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 Kidney Transplantation: Past, Present, and Future

 As Cross-Species Transplantations

Move Ahead, Some Scientists Call For Caution, Restraint

New transgenic tactics and immunology advances push xenotransplantation forward--but has the science base been laid?

Author: Franklin Hoke

 Within just a few years, a growing number of surgeons expect to be able to transplant cells, tissues, and organs from baboons, pigs, and other animals into humans as accepted therapy for a number of life-threatening conditions and diseases. Driven by scientific innovation and powerful medical need, the field of cross-species transplantation, or xenotransplantation, is moving ahead with several ground-breaking experimental human procedures this year, and more expected in the near future.

EXERCISING RESTRAINT: Thomas E. Starzl has put the University of Pittsburgh xenotransplantation program onhold pending a better understanding of the problems.

At the same time, some scientists and surgeons are calling for caution and restraint as the pace of progress accelerates. As xenotransplantation--once considered a species of science iction--nears clinical reality, a number of far-reaching biomedical, social, and ethical questions will demand answers.

 Infectious disease experts have raised public health warnings about new viruses with epidemic potential that may piggyback on the transfers from animals to humans. Some researchers--including several responsible for major advances in transplantation in the past--say that the current scientific base is insufficient to support experimental xenotransplantation involving humans. They fear that, unless those within the transplantation community can demonstrate self-control, it may needlessly invite burdensome federal regulation.

 "We don't think we're good enough yet to do it," says Thomas E. Starzl, director of the Transplantation Institute at the University of Pittsburgh Medical Center. Starzl performed an early-1960s series of xenotransplants--baboon-to-human kidney transplants--with limited success and had discontinued the attempts by mid-decade. Then, three decades later, surgeons at the Pittsburgh institute performed two baboon-to-human liver transplants in 1992 and 1993 (F. Hoke, The Scientist, Sept. 28, 1992, page 1). The patients died at 70 and 26 days, respectively, from infections accompanied by kidney failure.

 Although approved by Pittsburgh's institutional review board (IRB) for four such experimental procedures, the team canceled the remaining two until the reasons for the organ failures could be better understood and ways found to counter them in future attempts.

 "Our whole investigative team is working on almost nothing else except xenotransplantation," Starzl comments. "So, perhaps we have a strong insight about how tough this really is. We're not going to open up again until we have something that we think is a very fundamental improvement. Even though we've had permission to go forward, we're not nuts."

 "Xenotransplantation is critical to the future of transplantation," says Hugh Auchincloss, Jr., an associate professor of surgery in the transplantation unit at Massachusetts General Hospital in Boston. "I desperately want to do it. But I don't think we're ready to do it in people, because it isn't going to work. I have a big problem with our scientific evidence that we've figured out how to make it work."

 An Institute of Medicine committee is currently reviewing the scientific, ethical, and public policy questions surrounding xenotransplantation. After an October meeting, the committee will produce a report and policy recommendations for probable release early in 1996, according to Norman G. Levinsky, committee chairman and chairman of the department of medicine at Boston University Medical Center. Questions to be debated include those concerning regulation of the field (see accompanying story).

Reasons To Proceed

 Among the factors pushing xenotransplantation forward are the clinical successes of allotransplantation--human-to-human transplantation--which have led to a demand for organs that has far outstripped the available supply from human sources. Also, recent advances in techniques for managing the immune system, contributions from transgenic technologies, and an increasingly effective arsenal of immunosuppressive drugs have raised the hopes of some researchers that xenografts may soon be possible.

 "We have the means to help patients, but we lack the organs," says Jeffrey L. Platt, a professor of surgery, pediatrics, and immunology at Duke University Medical Center. "The fact that transplantation can only be applied to a small percentage of the patients who can be benefited by it is a great frustration. And it's because of new abilities to carry out genetic engineering and to develop new drugs that many of us have been very enthusiastic about the possibility of being able to use animal organs in lieu of human organs."

 If it can be made to work, xenotransplantation has a number of potential advantages over allotransplantation, according to Keith Reemtsma, a professor of surgery at Columbia University College of Physicians and Surgeons. Animals and their organs can be prepared transgenically and their deaths scheduled, both of which would be unethical in the case of human donors. Also, animals are resistant to some human diseases. Baboons and their livers are resistant to hepatitis B, for example. The virus can destroy a human liver and then do the same to a human organ transplanted into the patient to replace it.

 In 1963 and 1964, Reemtsma performed two chimpanzee-to-human kidney transplants, with the first patient surviving 63 days and the second approximately nine months. Today, Reemtsma is quick to point out that those experimental procedures, like Starzl's, were performed on critically ill patients in the period prior to the kidney dialysis machine's becoming available in the mid-1960s; they were not sufficiently promising as treatment to be ethically justifiable after that. Those early xenotransplants also predated the chimpanzee being recognized as an endangered species. At Columbia, Reemtsma is now involved in a number of xenotransplantation research projects, including efforts aimed at transplanting pancreatic islet cells from other species into humans as a treatment for diabetes.

 In July, Platt and his research team at Duke received approval from the Food and Drug Administration (FDA) to use livers from transgenically altered pigs as ex vivo supports for 10 liver-failure patients waiting for a human organ to become available. Platt's pigs, developed by Nextran Corp., a Princeton, N.J.-based biotechnology company, incorporate three human genes that code for proteins that, in the human, protect the endothelial cells lining blood vessels from autoimmune attack. The expectation is that the human genes will enable the blood vessels in the pig livers to avoid attack by the human immune system, thereby mitigating the rejection of the organs. Other biotechnology companies are also developing similar transgenic animals for xenotransplantation, including Alexion Pharmaceuticals Inc., New Haven, Conn., and Imutran Ltd., Cambridge, England.

 In the long term, the use of pigs for xenotransplantation would also address important ethical issues, as well as several practical ones. Animal rights activists and others have protested the use of nonhuman primates as sources for organs, on the grounds that primates are intelligent and social beings with inherent rights to life similar to those of humans. Primates also reproduce at rates too slow for them to represent a lasting solution to the human-organ-shortage problem. Because pigs are a commonly farmed animal used for food, issues of limited availability and of the ethics of sacrificing them for their body parts are largely obviated. Pig organs are also similar in size and other physical aspects to human organs.

Baboons and AIDS

 Most researchers involved in xenotransplantation say that clinical success is likely to be first achieved with cells and tissues, rather than with solid organs. Procedures for which they have high hopes include pig fetal tissue transplantation into the brains of Parkinson's patients as therapy, as well as pancreatic islet xenotransplantation to treat diabetes.

 One reason investigators expect cells and tissues to be more easily transplanted than solid organs is because they avoid much of the hyperacute early-stage rejection. The type of rejection that targets the blood vessels for immune-system attack is not invoked because cells and tissues have no blood-supply vasculature to be attacked. The later-stage cellular rejection presents the major obstacle to these xenotransplants, and new drugs and other tactics to overcome it are in development.

 In a cell-based procedure approved by FDA in July, a 38-year-old AIDS patient named Jeff Getty will receive a baboon bone marrow transplant at the University of California, San Francisco, in September or October, in an effort to reconstitute his devastated immune system. The clinical concept turns on the fact that baboon cells are resistant to HIV infection. If the baboon bone marrow can be successfully transplanted into Getty and then produces baboon T cells, Getty may regain immune function.

 Suzanne T. Ildstad, chief of the division of cellular therapeutics at the University of Pittsburgh Medical Center, developed the experimental protocol. Ildstad claims to have discovered a new type of bone marrow cell called a facilitator cell that promotes successful engraftment. If her concept should prove workable, it could lead to more successful transplantations of all kinds, whether allografts or xenografts.

 "One of the potential ways of overcoming the vigorous rejection of solid organ transplants is to achieve engraftment of bone marrow, because it confers tolerance to solid organs," Ildstad says. "And bone marrow is the only graft that is permanently accepted without drugs, without the requirement for antirejection agents. If I transplant a kidney or a liver into a patient, that patient must take antirejection drugs every day for the life of the graft--not just for a few days, but forever. And those can be quite toxic."

 She cites recent follow-up data on heart transplant patients at Pittsburgh showing that one in 10 developed kidney failure as a result of the toxicity of the necessary immunosuppressive drugs.

 "So, clearly, there's room for improvement," Ildstad comments.

New Disease Risks

 Ironically, it appears that one of the reasons that an FDA review committee gave permission for the San Francisco baboon-to-human bone marrow experiment is that its members were able to convince themselves that the patient is likely not to survive. Based on their review of Ildstad's animal-model studies done in support of the facilitator-cell theory, most have little expectation that the procedure will be successful. In weighing fears that the baboon cells might carry viruses--particularly retroviruses--that might prove dangerous to humans, the fact that Getty probably would not have a chance to infect others proved a factor in the group's decision.

 "Based on the advisory committee meeting and our own discussions, it does appear that this particular experiment will not likely work in terms of extending the patient's life, so that it's unlikely he will survive long enough to really run into the risk of transmission of infectious diseases," says Philip Noguchi, director of FDA's division of cell and gene therapy.

 Faced with an emotional plea from Getty and his family to make a humanitarian exception in allowing the experimental procedure, all of the committee members but one voted for approval. Even Jonathan S. Allan, a virologist at the Southwest Foundation for Biomedical Research who opposes xenotransplantation, abstained in the final vote rather than go against Getty's expressed wishes. Southwest Foundation provided the two baboons used in Starzl's recent experiments and will be the source for Ildstad's baboon.

 Allan is opposed to xenotransplantation because the human infectious-disease risks posed by baboon viruses brought into the human under immunosuppressed conditions are too great, in his view. He speculates that unknown retroviruses could result in long-latency diseases similar to AIDS or, depending on where they integrate themselves into the human genome, to cancers.

 "The members of the panel opted out and said, `Do we really need to worry about the infectious disease risk if it's just one patient?'" Allan reports. "But, if one takes a broader perspective, one sees that this isn't a one-experiment deal. We're opening up the door."

 Stephen Morse, an assistant professor of virology at Rockefeller University and a member of the committee, acknowledges the possibility of the "frightening scenario" described by Allan.

 "But this is an unresolvable question. I personally think the risk is small, but what bothers all of us is that the risk is unquantifiable. We have absolutely no idea how we would estimate the risk, and the potential consequences are very great.

 "There are going to be increasingly strong political pressures and increasingly good scientific and medical reasons for contemplating doing this kind of work. And surgeons like Tom Starzl and others want to push the envelope to increase what can be done.

 "I think it's going to be impossible to put the genie back in the bottle."

Establishing Oversight

 Because of its therapeutic promise, xenotransplantation is likely to go forward, despite fears of the introduction of new epidemics into the human population and other concerns. The question now being raised in several quarters is whether local or federal authorities should oversee the field, and whether voluntary guidelines or more formal regulations should be invoked.

 Stephen Morse, an assistant professor of virology at Rockefeller University, says that the issues raised by cross-species transplantation are serious, but manageable. He suggests that appropriate safeguard systems can and should be put in place.

 "While our first line for these [experiment] approvals is always at the institutional level, looking at these issues requires some special expertise that is not that broadly distributed," Morse comments. "My view is that the regulatory aspects should not be more burdensome than necessary, but that there should be some sort of centralized resource that provides some oversight."

 According to Philip Noguchi, director of the Food and Drug Administration's division of cell and gene therapy, his agency already has jurisdiction over xenotransplantation of cells, tissues, and transgenically altered solid organs. To cover other solid organ xenografts, FDA is now considering the development of voluntary guidelines in cooperation with the Institute of Medicine (IOM), the Centers for Disease Control and Prevention, and other organizations.

 Norman G. Levinsky, chairman of an IOM committee currently studying xenotransplantation, says that questions concerning oversight of the field will be central to his group's deliberations.

 "If the science is sufficient to go forward, and if the risk of infection doesn't make us back off, then can clinical trials go forward on the standard basis of local institutional review boards [IRBs] and animal use committees?" asks Levinsky, who is also chairman of the department of medicine at Boston University Medical Center. "Do we need national guidelines that the IRBs should follow? Or, finally, are the considerations so important that they ought to be handled the way recombinant technology has been handled, with a national review body of some sort?"

(The Scientist, Vol:9, #16, pg.1 , August 21, 1995)(Copyright © The Scientist, Inc.) WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES:garfield@aurora.cis.upenn.edu71764.2561@compuserve.c om

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