The Opposition

Researchers Wait For Federal Guidelines Two reports, one from each side of the Atlantic Ocean, conclude that research on xenotransplantation-the transfer of organs, tissues, or cells from animals to humans-should be pursued because the potential benefits of the practice outweigh its possible risks. But scientists in the United States are frustrated by the Public Health Service's slow pace in issuing federal guidelines for the research. CAUTIOUS STEPS: Xenotransplantation pioneer Suzanne Ilstad says scientists must proceed carefully. Meanwhile, some critics of xenotransplantation say that not enough attention is being paid to the chance of disease transmission from animals to humans. And animal-welfare activists are concerned that xenotransplantation may provide an entirely new arena for animal exploitation. The two reports come from the Institute of Medicine (IOM) in the U.S. and the Nuffield Council on Bioethics in the United Kingdom. IOM, a private, nonprofit organization that provides health policy advice under a congressional charter granted to the National Academy of Sciences, released "Xenotransplantation: Science, Ethics, and Public Policy," on July 17. The Nuffield Council, the U.K.'s independent bioethics watchdog, released "Animal-to-Human Transplants: The Ethics of Xenotransplantation" in March. Both discuss the ethical, legal, biomedical, and social implications of xenotransplantation. On July 24, IOM hosted a workshop at which members of the authoring committees and other interested parties discussed the reports' findings. "The most significant effect of both the report of the Institute of Medicine and the Nuffield Council report is that they support the concept of proceeding with xenotransplantation," concludes Keith Reemstma, a professor of surgery at Columbia University College of Physicians and Surgeons and a member of the IOM committee. Reemstma began the modern era of xenotransplantation in 1963, when he conducted chimpanzee-to-human kidney transplants before either kidney dialysis or human-to-human "allotransplants" were available. "I'm extremely impressed," adds Suzanne T. Ildstad, professor and chief of the division of cellular therapeutics at the University of Pittsburgh. "There was an amazing amount of effort put in by many scientists with various areas of expertise, and I was reassured by the fact that they overwhelmingly said that the potential benefits of xenotransplantation across species barriers outweighed the risk." Ildstad garnered widespread media attention earlier this year, when she and her coworkers performed a baboon-to-human bone marrow transplant on a person with AIDS (S. Benowitz, The Scientist, March 4, 1996, page 3). In September, she will move to Allegheny University of the Health Sciences in Philadelphia as a professor of surgery and head of the newly formed Allegheny Institute for Cellular Therapeutics. 'CONCERNED': The Humane Society's Martin Stephens worries that animals will be raised to supply organs. Not everyone is as enthusiastic about the potential of xenotransplantation. "We're concerned about the possibility of tens of thousands of animals being raised for their organs," says Martin L. Stephens, vice president for animal research issues at the Humane Society of the United States, headquartered in Washington, D.C. "This would be a whole new arena of animal exploitation coming at a time when we feel that many other trends are in the right direction. "We would like to see a lot of the resources that are now being put into xenotransplantation be put into other, more promising, avenues of research-split-organ techniques, tissue engineering, public health measures to increase donation," Stephens continues. LIMITED SUPPLY: Keith Reemstma notes that the need for human organs and tissues is too high to meet. But Reemstma maintains that "there is a need for this supply of organs and tissues and cells which would not be met under even the most optimistic predictions using human tissues." The IOM report notes that while 7,600 people donated organs in the U.S. in 1994, 37,000 potential recipients were on waiting lists, and nearly 50 percent of those on the lists die before a suitable organ becomes available. Concerns about the public health-the fear that xenotransplantation might also introduce new diseases into the human population-are providing a strong impetus for caution. "What you're dealing with is a great unknown," states virologist Jonathan S. Allan, a scientist at the Southwest Foundation for Biomedical Research in San Antonio, Texas. "The best historical evidence we have for something like this is the AIDS epidemic. While there are still a few people who are difficult to persuade, most people generally agree that the AIDS virus had its origin in nonhuman primates in Africa." Allan, however does not oppose all xenotransplantation. He believes that the risk of disease transmission to humans is far greater when the source of the transplant is a baboon or other nonhuman primate. "Xenotransplantation in general, I think, has potential in alleviating the organ-shortage crisis. My concerns are generally with the animal model-primates vs. pigs." AN UNKNOWN RISK: The potential for virus transmission to humans for primates bothers virologist Jonathan Allan. "That's been very well looked at, very thoroughly looked at, and his is a minority view," asserts Reemstma. "The majority view of people who are experts in this field-and I am not an expert in this field-is that while there may be some risk involved, it is not a prohibitive one." The IOM report makes no recommendation about which animals should be used, although it does recommend provisions to decrease the risk of disease transmission that might be included in formal guidelines. The Nuffield Council report, however, specifically states that only non-primate species should be regarded as source animals for xenotransplantation. The basis for this recommendation includes not only the greater risk of disease transmission from primates, but also the "high degree of evolutionary relatedness between human beings and primates" and the rarity of some primate species in nature, particularly chimpanzees. Both reports state that more research needs to be undertaken to reduce the risk of disease transmission. The IOM report, for example, recommends that guidelines be developed for screening donor animals for potential disease-causing agents and that there be "consideration of the development of specific pathogen-free animals for use in xenotransplantation." In addition, the report advocates monitoring recipients throughout their lives as well as "periodic surveillance of their contacts," establishing tissue banks containing samples from donor animals and patients, and establishing national registries of xenotransplant patients. But this isn't enough to satisfy the critics. Allan notes that of the 3,000 baboons in his facility, 99 percent harbor "foamy viruses," whose pathogenicity in humans is unclear. "Those are the known viruses," he points out. "How do you find a virus before you know it exists, in a needle-in-the-haystack scenario such as a retrovirus?" The xenotransplantation community in the U.S. is awaiting the release of formal guidelines that will address many aspects of how research should be conducted. The guidelines are being developed by three agencies within the U.S. Public Health Service (PHS): the Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), and the National Institutes of Health. The PHS guidelines will go into more detail than the IOM report, says Philip D. Noguchi, director of FDA's division of cellular and gene therapies. After the guidelines are made public, FDA will issue a document called "Points to Consider," which will detail such things as how the source animals should be obtained and housed and what kind of animal testing should be done. Noguchi is unable to say when proposed guidelines will be released, but once they are available there will be a period of at least 90 days for public comment before final guidelines are issued. Reemstma is frustrated at the government's delay. "We've been waiting for a year. One year ago, almost to the day . . . the group was assured that those guidelines . . . would be available immediately. And it's a year later and they aren't." Jeffrey Getty, the 38-year-old Oakland, Calif., AIDS activist who was the recipient of the baboon bone-marrow transplant earlier this year, has very personal reasons for being impatient with the delay. "I need to know in a fair and meaningful way, what are the restrictions that they want me to live under? "I still must adhere to the very stringent guidelines that were established for me. I'm not supposed to have any sex and/or safe sex and/or casual contact with any other people. The last directive I received in writing . . . was very conservative. I was not supposed to share even eating utensils . . . or exchange saliva with another human being. When my mom comes over, or my ex-wife, and tries to kiss me on the lips, I have to turn my head and say, 'Careful.'" Both Getty and Ildstad maintain that, seven months after the transplant and following extensive testing, there's no evidence that he acquired any baboon disease. Whether the transplant did any good, though, is a subject very much in question. The rationale for the transplant rested on the fact that baboon bone marrow is resistant to infection by HIV, and the hope was that the baboon tissue would spur the development of HIV-resistant marrow cells and restore Getty's damaged immune system. Neither Ildstad nor Getty will discuss the results of the experiment in detail, citing three scientific papers in preparation that have not yet been submitted for peer review. But Getty expresses satisfaction with the experiment, although by three weeks after the procedure the baboon cells apparently disappeared from his body. "We set out to prove that this was a safe procedure. It was successful. Not only was it safe, it improved my health immensely. We don't even yet know why, although we have a couple of things we suspect caused that." For example, Getty believes that before the procedure his immune system was "inflamed." He thinks it's possible that the chemotherapy he received in preparation for the transplant may have interrupted the inflammatory process, after which his immune system grew back in a "quiescent state." Getty also advances the hypothesis that during their brief period in his body, the baboon cells may have transferred some factor to his own immune system that is inhibiting further HIV infection. Both the IOM and Nuffield Council reports urged continuing study of the ethical issues raised by xenotransplantation. One is the issue of informed consent. "The people who participate would have to hear not only of the hopes and enthusiasms of researchers, but also know forthrightly about the risks they are taking and the problems that xenotransplants have raised," explains Howard Y. Vanderpool, a professor of the history and philosophy of medicine at the University of Texas Medical Branch in Galveston. WIDE IMPACT: Howard Vanderpool points out that transplants affect family members and health-care workers, too. "I think informed consent for the earliest xenotransplant trials would be difficult to obtain insofar as these [patients needing organ transplants] are desperate people," says Vanderpool, who was a member of the IOM committee on xenograft transplantation. "The British, through the Nuffield report, believe that it would be impossible for a member of the xenotransplant team to secure truly informed consent from patients because of their hopes and enthusiasms, career investments, and so on. I think that the American tradition has said no, the researcher himself or herself should obtain that consent." Copies of the IOM report "Xenotransplantation: Science, Ethics, and Public Policy" are available from the National Academy Press. For more information, call (800) 624-6242. For copies of the Nuffield Council report "Animal-to-Human Transplants: The Ethics of Xenotransplantation," call the Nuffield Council at 01-71-631-0566. The recipient of the transplant may not be the only one who should provide informed consent, says the IOM report. "I think the question of securing informed consent from others who could be affected is significant," notes Vanderpool. "Now maybe consent forms should be developed for health-care workers or for family members." Another important ethical issue involves the question of publicity. Getty clearly relishes the public prominence that his role has thrust upon him. Others may feel differently, says Vanderpool. "Maybe there are people who don't want their friends and neighbors to know that they have a pig's heart that's keeping them alive." About both the ethical and scientific issues, Ildstad acknowledges, "I agree that, as in any new emerging field, we have to go carefully. We have to maximize the brain trust of the collective scientific community so that we learn as much as we can and protect the recipient and protect the public, and I think that people are doing that." "The whole field is now dependent on an improved understanding of the basic mechanisms involved, and the appropriate application of these advances in carefully conducted, small, focused, clinical trials," concludes Reemstma. "I think that we will probably see the same pattern we saw with human transplantation 30 years ago, and that is, we will probably not see a single magic bullet that will miraculously solve all the problems of xenotransplantation. Rather, we will see a series of incremental improvements, step by step, as this field moves forward." Robert Finn, a freelance science writer based in Long Beach, Calif., is online at finn@nasw.org

The Opposition

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