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.

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. 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. In another experiment, researchers at CytoTherapeutics, Inc., in Lincoln, R.I. implanted cow adrenal cells—which produce a natural painkiller—into the spinal columns of patient suffering intractable pain. The cells survived and functioned, but the patients unfortunately felt no pain relief.

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.

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.

Most xenotransplantation researchers agree that chimpanzees are not suitable organ donors. Researchers also 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.

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 attack mercilessly. But there may be ways around that, and researchers are exploring at least two quite different approaches.

One way is to change the pig, through genetic engineering. Using existing laboratory techniques, several research teams have deleted specific pig genes—and added specific human genes—to make pig cells seem, as John Fung, of the University of Pittsburgh Medical Center puts it, “less piggish.” For example, Imutran, a biotechnology company in Cambridge, England, and Nextran Inc. in Princeton, N.J., have developed pigs that carry human genes that block activation of the complement system—and thus presumably will prevent hyperacute rejection.

Other researchers are have modified a sugar molecule that appears on cell surfaces in most mammals—but not in humans and their close primate relatives. This molecule, galactose alpha-(1-3) galactose, is apparently the target for the “xenoreactive antibodies” that all adult humans have, says Jeffrey Platt, of the Mayo Clinic in Rochester, Minn. So researchers are trying to insert into pigs a human gene that will replace the pig molecule with a human sugar residue, fucosyl transferase. Whether the transgenic pigs will function normally—and whether their organs won’t provoke the human immune system—is not yet known

Suzanne Ildstad, director of the Institute for Cellular Therapeutics of the University of Louisville, and other researchers are taking a very different approach. They are trying to alter the immune system of the transplant recipient so that the person will more easily tolerate a xeno—or, for that matter, human—transplant. Ildstad induces “tolerance” by giving the transplant recipient an infusion of specially purified bone-marrow cells from the donor. If the donor’s marrow cells survive and function to produce mature blood cells, the patient’s immune system becomes “chimeric.” It includes some blood cells that belong to the patient and some that are produced from the donor’s bone marrow. And in experiments with animals, Ildstad has found that the chimeric immune system accepts both same-species transplants and xenotransplants.

Ildstad has performed three human-to-human heart transplants using this technique, and she plans to try it with kidney transplants, too. In experiments with rats and mice, she has shown that inducing a chimeric immune system also gives xenotransplants a better chance of success.

Despite the obstacles, some xenotransplantation experiments involving humans are going on today—although not whole-organ transplants. By the end of 1998, says Amy Patterson, a scientist with the NIH Office of Biotechnology 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 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.”

This was originally published by The National Institute of Health