Apr 26, 1999

May 3, 1999


Better Luck With Cells

Sidestepping The Immune System

Viruses Pose Problems

Questions and Comments
Xenotransplants: Using Animal Organs To Save Human Lives by Bruce Agnew

When surgeon Joseph Murray performed the world's first successful human organ transplant in 1954-a kidney transplant between identical twins-he had no idea what he was beginning. Today, organ transplants no longer make news: about 20,000 Americans each year receive life-saving transplants of hearts, kidneys, livers, or lungs, from people who have signed organ-donor cards or whose relatives approve the donation. But at any given moment, about 50,000 people are getting sicker and sicker while they wait for such organs-and about 4,000 die each year, still waiting.

To address the shortage of human organs, many scientists and several biotechnology companies have been working on an answer that, at first glance, might seem like science fiction: use organs from animals. The procedure is called "xenotransplantation" (from the Greek "xeno" meaning "stranger"; the "x" is pronounced like a "z" as in Xerox). And some researchers believe they are on the verge of making xenotransplantation of whole organs work-although the attempts carried out so far have not been very encouraging.

  AIDS patient Jeff Getty received a baboon bone marrow transplant in 1995.
Even if it turns out that animal organs can not be successfully transplanted, researchers also have ideas for transplanting animal cells for therapeutic effect. In fact, transplants of living animal cells into people are already are being tried-with apparent success in early experiments. For example, Suzanne Ildstad, director of the Institute for Cellular Therapeutics in Louisville, Kentucky studies bone-marrow transplantation. In 1995 she transplanted baboon bone-marrow into a man named Jeff Getty, who is infected with HIV and has AIDS. Bone marrow produces immune system cells. The hope was to replace Getty's crumbling immune system with an HIV-proof baboon immune system that could protect him from infection. Although the baboon cells functioned for only two weeks, Getty is still alive and the researchers learned a great deal.

If the potential benefits are huge, so are the barriers.

The human immune system-a complex network of defenses against disease organisms and other foreign substances that evolved over millions of years-fiercely resists even human-to-human transplants. When confronted with an organ from an animal as evolutionarily distant as, say, a pig, the human immune system reacts violently. In a response known as hyperacute rejection, antibodies that seem pre-primed to attack tissues from another species summon into action the so-called complement cascade, an array of proteins in the blood that attacks the internal walls of the transplant's blood vessels, rejecting the organ within hours or even minutes.

Microscopic sections of heart tissue from a rat-to-rat heart allotransplant (left) and a hamster to-rat heart xenotransplant (right). Examined 60 days after the transplant, the rat heart is healthy, while the hamster heart shows extensive damage. Courtesy A. J. Demetris, M.D., University of Pittsburgh Medical Center.

Even if hyperacute rejection can be tamped down, the human body mounts a more vigorous long-term attack on animal organs than it does against transplants of human organs. More blood cells, primarily B lymphocytes and natural killer cells, join the attack on the foreign tissue. Today, physicians can suppress many immune responses with drugs such as cyclosporine, FK506, and prednisone. These drugs are used in human-to-human transplants, known as allotransplants. In xenotransplants, heavier doses are required, and the patient's immune defenses against infectious organisms may be crippled.

This is exactly what happened when Thomas Starzl, of the University of Pittsburgh Medical Center, transplanted baboon livers into two patients with hepatitis in 1992 and 1993. Both patients died, not from a rejection response to the transplants but from runaway infections caused by microbes that are common in the environment and in the human body.

"There were probably some unusual rejection mechanisms that we haven't quite figured out," says John Fung, a member of Starzl's team. "But the real reason they died was from everyday bacterial and fungal infections, because their bodies were so immunosuppressed from the drugs."

The easiest way to deal with immune-system rejection of xenotransplants would be to sidestep them-to use organs from the animal that is the closest possible to human beings. That, of course, is the chimpanzee, whose genome is more than 98 percent identical with the human genome.

But chimpanzees are an endangered species. They are costly to raise, and they grow slowly to adulthood. Chimpanzees may also harbor unknown viruses that do them no harm but that might cause devastating diseases in humans-diseases that might be transmitted to other people. For example, researchers have strong evidence that HIV crossed into humans from chimps during the first half of this century. The term for such a species leap is zoonosis, and the term that is becoming accepted for an animal-to-human leap because of a xenotransplant is, naturally, xenozoonosis. (See sidebar Viruses Pose Problems").

Too Much Like Us? Kanzi, a pigmy chimpanzee (Bonobo), has been taught to communicate with humans using lexigrams on a computer keyboard. Even if chimpanzees were not an endangered species, their close relationship to humans makes them an unlikely source for xenotransplant organs.

Finally, the use of chimpanzees for xenotransplant organs would raise a fierce ethical storm. The question of whether humans have a moral right to take an animal's organs even to save a human life already concerns bioethicists and animal-rights advocates. Most bioethicists conclude, as did cell biologist Ernest Prentice, of the University of Nebraska Medical Center in Omaha, and his colleagues in a 1995 paper, that "pitting the life of a human being against the life of a baboon and to a much greater extent the life of a pig is effectively a 'no contest.'" But use of an endangered species might change the calculation.

Animal-rights advocates, however, oppose all xenotransplantation as "speciesism"-the contention, which they reject, that a human being has a higher moral value than an animal. Their argument would probably have its greatest public appeal in the case of chimpanzees, which may be just too much like us. Some researchers who study the cognitive abilities of chimpanzees say that they are capable of reasoning, learning language, and communicating with humans-not about philosophy, but certainly about wishes and perhaps about emotions.

For all these reasons, most xenotransplantation researchers agree that chimpanzees are not suitable organ donors. Researchers also appear to agree that other "higher" nonhuman primates such as baboons are out, too. Although organs from these animals are less likely than those of more distant species to set off hyperacute rejection, they, too, harbor microorganisms that might leap to humans easily and with dangerous consequences. And like chimpanzees, baboons are costly to raise and, in some cases, suffer from population decline.

Human and pig parts are similar, but not identical. But for transplants, the fit may be close enough.
Strange as it may sound, the animal that is emerging as the most likely source of transplantable organs is the pig. Pigs' organs are the right size. The animals are highly domesticated, they have large litters, and they grow quickly to maturity. They can be raised in sterile environments, which would reduce the likelihood of transmission of at least some pig diseases to humans. Many researchers, however, still worry about viruses that are unknown or that have become part of the animals' genome and cannot be dislodged.

Unfortunately, pig organs have molecular characteristics that make the human immune system react violently. But there may be ways around that, and researchers are exploring at least two quite different approaches. (See sidebar: "Sidestepping The Immune System").

Despite the obstacles, some xenotransplantation experiments involving humans are going on today-although not whole-organ transplants. (See sidebar: "Better Luck With Cells"). By the end of 1998, says Amy Patterson, a scientist with the NIH Office of Recombinant DNA Activities, more than 200 people in the United States had received xenografts of animal cells or tissues. These experiments included implanting fetal pig neurons into the brains of people with Parkinson's disease, and using plastic-wrapped pig liver cells to cleanse the blood of people with liver failure, keeping them alive until a human donor liver can be found.

Researchers who would transplant whole organs have another big, unanswered question-how well will the animal organs will work in the human body? "Will the pig heart, for example, or the pig kidney function in a normal way in the human as it did in the pig?" asks Jeffrey Platt, of the Mayo Clinic in Rochester, Minn. So far, the signs have been "encouraging," he says, "but this is clearly an issue with which we need to grapple."

Web Resources

Kidney Transplantation: Past, Present, and Future is a site prepared by the Stanford University program on the History and Philosophy of Science. It includes a good discussion of xenotransplantation issues generally (see section on "Xeno") as well as information about donation, and the development of transplantation surgery.

Can We Transplant Organs From Animals? is a very easily understood (if a bit simplified) account of xenotransplantation from The Why Files, a project of the National Institute for Science Education and the National Science Foundation.

Xenotransplantation: An Anglo-American Update is a scholarly overview of legal and ethical issues surrounding xenotransplantation. Written by Andrew Trew, LLB, International Scholar at the Cleveland Clinic in Ohio.

Print Resources
Robert P. Lanza, David K. C. Cooper and William L. Chick, "Xenotransplantation," Scientific American, July (1997).

Jeffrey L. Platt, "New directions for organ transplantation," Nature 392, 11-17 (1998)

"Last chance to stop and think on risks of xenotransplants" Nature391, 320-324 (1998).