In the early 1990s, at the University of Pittsburgh, Thomas Starzl transplanted baboon livers into two patients with advanced hepatitis B infection, using special immunosuppressive therapy. A third patient with AIDS was implanted with baboon bone marrow that did not engraft. One of the two liver transplant patients1 survived 70 days and the other survived 26 days. Both patients died of infection due to excessive immunosuppression. Even though graft failure was not the cause of death, the grafts did not function normally for reasons that are still not understood (Starzl, 1995). At present, there are no ongoing U.S. clinical trials of solid organ xenotransplants, although an unknown number of proposals are under review. Several clinical trials are proposed or under way with tissue xenotransplants for treatment of AIDS or Parkinson's disease, respectively. Cell and tissue xenotransplants, such as pancreatic islet cells or certain types of nerve cells, can encounter a lesser immune response than organ xenotransplants. The reasons for the diminished immune response vary, but include protection of the cells by encapsulation, use of fetal cells that lack immune system ''recognition" markers, and separation of the cells from the organ vasculature, the lining of which elicits a strong immune response. Since the early 1990s, the transplant communities of the United States and many European nations, including Sweden, have not engaged in active clinical trials of xenotransplantation. However, several countries, including Russia, China, and some Eastern European nations, have forged ahead. According to anecdotal reports, hundreds of xenotransplants have been performed in these countries for the treatment of diabetes, using pancreatic tissue from pigs, cows, and rabbits. The magnitude and possible efficacy of these efforts are not 1   One of the patients received a combined bone marrow and liver transplant from the same animal donor. The purpose of the bone marrow was to help engraft the liver by promoting chimerism (the coexistence of human and animal cell populations within the host), a topic described in greater detail in Chapter 2.

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--> known because of poor patient documentation, follow-up, and publication (Ricordi, 1995). Study Process And Report Organization In the early 1990s, informal discussions among the members and staff of the Institute of Medicine (IOM) Council on Health Care Technology suggested that, given the rapidly growing interest in the technology, examination of the science base and ethical implications of xenotransplantation would be appropriate. This report is the result of those early discussions and initial major support from the Greenwall Foundation. Additional support was obtained from the Howard Hughes Medical Institute; the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK); the National Heart, Lung, and Blood Institute (NHLBI); the National Cancer Institute; the National Institute of Allergy and Infectious Diseases; the Food and Drug Administration (FDA); the Centers for Disease Control and Prevention; the Health Resources and Services Administration; and the U.S. Navy. In October 1994, the IOM convened a committee to plan a workshop to examine the scientific and medical feasibility of xenotransplantation and to explore the ethical and public policy issues applicable to the possibility of renewed clinical trials of xenotransplantation. Just before the committee met, another area of focus was added in response to increasing concern about the potential risk of animal-to-human disease transmission (zoonoses) through xenotransplantation (xenoses or xenozoonoses). The committee expanded the workshop to address this issue with additional support from the FDA, NIDDK, and NHLBI. The workshop was held in late June 1995 (see Appendix A) and involved 43 speakers and presenters and more than 200 participants. This report is based on the deliberations of an expert committee convened by the Institute of Medicine. The committee included clinicians, transplant surgeons, immunologists, specialists in infectious diseases, and social scientists with expertise in health services research, ethics, sociology, and law. The principal source of background information considered by the committee was the workshop it organized. At this workshop 43 speakers reviewed the key areas relevant to xenotransplantation, including the current status of the science base, the infectious disease risk to the public posed by xenotransplantation, and a number of ethical and public policy issues. The presentations were discussed by the more than 200 participants who attended the workshop. The staff also provided the committee with a large number of key articles on the scientific and policy issues relevant to its deliberations. Based on these sources of information and on the expertise of its members, the committee held two day-long meetings at which it discussed and debated the implications of the information for public policy. From these deliberations came the conclusions

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--> and recommendations in this report. The body of the report largely incorporates material presented at the workshop, edited for clarity and continuity, and modified and supplemented by the expertise and judgments of the committee. Although the audience for this report is likely to be broad, the committee hopes it will be particularly useful to members of institutional review boards and institutional animal care and use committees that are considering proposals for human trials of xenotransplantation and to policymakers who are charged to participate in the coordination of efforts of the multiple federal agencies involved in xenotransplantation. The report is organized into five chapters. This first chapter sets the stage by outlining some of the controversial issues that pertain to animal-to-human organ and cell transplants. The next two chapters describe the science base for xenotransplantation and examine the scientific arguments regarding the potential of infectious agents being transmitted to the human population from xenotransplantation. The fourth chapter summarizes the presentations and discussions related to the ethics and public policy implications of xenotransplantation, including consideration of the views and concerns of individual patients and their families. Although Chapters 2, 3, and 4 are based largely on workshop presentations, necessary expansion of background information and key points from committee discussions are included as resources for the reader. The final, brief chapter provides the committee's recommendations regarding the scientific feasibility, ethics, oversight, and regulation of xenotransplantation. Approaching Questions Of Opportunities And Risks All medical innovations, particularly those with the public visibility of xenotransplantation, involve a number of interested groups that are stakeholders in the eventual applications of the innovative developments that ensue. The stakeholders include patients and their families; physicians; scientists; private corporations; public agencies and policymakers; advocacy groups, including patients' rights and animal rights groups; the news media; academics from disciplines such as ethics, law, and economics; and finally, the public at large. Each group is comprised of individuals who hold a variety of viewpoints and beliefs and, thus, are likely to disagree among themselves. In some cases, there are natural partnerships among individual stakeholder groups. In other cases, natural conflicts exist. Some of these partnerships and conflicts are based on key differences in power, investment, organization, and motivation among stakeholder groups. For example, physicians and patients are often partners in medical care and treatment, but when experimental treatment is considered, the patients become research subjects and physicians must take on additional responsibilities as scientists. Doctors who are clinical investigators may face

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--> important conflicts of interest between their responsibility as physicians, primarily to the needs of the patient, and as scientists, to the success of the experiment. Although patients are a subset of the public, the two groups can come into conflict when the benefit to one, in this case the patient receiving a xenotransplant, has the potential to harm the other, the public that may be affected by an infection transmitted from this patient or may benefit from a cure. Public policy must take into account the complex interplay of these stakeholder groups and recognize that this interplay has effects on the development and utilization of new technologies. Xenotransplantation also involves certain key conflicts related to social, moral, and ethical principles. The most prominent conflict involves the willingness of many groups (e.g., physicians, patients, and families) to continue human application of xenotransplant technology, based on the need for better medical approaches to a number of serious human diseases. In opposition, others (e.g., some scientists and government officials) argue that there are significant threats of disease transmission from source animals, threats not only to recipients but to health care professionals, families, and the public at large. A number of controversies about xenotransplantation pose the same kind of need-versus-risk questions, including the use of limited health care dollars. This report will not resolve these questions completely. The committee hopes, however, that the report is useful in identifying some important questions and providing reasonable approaches for the future, within the context of the larger debate and emerging federal guidelines. The Potential Benefits of Xenotransplantation Providing Adequate Organ Supply The case for demand exceeding organ supply could hardly be more stark. According to the United Network for Organ Sharing (UNOS), in 1993 about 33,000 patients who needed organs were on the waiting list; 2 whereas only 2   Once a patient is placed on a waiting list, organ allocation proceeds according to criteria adopted by the board of UNOS after extensive public participation. Allocation criteria include time on waiting list, quality of match for histocompatibility, age of the patient, and medical urgency. These criteria favor the sickest people, including those who require a second or third transplant.

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--> about 7,600 people donated organs (UNOS, 1994).3 Demand, as defined by the number on the waiting list, grew by more than 100 percent over the five-year period 1988–1993 (Table 1-1). The real need is even higher because many potential recipients, who are too frail or are unable to pay, are not placed on the waiting list (a topic discussed in Chapter 4). In 1993, approximately 3,000 people died waiting for organs. This number represents a 95 percent increase over the number of waiting list deaths reported in 1988. Not surprisingly, the waiting time for some types of organs almost doubled over the same period. From 1988 to 1992, the wait for kidneys, for example, rose from a median of 360 days to 621 days. The plight of those on the waiting list is best captured by the often-quoted statistic that about 50 percent of those on the list die owing to the lack of a suitable organ. Although other technologies have been developed to assist patients waiting for organs, none of these achieves optimal results and, often, none is sufficient to prevent death if an organ does not become available. For example, kidney transplant candidates have two options—kidney dialysis and the possibility of receiving a kidney from a living donor. In addition, some patients with heart disease can be aided by left ventricular assist devices. Even these technologies, however, do not obviate the possible benefits of xenotransplantation. Dialysis is only a stopgap measure; it involves dramatic and sometimes long-standing disruption of normal daily life and can, by itself, cause debilitating side effects. The use of left ventricular assist devices confers benefits for an even shorter period than dialysis and negatively affects the patient's quality of life. Both dialysis and assist devices often fail, and patients die before an organ becomes available. The use of organs, such as kidneys and single lungs, from living donors has increased. For example, a recent study found excellent three-year survival rates (80-85 percent) among patients with kidney disease who received a transplant from a spouse or an unrelated donor, despite a histocompatibility mismatch (Terasaki et al., 1995). Such donations, however, carry varying degrees of risk, pain, disfigurement, and disability for donors. They also raise new social and ethical issues. It is important to note that there are some groups of transplant candidates for whom such donors would not be suitable—infants, for example, for whom the correct size of the transplanted organ is an important factor. In addition, only fetal cells are useful for treating spinal cord injuries or Parkinson's disease, but legal prohibitions in many states prevent the use of human fetal cells. 3   Of this total, the majority were cadaveric donors (4,845) and the remainder were living donors. The total number of organs recovered from these donors reached almost 18,000 because more than one organ can be obtained from each donor.

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--> TABLE 1-1 Size of Organ Procurement and Transplantation Network Waiting List, by Organ at End of Each Year Organ 1988 1989 1990 1991 1992 1993 1994 Kidney 13,943 16,294 17,883 19,352 22,376 24,973 27,498 Liver 616 827 1,237 1,676 2,323 2,997 4,059 Pancreas 163 320 473 600 126 183 222 Kidney-Pancreas 0 0 0 0 778 923 1,067 Heart 1,030 1,320 1,788 2,267 2,690 2,834 2,933 Heart-lung 205 240 225 154 180 202 205 Lung 69 94 308 670 942 1,240 1,625 Total 16,026 19,095 21,914 24,719 29,415 33,352 37,609   SOURCE: United Network for Organ Sharing Scientific Registry data, 1995.

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--> The National Organ Transplant Act (NOTA) of 1984 established a national network of registries and organ procurement organizations. After the passage of NOTA, the solution to the organ shortage was first thought to reside with increased public education. It seems, however, that public education does not increase the donation rate significantly, because donation has remained fairly stable over time, despite educational efforts and a requirement in more than 25 states for physicians to request organ donation from families of suitable donors. Only about 40 percent of potentially eligible donors are successfully recruited (Siminoff et al., 1995). The organ shortage has led to numerous other proposals designed to increase donation. For example, some European countries have instituted a policy of "presumed consent" in which organ donation is presumed to be the wish of the patient in the absence of documentation or family statement to the contrary. Yet, this policy does not seem to have resulted in greatly reduced organ shortages. Cash payment for organs is strictly prohibited under NOTA, because many believe that such an approach makes the human body a commodity and, thus, greatly increases the risk of abuse. Other proposals, based on the concept of "rewarded giving," have included, for example, help with funeral expenses. None of these proposals, however, has been accepted or put into operation in the United States. Much publicity has focused on reports from other countries, such as China, in which organs "on demand" have been obtained and sold to the highest bidders by deliberately scheduling executions of prisoners to coincide with a planned transplant. Further, these executions were carried out by using methods that maximized organ viability for transplant. Even if such obvious violations of human rights were isolated or prevented in most countries, there are many in the transplant community who believe that measures to compel or remunerate donation would nevertheless undermine a fragile system that rests on ''gifts of life" or voluntary donation for altruistic reasons. Providing Cells and Tissues to Treat Disease The second major potential benefit from xenotransplantation is the ability to use cells and tissues from animals to restore the functions of critical physiological systems affected by a variety of diseases. Experiments in laboratory animals and experiments currently under way (mostly outside the United States) with human subjects suggest real promise for xenotransplantation of cells and tissues. For example, clinical trials outside the United States have shown that transplantation of insulin-producing pancreatic islet cells from pigs into humans with diabetes results in nearly normal, and stable, levels of insulin. This would confer an improvement over insulin injections, which result in varying blood levels of insulin over time, because stable levels of insulin in diabetics are important in preventing the devastating side effects of severe

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--> diabetes, effects that include blindness, painful neuropathies, hypertension, and life-threatening infections. It is also important to note that the use of pancreatic tissue from humans to treat diabetes is not a suitable option. To provide enough tissue to transplant one person, pancreases from two persons are required and the organ must be "fresh" or taken before death, as in whole organ transplants. Thus, the organ shortage for human pancreases would be even more severe than that for hearts, lungs, and kidneys. The promise of xenotransplantation of cells and tissues is heightened by the observation that cells and tissues are not rejected as readily as whole organs because strategies have been developed to "protect" the transplanted cells and tissues from the recipient's immune system (discussed more fully in Chapter 2). One of the innovative approaches is to enclose animal cells and tissues in tubes or spheres having holes, or pores, that are large enough to allow passage of physiologically relevant substances—such as insulin—from the cells into the recipient, but are too small to allow passage of immune system cells or antibodies. Compared with whole organ transplantation, the success of cell and tissue xenotransplantation would potentially provide viable treatments for diseases that affect many more lives. In addition to their use for diabetes, xenotransplants of dopamine-producing neural cells could replace the dopamine cells destroyed in patients with Parkinson's disease. The possibility also exists for replacement of myoblasts in patients with muscular dystrophy. For diabetes and Parkinson's disease, successful methods for cell and tissue xenotransplantation could become a useful therapy if used early in disease progression. Early intervention might yield savings in the required medical care of these patients and decrease losses due to disability. One proposed human experiment in the United States generated much publicity and debate at the workshop and throughout the preparation of this report. The proposal was to inject baboon bone marrow cells (known to be resistant to the human immunodeficiency virus that causes AIDS) into a person with AIDS in San Francisco. After a long period of review by numerous groups, the patient received the experimental transplant in December 1995 and was still alive in February 1996. By that time, although there was no evidence that the baboon cells had engrafted, the patient's health had improved, as measured by increased numbers of the patient's own white cells, possibly due to an unexpected effect of the radiation used before the transplant to partially destroy his bone marrow. In summary, the opportunity potentially exists to improve or save the lives of hundreds of thousands of people by development of xenotransplantation. With the success of xenotransplants of cells and tissues already on the horizon, whole organ xenotransplantation has become the subject of renewed investigation. Such potential benefits provide a strong motivation for physicians and scientists to move ahead and for patients to hope. The opportunity to realize these benefits,

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--> however, is not without risks, which by themselves provide equally strong motivation to be wary. Risk: Precedent and Uncertainty As noted above, the most prominent controversy about whether or not to continue with xenotransplantation involves the possibility that harmful or deadly infectious agents from animals may be transmitted to humans through xenotransplants and could even pose a significant public health threat. Unquestionably, there is ample justification for raising this argument, but there is also great uncertainty over the actual level of risk and how to balance the risks against the potential benefits of proceeding (see Chapters 3 and 4). What is less immediately apparent is how this controversy has changed some of the classic issues that accompany the initiation of clinical trials of any new medical procedure or treatment. Risk is typically viewed on a highly individual level in clinical trials, and the regulations governing human subjects research reflect this individual focus. These regulations require that a person who agrees to become a research subject be fully informed about the risks of the procedure or treatment before the person consents to participate. The principle of informed consent applied to research subjects has been a key area of study since the Nuremberg trials in the late 1940s, and especially since the emergence of academic disciplines focused on bioethics more than 25 years ago. The controversy about infectious disease from xenotransplants poses a novel issue in research ethics that will require extensive exploration and public debate. Who can give "informed consent" to a procedure that may cause harm not only to the research subject, but also to many others not directly involved in the research and not direct beneficiaries of success? Will it ever be possible to know the level of risk and to balance it against benefits? Are there ways to manage the risk and prevent harm to others? Such questions were discussed extensively in the workshop and by the committee. One tentative answer generated before this report was completed derives from approval of the much-publicized trial to use baboon bone marrow cells to treat AIDS. This approval, with numerous special requirements for disease surveillance, was given by the Food and Drug Administration after approval from the Institutional Review Board and the Laboratory Animal Care and Use Committee at the University of California, San Francisco. Far short of an enduring resolution to the questions above, the approval of this protocol nevertheless represents a decision to proceed cautiously and evaluate along the way (Chapman, 1995).

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--> Although most prominent, infection is not the only risk presented by xenotransplantation. For example, some transplant surgeons and others fear that too much publicity about xenotransplantation will decrease public willingness to donate organs, even though the technology is years away from providing a practical resolution of the needs of people who require whole organ transplants. Still others are concerned that clinical practice may forge ahead despite the absence of an adequate scientific base, which happened, for example, with in vitro fertilization.4 In addition to the adverse effects of immunosuppression and the vascular damage that can accompany allotransplantation, there are risks that xenotransplantation may have negative effects on the quality of life of recipients, despite providing a medically effective outcome. There is also uncertainty about the eventual expense of xenotransplantation—a complex issue that will be a critical determinant of the extent of eventual use of various types of xenotransplantation and must be considered in light of any eventual savings (e.g., decreased health care expenditures for diabetics with xenotransplants of pancreatic islet cells; also see Chapter 4). Important ethical and social issues regarding xenotransplantation need extensive further consideration. Indeed, some of these issues have not yet been resolved for human-to-human organ transplantation. How will animal and human organs be allocated? Will socioeconomic status influence allocation, so that the affluent and powerful are more likely to receive human organs, while the poor and disenfranchised receive animal organs? Should animals be killed to provide organs? Are there fundamental psychological factors that will lead to problems for recipients of animal organ transplants? People who have received human organ transplants often report having deep and complex emotions about having another person's organ in their bodies. Will this be magnified in people who receive animal organs? Will the expense of xenotransplants outweigh the benefits? Questions such as these were raised throughout the workshop and in the deliberations of the committee amidst discussion of significant scientific progress and hope for the potential benefits of xenotransplantation. The issue of public health risks, however, clearly dominated and molded these discussions. As a result, the report that follows presents many scientific and ethical issues interwoven with scientific discoveries and hypotheses, which raise both familiar and novel ethical and legal issues at the frontier of medical innovation. 4   The success rate of in vitro fertilization remains only about 20 percent in the best facilities, in part because the growth of the science base has been seriously hampered by political and ethical debates concerning abortion and research on human embryos.