Transplanting Animal Organs Into Humans Is Feasible

USA Today (Society for the Advancement of Education), Nov, 1999 by John J. Fung

With the success of human-to-human transplantation, e need for organ replacement as grown to critical levels. (An estimated 65,000 Americans suffering from end-stage organ failure currently are awaiting organ transplantation and the number is growing each year.) The demand for organs has inspired concerted research efforts in the field of xenotransplantation--the use of animal organs as replacements for human organs. Nearly 5,000 people die each year because suitable donors are not found in time, so any progress toward expanding the pool of organs--including the use of animal organs--has implications that literally translate into human lives.

Despite heightened public awareness to address the need for organ donation, there appears to be little prospect of increasing supplies to meet current shortages satisfactorily. The ability to use animal organs successfully as permanent replacements for failing human organs would end the suffering and death of patients awaiting transplantation. (More than 10% of patients awaiting transplantation die each year because of lack of human organs.) While artificial organs may become a reality with future developments, their ability to replace complex organs, such as the liver, is likely to be years away. Recent developments in understanding the barriers to successful xenotransplantation, along with access to novel drugs and approaches to manipulate the immune system, are making xenotransplantation more clinically feasible and bringing it much closer to reality.

Case reports of using animal kidneys appeared in the early 1900s from sources including pigs, goats, nonhuman primates, and lambs, but they met with failure, as did the earliest attempts at human-to-human transplantation. In the 1960s, a number of nonhuman primate-to-human kidney transplants were attempted, due to the pressing need for organs prior to the adoption of legislation that defined brain death and allowed cadaveric donation. Even with relatively ineffective forms of immunosuppression, function of non-human primate xenografts could be demonstrated, in one patient up to nine months after transplantation of a chimpanzee kidney.

In 1963, seven patients received baboon kidneys, all of which functioned immediately. These xenografts maintained dialysis-free function for up to 60 days before failing from rejection. With advances in immunosuppression and facing a severe shortage of pediatric donor hearts, Dr. Leonard Bailey transplanted a baboon heart into "Baby Fae" in 1983. Although that immunosuppressive regimen included cyclosporine, a new antirejection drug widely used today, the heart was eventually rejected 20 days after transplantation. No further attempts at xenotransplantation were done for almost a decade, until three attempts at liver xenotransplantation were reported between 1992 and 1993.

When organs are transplanted across closely related species (e.g., baboon to human), such xenotransplants are referred to as "concordant." On the other hand, organs transplanted across widely divergent species (e.g., pig to human) are termed "discordant." These terms characterize the extent of difficulty that exists in striving for successful organ transplantation across these barriers. It is much easier to achieve xenograft acceptance across concordant than discordant combinations. Chimpanzees are considered the most biologically superior donor because they are genetically the closest to humans, but their threat of extinction precludes their use. Baboons, while not as similar to humans as chimpanzees, can be easily raised in captivity and are not an endangered species.

Pigs are available in sufficient quantities, have similar anatomy and physiology to humans, and can be bred under conditions in which they can be genetically modified. While these factors have prompted the consideration of this species as a source for clinical xenotransplantation, organs from discordant species are confronted with a formidable barrier--almost immediate rejection within minutes mediated by naturally occurring antibodies (also called preformed xenoantibodies) which are present in the recipient. Because of the difficulty in controlling such rejection (also known as hyperacute rejection), novel approaches are required to overcome this barrier to successful discordant xenotransplantation.

All humans have preformed antibodies to pig tissue, which would lead to hyperacute rejection of the transplanted xenograft. However, genetically modifying pigs--in essence, "humanizing" them--shows promise in preventing such a virulent rejection from taking place. A number of biotechnology companies and a handful of universities, including the University of Pittsburgh Medical Center, are taking a closer look at the potential this approach may yield for patients awaiting lifesaving organ transplants.

What about the controversies surrounding the field of xenotransplantation? These are extensions of debates regarding broader issues of health care, biomedical research, organ transplantation, and human experimentation. The most recent discussions have focused on the possibility that infections from the donor would be transmitted to the human species. In the broadest sense, concern has been raised for society as a whole. It is the limited availability of data on the transfer of animal-derived, infectious pathogens to humans via xenotransplantation that has endangered the debate among scientists, physicians, regulatory agencies, and public representatives.