ILAR Journal Online, Volume 37(1) 1995: Perspectives on Xenotransplantation

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ILAR Journal V37(1) 1995
Perspectives on Xenotransplantation

Ethical Aspects of Animal-to-Human Xenografts
Charles R. McCarthy

Charles R. McCarthy, Ph.D., is a senior research fellow at the Kennedy Institute of Ethics, Georgetown University, Washington, DC.

INTRODUCTION

The demand for organs suitable for transplantation into human beings is increasing. It has been estimated that, in the United States, as many as 15,000 human patients per year could benefit from heart transplantation. The demand for livers, kidneys, pancreases, lungs, corneas, and other organs is also on the rise. Even if efforts to persuade persons to donate organs are increased, and even if consent to donate should become a legal presumption, there is little prospect of developing a sufficient supply of transplantable human organs to meet the growing demand (Evans and others 1986). The United Network for Organ Sharing reported that 560 patients on the UNOS waiting list died while waiting for a liver transplant during calendar year 1993 (Annual Report 1994).

New drugs and new combinations of existing drugs have improved the chances of successful medical outcomes for patients. It is now recognized that serial application of immunosuppressive drugs can reduce the likelihood of both short- and long-term organ rejection (Makowka 1994). Improved understanding of both human and animal immune systems; insights into histocompatibility; new agents to control graft-versus-host disease; animal breeding programs for the production of transgenic animals; and perfection of surgical techniques have opened, as never before, the possibility of successful transfer of organs from animals to humans. Some rate the chances of good patient outcomes as high, others make more conservative predictions, but virtually all experts believe that the chances for successful patient outcomes resulting from xenotransplantation are improved.

The demand for organs to treat human beings coupled with the new scientific understanding of the immune systems of both humans and animals make it probable that animal-to-human xenografts will soon be attempted at a frequency rate unknown in the past. Optimism for animal to human organ transplantation is at an all time high. As technical and biological barriers to successful xenotransplantation are lowered, the prospect of raising dedicated animal colonies to provide a ready supply of organs for human transplantation is now seriously discussed. (Nelson (1993) calls for careful consideration of the ethics of whether we morally wrong animals in taking their organs and their lives. He cautions against rushing to create colonies of primates dedicated to xenografts.

The potential resource of an ample supply of animal organs, genetically altered to reduce the probability that human hosts will reject them, now appears to be technically feasible. Some believe that investment in colonies of purpose-bred animals to serve as a source of transplantable organs is close at hand (Leventhal 1994).

HISTORY SUGGESTS CAUTION

Nevertheless, the history of previous failed attempts to carry out xenografts should send a caution signal to the research community. Some will perceive the history of xenografts as flashing an amber light, while others are likely to interpret that historical data as a red stoplight. Past efforts to prolong human life by implanting animal organs into human recipients have all met with failure--usually relatively quickly. Past failures, summarized below, should serve to dampen enthusiasm for efforts to use animals as a source of spare organs for human beings.

Xenotransplantation, resulting in early death for all recipients, was attempted early in the twentieth century (Neuhof 1923). More sophisticated efforts occurred in the late 1960s and early 1970s during the period when anti-rejection drugs began to make allografts more feasible. Although one recipient of a xenograft survived for 9 months, most patients died within a matter of minutes, hours, or days after engraftment of organs from chimpanzees or baboons (Starzl and others 1964; see also (Millard and others 1985).

A well-known xenograft involved the transfer in 1984 of a baboon's heart into 14-day-old "Baby Fae" by Dr. Leonard Bailey at Loma Linda Hospital. The "Baby Fae" xenograft was occasioned by the introduction of cyclosporin A into the armamentarium of drugs used to prevent organ rejection. Because human organs suitable for transplantation into infants are extremely rare, a search for an alternative organ source to fill this need led to a decision to transplant a baboon heart into a human baby whose own heart was unable to sustain life for more than a few days. Coming as it did at the zenith of organized protest against the use of laboratory animals, the "Baby Fae" case generated enormous controversy and unprecedented coverage by news media. In general, the public press first praised and subsequently condemned the Loma Linda xenograft. "Baby Fae" died of progressive graft necrosis 20 days after receiving the baboon heart (For a sampling of public and professional comment on the "Baby Fae" case, see Annas 1985).

With the advent of the new drug FK506 and other immunosuppressive agents, at least two new xenotransplant efforts have been attempted in the 1990s (Starzl and others 1993). Liver transplants from animals to humans are under consideration in several centers, either as permanent organ transplants or as a "bridging" procedure to sustain patients awaiting human liver transplants. One technique involves a donor baboon liver used as a bridge that can be removed with relative ease because, although connected to the subject's liver, it remains extracorporeal (Prentice and others 1994). Similar experimental techniques are planned involving baboon hearts to be used as bridges for pediatric cardiac patients. Plans to conduct animal-to-human xenotransplants for bridging are under consideration in at least five major U.S. transplant centers.

Before major new animal-to-human xenograft research programs are initiated, both the scientific and the ethical aspects of such programs should be carefully considered and debated. Many of the scientific issues are addressed in other articles in this issue of ILAR Journal. This article will address ethical aspects of xenotransplantation from animals to humans.

The position taken in this article is intended to be a part of the debate over xenotransplantation and should not be considered as a final word on the ethics of research in this area.

MORAL OPPOSITION TO XENOGRAFT RESEARCH

Animal-to-human xenograft research will encounter strong opposition from persons who regard such research as unethical or immoral. Xenotransplantation requires the sacrifice of healthy animals whose organs, engrafted into human hosts, will constitute one of the most intimate associations possible. It is not surprising that many regard it as morally offensive. Those who oppose xenografts on ethical or moral grounds are likely to fall into one or more of the following groups:

Those who regard animal-to-human transplantation as immoral for theological reasons may include: (a) some Jewish groups that consider the engrafting of animal parts into human beings as defiling to the recipient, particularly if the animal parts are derived from a species regarded as unclean; (b) some Christian groups that object to xenotransplantation because they regard the action of engrafting animal parts into human beings as "playing God," that is, attempting to usurp or interfere with God's role as Creator (Scientific creation of chimeras composed of both human and animal parts is regarded as blasphemous by such persons); and (c) because successful xenotransplants will almost always require blood transfusion, Jehovah's witnesses, who are morally opposed to transfusion of blood ipso facto and opposed to xenotransplantation.

Those who object to xenotransplantation on philosophical grounds. These include: (a) those who regard any sacrifice of higher vertebrate animals for purposes that can only benefit human recipients as morally objectionable; (b) anyone who regards animals as the subjects of rights, particularly the right not to be interfered with; and (c) those who consider that the interest of each animal in maintaining life and bodily integrity is at least equal to any human interest in receipt of an animal organ. (In this view, the deliberate taking of the healthy animal's life--a life for a life--can never be justified by resultant human benefits); (d) those who oppose the use of highly intelligent, and perhaps self-conscious, nonhuman primates as the source of organs for xenotransplants, but are not inexorably opposed to the use of other less advanced animals for xenograft purposes (pigs, for example); (e) those who argue that prior to obtaining organs derived from robust, healthy animals, organs should be taken from humans whose quality of life is poor (such as anencephalics or people in a permanent vegetative state; and (e) those who object to the transplantation of animal organs into humans on the grounds that such transplants are aesthetically repugnant. ¹

Those who may be opposed to initiating animal-to-human xenograft research on the grounds that the benefits do not justify the economic costs, and that xenotransplantation will introduce additional inequities into a health care delivery system that is already inherently unfair. They argue that even if the research results in long-term survival of some who would otherwise almost certainly die, xenotransplantation will introduce an extremely costly form of high technology into a health care system that already overburdens the economy and that is tilted in favor of the affluent. They contend that it is unethical to conduct costly research that, if successful, can only lead to additional high cost, high technology medical service. They argue that xenotransplants will be available only or primarily to the privileged few who are already relatively wealthy or who are able to afford expensive, comprehenive health insurance, while lack of funds prevents the provision of even minimal, routine health care for a significant segment of the society.

IN DEFENSE OF THE MORAL USE OF ANIMALS

This article cannot deal in depth with the arguments summarized above. However, I believe that each of the moral objections can be met with a counterargument that is at least as compelling. I want to advance the argument that it is morally acceptable to use animals in research such as xenotransplantation designed solely or primarily to benefit human beings. The argument contends that both theology and philosophy support the position that humans have an obligation to exercise wise stewardship over the entire ecosphere, including animals. The degree of animal care and the kind of use that humans permit will vary according to circumstances. Obligations to provide for humane care and use of laboratory animals will differ from obligations to animals used as pets, industrial animals, and animals in the wild. Although all animals have a claim on human stewardship, higher obligations may justify the use of animals for ends not consistent with the best interests of particular animals.

The argument has three parts:

2. Humankind enjoys relative moral superiority over nonhuman animals. Humans are characterized as possessing capabilities for: conceptualization, making judgments, exercising wisdom, exercising creativity, freedom of choice, moral decision making, social adaptability, appreciation of beauty, seeking justice, exercising compassion, learning from the past, planning for the future, altruism, and exercise of responsibility for valued and valuable things (ranging from one's own self and family to the entire ecosphere). Although many human traits are possessed in limited ways by animals, the level and complexity of these traits as they exist in humans, establishes humankind, taken as a whole, as morally superior to nonhuman animals. Of course not all humans exercise all of these capabilities, and some humans possess few or none of them. This is not the place to defend the relative moral superiority of humans who are incapable of exercising full human potential (such as infants, the senile, and those in permanent vegetative state). This problem has vexed ethicists for a very long time. My own view is that a defense of the moral superiority of humans who do not manifest the full range of human characteristics is best made on theological rather than philosophical grounds.

3. Since the dawn of history, humans have domesticated animals for their use. All domestic and many wild animals depend on humans for survival and well being. Conversely, major elements of human civilization, including the understanding and preservation of the environment, nutrition (for animals and plants as well as for humans), clothing, tools, and the preservation and promotion of health for animals and humans are dependent on and inextricably intertwined with human use of both domestic and wild animals. To argue that the use of animals for human ends is immoral, is tantamount to saying that humans cannot and never have been able to live morally upright lives. In effect, such a position condemns the conduct of all living human beings (since all participate in societies that require the use of animals for human ends), and the conduct of previous generations of human beings as well. To say the least, this would be an eccentric conception of morality.

However, if the fact that humans and animals depend on each other in an unequal web of relationships argues against condemnation of all use of animals for human ends, it does not justify the moral permissibility of every use of animals. Rather it makes it incumbent on human society to strive for consensus concerning how to use animals in appropriate ways that reflect both the relative moral superiority and the responsibility of humans for animals. Creation of colonies of animals ideally suited to provide replacement organs for humans appears to be consistent with good stewardship. Surely the sacrifice of animals to preserve human life is at least as defensible as creating and sacrificing colonies of animals for use in the food chain. Both xenotransplantation and use of animals for food appear to be reasonable if one accepts the moral superiority of humans; neither can be justified if the moral superiority of humans is denied. These summary arguments are presented, not as a complete case for the use of animals in research, but to suggest to the reader that powerful philosophical and theological arguments can be made to support the responsible use of animals in research designed primarily for human ends.

SPECIFIC CRITERIA FOR XENOGRAFTS

If one accepts the argument that xenotransplantation is not immoral a priori, then one must ask: What are the conditions that must be met in order to carry out xenografts in a reasonable, defensible manner? The following conditions are suggested as necessary for reasonable xenotransplantation:

Prior to animal-to-human xenotransplantation, successful organ transfer between species other than human must have provided credible evidence of a significant chance of successful transplantation of organs from animals to humans, with the prospect of long-term human survival.

The subsequent animal-to-human xenograft research must be carefully designed to achieve a non-trivial outcome for human subjects, and to provide more good than harm to society.

A sufficient, but not excessive, number of animals has been used to accomplish the research. (In the case of xenotransplantation, research investigators may tend to use an insufficient number of animals by failing to carry out enough carefully controlled xenografis between animal species to provide a solid scientific basis for animal-to-human xenotransplantation and to evaluate both short- and long-term consequences of the procedure.)

Pain and distress to the animals must be minimized.

Until xenotransplantation is well established each animal-to-human xenograft must be thoroughly evaluated before additional animal-to-human xenograft research efforts are undertaken. If any xenograft research produces serious harmful consequences, then further research should be suspended until the harms can be understood and prevented or overcome in the future.

RESPECT FOR CONSCIENTIOUS OBJECTION

It must be recognized, nevertheless, that many competent, thoughtful, conscientious persons do not agree with either the philosophical or theological positions regarding the moral permissibility and the responsible use of animals outlined above. Even among those that consider some use of animals as morally acceptable there are some who consider xenotransplantation morally wrong. Most people who object to the use of animals for human ends or who object specifically to xenotransplantation appear to be principled and conscientious in their objection to the use of some or all animals in research, or to the use of animals in xenograft research that benefits humans but offers few, if any, benefits to animals. Therefore, any research program that proposes to conduct animal-to-human xenografts must make allowance for conscientious objection.

Those who object to animal-to-human xenotrans-plantation research on moral grounds must not be coerced or pressured to cooperate with xenograft research in any way. Without prejudice, animal vendors, caretakers, veterinarians, technicians, co-investigators, surgeons, transplant recipients, and nursing staff must be given the opportunity to separate themselves from cooperation with xenograft research. The employment, wages, opportunity for advancement, working conditions, and right to actively oppose xenotransplantation must not be adversely affected by a person's conscience-based refusal to cooperate with animal-to-human xenograft activities.

REACHING A DECISION CONCERNING PROPOSED XENOTRANSPLANTATION RESEARCH

Actual decision-making should occur in a manner similar to other research decisions. Xenotransplantation may go forward if:

The proposed research complies fully with federal, state, and local laws, policies, and regulations governing both the care and use of laboratory animals and the protection of the rights and welfare of human research subjects. Compliance, at the very least, will require careful review and approval of the research activity by the relevant Institutional Animal Care and Use Committee (IACUC) and by the relevant Institutional Review Board (IRB). ² In the case of animal-to-human xenograft research proposals it is recommended--but not required--that the IACUC and the IRB meet together to review and evaluate the research design. Joint meetings are likely to enhance the quality of the review by both committees. Of course each committee must take action on each research proposal (each IRB/IACUC may approve, approve with modification, or disapprove) independently of the other. Disapproval by either committee will be sufficient to prevent the research from going forward.

The proposed research has the approval of the institution under whose auspices the research is conducted.

CONDITIONS OF IACUC APPROVAL ³

Prior to giving approval to the proposed research activity, the IACUC should find and document that the following conditions have been met:

The animals must not be members of a rare or endangered species (Donnelley and Gaylin 1989). Although most past xenograft attempts have used nonhuman primates, the committee should give careful consideration to other species, such as pigs, whose organs appear to be well suited for xenotransplantation, and whose genetic suitability and pathogen-free status is more easily ascertained than is the case with primates.

The animals will be obtained from an approved vendor, dealer, or breeding program. The species must be chosen on grounds that it offers the best chance of successful xenograft to human recipients. To the extent possible within the state of the art, principal investigators must demonstrate that candidate animals are free of zoonotic and pathogenic agents, even if these agents are usually considered harmless. Primates that are considered acceptable as xenotransplant donors should be screened for Toxoplasma gondii, Mycobacte-rium tuberculosis, Marburg virus, herpes virus, Simian cytomegalovirus, herpes simplex 1 and 2, and any other pathogens known to reside in the species. Blood from candidate animals must be screened for HIV- 1, HIV-2, HTLV and hepatitis (Prentice and others 1994). Animals found to harbor pathogens or zoonotic agents must not be used as xenograft donors. Animals found to be free, or as free as possible, from zoonotic or pathogenic organisms should be selected on the basis of histocompatibility and suitable organ size and morphology for successful xenotransplantation.

Donor animals are to be maintained in as healthy a condition as possible prior to their being sacrificed for xenograft purposes. To this end, the IACUC should consider how long, and under what conditions the animals will be quarantined prior to use as xenograft donors. Careful attention to the animals' environment as well as to food and fluid intake must be given to assure that the animal is healthy.

Donor animals must be sacrificed in a humane and painless manner in accord with American Veterinary Medical Association standards.

Those removing the animal organ (or organs) must possess the requisite skills, staff, and equipment needed for prompt removal and preservation of animal parts with a minimum of insult to those parts prior to transplantation into the human recipient.

CONDITIONS OF IRB APPROVAL

The IRB should find and document that the following conditions have been met prior to giving approval to the research activity (Federal Policy 1991):

Human candidates for receipt of animal organs have a genuine need for an organ that cannot be met by other morally acceptable, less risky means.

Human candidates meet the selection criteria factors established by the United Network for Organ Sharing, for receiving organ transplants. Human candidates who elect not to participate in xenograft research must not lose their standing in the list of those seeking human organs.

The surgeon or surgical team introducing the animal organ into the human recipient must be well qualified to carry out the transplant.

Nursing and other support staff must be well trained in monitoring and caring for transplant patients.

Potential human recipients must be well informed concerning all aspects of the study, especially risks that they face if they consent to xenotransplantation. Informed consent must include the following:

A statement of the care and compensation that will be provided to subjects during the course of and subsequent to the research.

Frank disclosure of the fact that participation must be entirely voluntary on the part of subjects; disclosure of how subjects will be cared for if they elect not to participate as research subjects; disclosure of a source to provide additional information or to answer additional questions.

Disclosure to subjects of the degree of confidentiality that can be provided. This disclosure must include frank discussion of expected media coverage of the project, and the probability that subjects, family, friends, and staff may be subjected to unwanted attention by the media. Disclosure should also deal with the fact that media may try to "buy" stories from subjects, family, friends, or staff. Agreement should be reached prior to initiation of the research concerning who will make statements to the press, and who, if anyone, will be permitted to sell stories or interviews.

If the research involves children, then the IRB must meet all relevant additional legal and regulatory requirements for children.

CONDITIONS OF INSTITUTIONAL APPROVAL

The research institution may allow the research to go forward if and only if the following conditions are met:

The institution will provide the necessary staff, personnel, and logistical and financial support necessary to conduct both preliminary research in animal models and the actual animal-to-human xenotransplantation.

The institution will provide fiduciary support of the investigative team including handling public relations, legal council, and a willingness to defend investigators against criticism.

The institution is willing to continue to provide xenotransplant services if the technique proves to be useful and effective. This willingness includes facing the fact that xenografts used as a bridging device involve not only high cost in dollars and personnel for human-to-human transplant, but additional high cost in dollars and personnel tot the bridging technique (If bridging is contemplated, the institution must be aware that bridging will not help to solve the problem of greater demand for transplantable human organs than can be met by the existing supply of human organs).

The research should not be initiated unless the institution is prepared to support xenotransplantation, assuming that the research proves it to be successful, until it becomes a program for standard health care delivery. In other words, the institution should not start xenotransplantation research unless it is prepared to develop the research to the point where it may be adopted as a standard therapy for future patients.

Institutions must also be aware that IRBs are responsible for the rights and welfare of the subjects. IRBs are not required to assess public health risks. Nevertheless, there remains a real but unspecified possibility that a pathogen that was harmless when it was in the animal host, could be transformed in its new, immunosuppressed human host into a serious or deadly disease that could attack the organ recipient or others who come in contact with the transformed pathogen (Allan 1994). ⁴

CONCLUSION

Institutions must decide whether they are willing to assume responsibility for the low probability but high magnitude risk to the public health of introducing a new disease into society (Science 1995). ⁵

Institutions must also consider carefully whether they are willing to undertake the heavy costs and responsibilities associated with xenotransplantation. Meeting all of the conditions cited above will be no easy task.

No doubt a few institutions will express a willingness to shoulder the costs and responsibilities that accompany xenotransplantation and will make the judgement that they have met the required conditions. Citing the desperate need of subjects whose best hope for survival lies in the receipt of transplanted organs from any reasonable source, a few institutions are likely to proceed with xenotransplantation. Many institutions, however, will choose to wait until such time as (1) xenograft research demonstrates greater, more efficient, long-lasting success of xenografts between species of nonhuman animals; (2) colonies of pathogen-free, purpose-bred animals ideally suited for xenotransplants are readily available; and (3) additional evidence is developed to show that xenotransplantation researchers will not be risking the public health by inadvertently creating or releasing new pathogens.

¹ For references to a range of literature on the morality of using animals for research purposes, and a summary of moral positions opposing or questioning the use of animals in research see: Donnelley, S., and K. Nolan, eds. 1990. A Special Supplement to The Hastings Center Report entitled Ethical Theory and the Moral Status of Animals by Lilly Mariene Russow, in collaboration with K. Danner Ciouser, David DeGrazia, and James Stephens, Sec. I, pp. 4-8. A more complete summary and critique of leading philosophical positions is presented by David DeGrazia, March, 1991, in the Kennedy Institute of Ethics Journal, 48-69. DeGrazia seeks to find some degree of convergence in the thought of leading opponents to the use of (some or all) animals in research, Singer, Frey, Regan, Midgley, and Sapontzis. Nevertheless, he is not entirely satisfied with the thought of any of them. He dismisses the arguments of Cohen and H.J. McCloskey (proponents of the use of animals in research) because, in his view, they do not represent significant contributions. By finding more consensus than may actually exist, DeGrazia seems to suggest more unanimity in positions opposed to the use of animals than this author believes is justified.

² Careful attention must be given to assure compliance with the Public Health Service Policy on Humane Care and Use of Laboratory Animals, revised, Sept. 1986 (U.S. Govt. Printing Office: 1991-294-776). See also The Improved Standards for Laboratory Animals Act, December 23, 1985 (Subtitle F of the Food Security Act of 1985 (P.L. 99-198, #1751-1759). This Act amended the Animal Welfare Act (AWA) of 1966 (P.L. 89-544), amended in 1970 (P.L.91-579), and 1976 (P.L. 94-279). Regulations imple-menting the 1985 law and amending parts I and 2 of the Animal Welfare Act Regulations were promulgated by the USDA March 15, 1989 Federal Register 54:10822-10954. Final regulations amending part 3 of the AWA regulations were promulgated Feb. 15, 1991, F.R. 56:6426-6505.

³ See U.S. Department of Agriculture Regulations implementing the Animal Welfare Act as amended in December, 1985. The Regulations are found at Title 9 CFR Pan 3, Subparts A through D. See Also the Public Health Service Policy on Humane Care and Use of Laboratory Animals, May, 1985.

⁴ Allan's letter stated that, "The identification of a previously unknown virus in nonhuman primates illustrates the possibility of doing more harm than good through xenograft transplantation: any pathogen carried by a baboon donor would be introduced to the human recipient along with the baboon organ. Most new pandemics arise through inadvertent transmission of viruses from another species (which Junctions as a natural reservoir) to humans."

⁵ In Science's section entitled Sciencescape, the following statement appeared: "Renewed interest in transplanting animal organs into people is causing consternation at the Food and Drug Administration (FDA), where officials plan to issue a warning that could slow clinical trials set to begin this year. The FDA's concern: "Xenografts" might allow dangerous pathogens lurking in animals to jump to humans....But screening for known viruses does little to apprehend novel pathogens. So FDA officials want stricter safeguards that could include improved tests for pathogens, protocols to quarantine patients, and the creation of colonies of "clean" animals. FDA has the muscle to demand such provisions...but for now.., the agency only plans to alert surgeons, health officials and review boards to xenograft risks."

REFERENCES

Allan, J. S. 1994. Letter to the Editor, September. Science 265(2):1345.

Annas, G. J. 1985. Baby Fae: The "anything goes" school of human experimentation. Hastings Center Report 15:15-17.

Bulger, R. E. 1987. Use of animals in experimental research: A scientist's perspective. Anat. Rec. 219:215-220.

Donnelley S., and W. Gaylin. 1989. The heart of the matter. Hastings Center Report 19(1):26-28.

Evans, R. W., D. L. Manninen, L. P. Garrison, A. M. Mater. 1986. Donor Availability as the Primary Determinent of the Future of Heart Transplantation. J. Am. Vet. Med. Assoc. 255(14):1892-1898.

Federal Policy for the Protection of Human Subjects; Notices and Rules, 1991. Federal Register, Vol. 56, No. 117, Tuesday, June 18, 1991, pp. 28003-28032.

Improved Standards for Laboratory Animals Act The, December 23, 1985 (Subtitle F of the Food Security Act of 1985 (P.L. 99-198, #1751-1759).

Leventhal, J. 1994. The Use of Sinall and Large Animal Models in Transplantation Research. Paper delivered at Workshop on Transplantation Medicine and Surgery sponsored by The American Society of Laboratory Animal Practitioners (ASLAP), and The Association of Primate Veterinarians (APV), Pittsburgh, Penn., October 16.

Loeb, J. M., W. R. Hendee, S. J. Smith, and M. R. Schwarz. 1989. Human vs. animal rights--in defense of animal research. J. Am. Med. Assoc. November 17 262(19).

Makowka, L. 1994. History, Progress, and Future of Transplantation. Paper delivered at Workshop on Transplant Medicine and Surgery, sponsored by The American Society of Laboratory Animal Practitioners (ASLAP) and the Association of Primate Veterinarians (APV), Pittsburgh, Penn., October 16.

Millard, C., N. E. Shumway, T. E. Starzl, and others. 1985. Xenografts: Review of the literature and current status. J. Am. Vet. Med. Assoc. 254:3353-3356. Best known among attempts at xenotransplantation was the transplant of a sheep heart into a human recipient by Denton Cooley in 1968. This controversial attempt is described in an article by D.Z. Cooley, G. L. Hallman, R. N. Bloodwell, and others. 1977. Human heart transplant: Experience with 12 cases. Amer. J. Cardiol. 22:804-810.

Nelson, J.L. 1993. Moral sensibilities and moral standing: Caplan on xenograft donors. Bioethics 7(4):315-322.

Neuhof, H. 1923. The Transplantation of Tissues. New York: Appleton and Company.

Prentice, E.D., I.J. Fox, R.S. Dixon, S. Robert, D.L. Antonson, and T.A. Lawson. 1994. History, Donor Considerations and Ethics of Xenotransplantation and Xenoperfusion. Pp. 1-12 in Research Animal Anesthesia, Analgesia, and Surgery, A. S. Smith, and M. M. Swindle, eds. Beltsville, Md.: Scientists Center for Animal Welfare. Science 267 (Jan. 6, 1995):19.

Starzl, T.E., T.L. Marchtoro, G.N. Peters, and others. 1964. Renal heterotransplantation from baboon to man: Experience with six cases. Transplantation 2:752-776.

Starzl, T. E., J. Fung, A. Tzakis, and others. 1993. Xenotransplantation 1:27-29. 1994 Annual Report of the U.S. Scientific Registry of Transplant Recipients and Organ Procurement and Transplant Network.