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The ultimate piggybank

Xeno: The Promise of Transplanting Animal Organs into Humans

2000 Oxford University Press, 274 pages, $30.00 hardcover

Xeno offers both scientific and lay readers a lively, cogent, and comprehensive account of the scientific and ethical issues surrounding the use of animal organs and tissues for human transplantation. Written by two researchers who are deeply involved in xenotransplantation and therefore have a great stake in seeing the field move into the clinic and succeed, the book may also be viewed as a manifesto of sorts. It takes an optimistic stance toward solving some of the problems that stand in the way of humans being able to safely accept pig organs and tissues for lifesaving purposes. However, to their credit, the authors also go to great lengths to articulate and explore the difficulties that still exist in creating tolerance to animal tissues, and to tally the risk/benefit ratio that xenotransplantation poses.

Early in the book, Cooper and Lanza give the reader a historical context in which to view such “futuristic” uses of animal organs. They observe that the attempt to use animal organs for transplantation is hardly new. They also give the situation a human face by illustrating the current dearth in organs for transplantation and describing the expected exacerbation of medical need for organs, rationalizing the taking on of considerable risk of using animal organs in light of great potential benefits. Indeed, they contextualize current research and urge the reader to look into the future by comparing xenotransplantation to another type of transplant surgery that was not long ago experimental:

We believe that just as the early pioneers of open heart surgery in the 1950s did not envisage heart surgery on the scale it is performed today, the physicians of the 1990s do not envisage the role of xenotransplantation as it may be in 40 or 50 years' time. The ready availability of new organs to replace diseased ones will make it unnecessary to the average patient to endure inadequate medical therapy that provides a suboptimal quality of life.

The authors elaborate on the many potential uses of xeno cells and organs, and make an excellent case for scientists' attempts to genetically engineer animals—making the strongest case for pigs. The reasons why no patients have survived for longer than 70 days after receiving a whole-organ xenotransplant are elucidated, followed by a review of all animal candidates, with pros and cons for each as candidate donors. The authors also describe the formidable hurdles of acute cellular and chronic rejection, as well as strategies to combat the activation of the complement cascade and the need to deal with production of anti-pig antibodies. Also discussed is the use of current anti-rejection drugs, their mechanisms of action and limitations, and improved specificity of newer drugs in suppressing only T cells, which generate the cellular response to an organ grafts.

Much attention is given to how donor pigs are being targeted for knockout of the α-galactose gene, although to date, only adding genes to pigs has been accomplished. The “immunological Holy Grail” of producing tolerance is then explained, along with two major approaches to this goal—that of Johannes Myburgh at the University of Witwatersrand, and David Sachs' work with mixed chimerism at Harvard. It would have been prudent, however, to explicitly state the authors' relationships with the companies involved in xenotransplantation and their particular interests.

Finally, the authors propose a means of inducing tolerance in the future: the injection of pig cells into a human developing fetus by the end of the fourth month. Though not currently possible, it may be a potential way to induce tolerance in all people if xenotransplantation becomes safe and viable, they suggest. Although they acknowledge that “mass tolerization” seems like a long shot, or science fiction, stranger things have occurred in medicine, they seem to say.

Following a strong chapter on the potential uses of xeno-organs and -tissues in diseases from diabetes to Alzheimer's, the authors deal with animal rights and zoonoses—two hot spots of public concern. Here, the authors may be overoptimistic concerning the transfer of pig viruses to humans. They state that no patients who have received pig grafts “have been found conclusively to harbor a pig endogenous retrovirus”—which is not completely accurate. Some patients have antibodies and pig cells themselves still in circulation, and it is unclear whether they have or have not been infected with viruses that are not yet known, or whether the antibodies detected in them are a sign of infection. Similarly, they state, “It is also not known if pig endogenous retroviruses will cause any disease even if they do infect the cells of the human recipient.” Although this is strictly true, we do know that humans have been infected in the last few years with Nipah virus and other pig viruses.

They do acknowledge the limitations of the human factor:

If recipients of pig organs are found to harbor hitherto unknown pig viruses that cause disease in humans, it may only take one non-compliant or irresponsible patient to begin the spread of that disease throughout the community, just as AIDS can be spread by similar individuals. There are therefore many ethical and legal questions that remain to be asked and resolved.

Indeed, this past January the FDA xenotransplant subcommittee met to grapple with the question of contacts of recipients becoming infected with and spreading pig viruses, with no conclusive resolution. Some members of the committee expressed doubt whether current use of mouse cells in transplantation can be considered 100% safe.

If it is true that legal decisions and the introduction of new laws will be influenced by the public attitude toward this kind of therapy, and will depend to a great degree on whether society embraces it wholeheartedly or not, this book has the potential to sway public debate toward the affirmative. The book largely succeeds in its readability and in making a strong case for xenotransplantation's cautious advance. My hesitancy in recommending it to the uninitiated is its somewhat overoptimistic point of view, which seems to give air to some reservations, but also may resolve ambiguities and dangers a little too neatly.

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Brower, V. The ultimate piggybank. Nat Biotechnol 18, 1011 (2000). https://doi.org/10.1038/79283

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