Xenotransplantation: Promising advances cause excitement, uneasiness

In Italy, the Vatican has recently endorsed transplanting animal cells, tissues, and organs into humans. In Canada, the government has sought the public's opinion on the issue. And, in the United States, the Food and Drug Administration has released proposed guidelines recommending that recipients of such transplants and their intimate contacts should not donate blood or blood plasma. Xenotransplantation is on a lot of people's minds these days.

Continuing with this trend, researchers at the recent annual meeting of the American Association for the Advancement of Science discussed the science, ethics, and policy behind developing the transplantation technique. Recent advances are moving the science ahead, but some warn that the public needs to be consulted before work continues.

Xenotransplantation is not new. French and English scientists first attempted to transfuse blood from animals to humans in the early 1600s. And throughout the 20th century, scientists attempted to transplant chimpanzee and baboon organs into humans, achieving survival ranging from a few hours to nine months.

In recent years, researchers have switched their focus from primates to pigs, a species deemed by the public to be a more acceptable donor, given that, in the United States, we currently slaughter one hundred million of them each year for food and transplant sixty thousand pig heart valves into humans. Pigs also grow quickly to a size adequate for human use and have large litters, making them inexpensive to use, compared with primates. But there are, as one would expect, rejection problems.

Miniature swine at three weeks of age

Among the biggest stumbling blocks for researchers are certain galactose sugars (galactoseα1, 3 galactose), which line the cells in the walls of pigs' blood vessels. These sugars are also found on the surface of various bacteria and viruses and, as a result, many primates have developed antibodies against them. When a pig organ is put into a primate, antibodies spring into action, attaching to the sugars and activating complement protein that punches holes in blood vessels. This so-called hyperacute rejection occurs within minutes of a transplant and renders the organ nonfunctional.

In experiments, researchers have been able to block this complement attack temporarily, only to find that a second phase of rejection follows—acute humoral. This rejection is also initiated by an antibody response against the galactose sugars but does not work by the same mechanism, said David Cooper, MD, PhD, an immunologist at the Transplantation Biology Research Center at Massachusetts General Hospital.

"We think it is initiated by the antibody binding, but we don't think complement is involved because you can block complement and still get it," said Dr. Cooper, who spoke at the AAAS meeting. He believes that organs from genetically engineered pigs that do not produce these sugars will evade the first two rejection phases. Researchers would then be left with a more familiar problem to tackle.

"A galactose knockout pig should get around these first two problems, and then we will probably see cellular rejection, which is what we see in human-to-human or pig-to-pig transplants," he continued. "We think we can manage [this] with the drugs we have, because we can manage human-to-human cellular rejection."

Researchers might be moving on to this familiar problem in the next year. On Jan. 4, 2002, researchers from the University of Missouri-Columbia and Immerge BioTherapeutics published a paper in Science announcing that they had cloned the world's first pig that was genetically engineered to lack the gene that induces the culprit sugars.

"We've knocked out one copy of the gene," said Randall Prather, PhD, MD, a professor of reproductive biotechnology at the University of Missouri, in a recent interview with JAVMA. "We now need to breed them so we get an animal that is a homozygous knockout or go through some molecular gymnastics and clone another one that has both genes knocked out."

The first pigs, born in September and October 2001, were also miniature, making their organs more appropriate for human recipients. Subsequent to this announcement, a second company, PPL Therapeutics, announced it has also created a galactose knockout pig.

While scientists are working on overcoming issues of organ rejection, however, other researchers urge caution. One is Fritz Bach, MD, a Harvard professor of immunology who also spoke at the AAAS meeting. He recommends that the government consult the public, citing the possibility that animal diseases could spread to humans. In particular, he worries about porcine endogenous retroviruses.

These viruses lurk in most animals, including humans, and are harmless to their host. But scientists are concerned that some swine retroviruses might cause disease in humans. Another possibility is that porcine endogenous retrovirus segments may combine with human endogenous retrovirus segments and form a new virus that may be pathogenic to humans or pigs.

"Most porcine endogenous retroviruses can get into human cells in culture, in the laboratory, but there are families of pigs that have PERVs that cannot infect human cells," Dr. Cooper said.

And this is exactly what researchers are focusing on. According to Dr. Prather, his team's genetically engineered pig is from a family that does not transmit endogenous viruses to human cells, at least in test-tube studies. He hopes that further tests will confirm this.

Other nonendogenous viruses, including Japanese encephalitis or pseudorabies may cause problems, but many scientists believe they will be able to control them through breeding or genetic engineering. But how should the possibility of unknown diseases be weighed?

"I don't think progress should stop because of unknowns," Dr. Cooper contends.

Dr. Bach, however, argues for a moratorium until the public can be consulted about the risks and the acceptability of the procedure. "What we are dealing with in xenotransplantation is individual benefit versus the possibility of collective risks."

He says that the United States should follow the example of countries such as Canada. Last year, Canada established a number of citizen juries to discuss the issue, allowing the juries to talk with panels composed of bioethicists, transplant surgeons, immunologists, and organ recipients. After workshops and discussions, the juries produced a joint report advising that preclinical research continue, the public be educated, and officials develop strict regulations to control eventual xenotransplantation.

Edna Einsiedel from the University of Calgary, who described the public consultation process at the AAAS meeting, said that the Canadian government would decide later this year which of the recommendations to follow.

"We need to approach this and involve the public," Dr. Bach advised. "Xenotransplantation, or the lack of it, is something for all of society to decide, not by any small outspoken group like surgeons." Not only does the disease risk need to be discussed, he continued, but, if people are offended by the idea of putting pig organs into humans, then this also needs to be addressed.

A worry of Cooper's is what he calls "xenotourism", scientists shopping around the world for research institutes in a country with less stringent regulations where they can conduct their research. The World Health Organization, he says, needs to step up to the plate and oversee some sort of international xenotransplantation regulatory framework.

Even if scientists can overcome rejection, disease, and societal objection hurdles, there is one final factor that might foil xenotransplantation success. "We have an upright posture, the size of red blood cells are different, [and] pigs' temperatures are five to six degrees higher than human temperatures," said Dr. Cooper, noting that these differences might cause problems. "There may be a whole new science of xenoincompatibility." His optimism, however, stems from the fact that pig organs function well in baboons for two to three months.

"We believe there is a basis that some of [the organs] will function well," Dr. Cooper said. "I predict that xenotransplantation is going to be the future of transplantation."