Will Pig Organs Bring a New Era?

Sometime this fall, English researchers will take the heart of a genetically engineered pig and implant it in a human whose own heart is dying.

It will not be the first time surgeons have attempted to use an animal organ in a human. But it may well be the first time such a transplant succeeds because researchers have given the pig heart human genes that make it less likely to be rejected.

The ability of biotechnologists to create “transgenic” animals with human immunological characteristics, combined with the development of powerful anti-rejection drugs, has brought surgeons to the brink of a new era, in which animal organs may routinely be implanted in humans.

That gives hope to many patients and doctors who are buoyed by sharply increasing success rates for human organ transplants, but frustrated by the shortage of donors. Because the demand for organs has grown while the supply of donors has remained constant, many patients whose lives could be saved die on transplant waiting lists.

Proponents argue that so-called xenotransplants of kidneys, livers, hearts and even brain cells could save the lives of tens of thousands of patients each year.

Tempering that promise, researchers still face a number of stumbling blocks, both scientific and ethical. And many scientists fear that transgenic organs will be a source of infectious diseases rivaling AIDS in their potential for devastation.

“Xenotransplantation is critical to the future of transplantation” if all the scientific hurdles can be overcome, said Dr. Hugh Auchincloss Jr., an animal transplant researcher at Massachusetts General Hospital in Boston.

The field seems poised for a major expansion from the laboratory to the clinic.

Britain’s main bioethics advisory group recently approved the use of pig organs in humans. The U.S. Food and Drug Administration and the Centers for Disease Control and Prevention are on the verge of issuing broad guidelines permitting xenotransplants.

Some researchers already have been trying such operations. Baboon livers have been used in several unsuccessful operations. Surgeons at Duke University Medical Center are expected to begin using pig livers--which are more widely available--later this year.

Fetal pig cells have been transplanted in the brains of at least five people with Parkinson’s disease in an effort to replace dead brain cells. Results have not yet been reported.

If the experiments with pig hearts and livers are successful, transplants of pig kidneys and lungs may follow quickly.

“We’re flush with excitement, but it’s a long road ahead,” said Dr. Fritz H. Bach, a transplant surgeon at Harvard Medical School.

The driving force behind using animal organs is the rapid improvement in human organ transplants. New anti-rejection drugs, new preservation methods and refinements in surgical techniques have greatly improved the survival rate of transplanted organs over the last five years while cutting the procedure’s cost nearly in half, according to Dr. Ronald W. Busuttil, head of the liver transplant program at UCLA. The cost of a transplant ranges from $50,000 for a kidney to as much as $200,000 for a liver.

These changes have triggered a sharp increase in transplants in the United States--from 12,786 in 1988 to 19,017 in 1994, according to the United Network for Organ Sharing.

But this 49% increase has been accompanied by only a 37% increase in donors, to 8,114. (Several organs can be taken from one donor.)

Meanwhile, the number of patients on waiting lists more than doubled during that period, to 56,066 in 1994. In that year, 3,072 patients died waiting for organs. Perhaps as many as 100,000 more died before even getting on a list.

“These are patients who would most likely be alive today if only there had been enough organs to go around,” said O. Patrick Daily, assistant executive director of operations for the organ sharing network.

But humanitarian concerns are only part of the story. Financial analysts suggest that successes with xenotransplants could lead to at least 100,000 such operations every year at an average cost of $10,000 per organ. This potential billion-dollar market for breeding the animals and supplying organs is enticing several biotechnology companies into the arduous and scientifically challenging field.

Some people express concern that patients’ desperation and the financial allure may be seducing surgeons into premature experiments with animal organs.

“I desperately want to do it [perform xenotransplants],” said Auchincloss, who has been researching the subject for more than a decade. “But I don’t think we are ready to do it in people, because it isn’t going to work.” Researchers, he argues, have not credibly demonstrated that the organs will survive in humans.

Others are disturbed by ethical questions involving the concept of animal-to-human transplants. Some critics say such operations are callous and exploitative. “We’re completely opposed to [xenotransplants],” said Lisa Lange of People for the Ethical Treatment of Animals. “Many animals have been killed for these needless experiments.”

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Surgeons tried xenotransplants long before the first successful human transplants were done in the 1940s. In 1905, a French surgeon tried to implant slices of rabbit kidney in a young girl. In 1923, a surgeon tried to transplant a lamb kidney. Both attempts failed.

It wasn’t until October 1984 that xenotransplants gained widespread public attention. Dr. Leonard Bailey of Loma Linda University Medical Center transplanted a baboon’s heart in 2-week-old Baby Fae, whose heart was fatally underdeveloped. She survived 20 days before her body rejected the baboon organ. Bailey has not attempted the procedure again.

Baboons were a natural choice for surgeons because they are closely related to humans. In particular, they are not susceptible to the immediate reaction--called hyper-acute rejection--characteristic of organs from other animals. When this happens, the recipient’s immune system shuts off blood flow to the donor organ within hours or even minutes, causing it to blacken and die.

But baboon organs, like other animal organs, do experience delayed xenograft rejection. This can take days to weeks and is similar to--but more intense than--the rejection encountered during a transplant of mismatched human organs. Surgeons have high hopes that they can control this delayed rejection with new drugs and other techniques.

Bolstered by those hopes, scientists in San Francisco recently transplanted baboon bone marrow in 38-year-old AIDS patient Jeff Getty. Surgeons at the University of Pittsburgh and elsewhere have tried to implant baboon livers in humans at least five times. None of those procedures has succeeded, but it seems likely that researchers will continue trying because the organs are naturally immune to the AIDS and hepatitis viruses.

But baboon organs contain their own natural viruses. Critics such as Jonathan Allan, a virologist at the Southwest Foundation for Biomedical Research in San Antonio, argue that these viruses present too great a risk. Animal viruses that are harmless in their normal hosts sometimes can take on vicious characteristics when they find themselves in a new and unusual host--such as a human body.

The AIDS epidemic almost certainly started when an African villager ate a monkey that carried the virus. Deadly Ebola virus outbreaks have occurred when people ate infected chimpanzees or were scratched or bitten by them.

A transplant only intensifies the process, making it much easier for the virus to do its dirty work, experts say. Instead of fighting its way through stomach acids and digestive enzymes, the virus has a direct path to the bloodstream.

Perhaps even more important, the viral intruder faces an immune system largely defanged by anti-rejection drugs. And baboons are related to humans closely enough that their viruses could find a ready foothold in a human.

“The question isn’t whether viruses will be transmitted via [transplants],” Allan said. “They will. The question is which viruses, will they cause disease and, if so, how serious?” Such concerns about primate organs, he said, “preclude their use as donors.”

The worries of critics are “hypothetical--that the transplant could contain a new, unidentified, cancer-causing virus,” said Dr. Suzanne Ildstad of the University of Pittsburgh Medical Center, who pioneered the procedure used on Getty. That theoretical risk is extremely small, she said. And even if infection should occur, she added, patients are briefed on ways to prevent its spread.

Baboons also present more practical problems that may prevent their use. The animals are expensive, they take a long time to raise to adulthood and their organs often are too small for adult humans. These factors, more than fears of viral contamination, may drastically limit their use.

For these reasons, surgeons are turning to pigs.

Pigs have organs that are the right size for human transplants. They mature quickly, have large litters and are easy to raise. Perhaps more important, some researchers believe they have found a way to overcome hyper-acute rejection involving pig organs.

The reaction is caused by a sugar molecule called alpha-gal that studs the interior of blood vessels in pigs and most other animals. Antibodies in humans recognize these molecules as foreign and immediately clamp onto them. This triggers an immune system attack that quickly kills the organ.

Human blood vessels, in contrast, bear molecules that prevent this process. The key advance in xenografting occurred last year when two companies, Nextran Inc. of Princeton, N.J., and Imutran P.L.C. of Cambridge, England, independently began producing pigs that had these molecules.

Both companies inject selected fragments of human DNA in fertilized pig eggs. Blood vessels in the resulting piglets are studded with two or more types of the molecules found in humans.

Immunologist David J.G. White of the University of Cambridge, founder and director of Imutran, reported in November that transgenic pig hearts survived for five days when transplanted in baboons, compared to only one hour or less for normal pig hearts. If anti-rejection drugs were used, the transgenic hearts survived two months or longer.

The results, White says, suggest that hyper-acute rejection “is a thing of the past.” Now, researchers are confident that they also can overcome delayed rejection.

The Imutran team would like to see xenografts survive somewhat longer in baboons before proceeding to human trials. But White predicted that such tests could begin within 12 months.

A team from Nextran and Duke University Medical Center has reported similar success with transgenic pig livers. Dr. Jeffrey L. Platt and his colleagues at Duke last year received FDA permission to connect livers to 10 patients’ bloodstreams, while keeping the organs outside the body--as a short-term measure while human donors are sought. If those grafts are successful, the team will begin implanting pig organs in human subjects.

Two companies, Alexion Pharmaceuticals Inc. of New Haven, Conn., and BioTransplant Inc. of Cambridge, Mass., also are developing transgenic pigs as organ sources.

The animals are raised in sterile environments to minimize exposure to potentially dangerous viruses, although most researchers believe there is little danger that pigs will transmit such viruses to humans. After all, White says, humans have been eating them for millennia and diabetics have been injecting insulin from pigs for 70 years.

Even Allan concedes that there appears to be little risk from using pigs.

“The nice thing about using pigs is that you know who the donor is going to be weeks or months before the transplant,” White said. “It’s not like you are waiting for someone to fall off his motorcycle.”

Delayed rejection can be controlled with high doses of anti-rejection drugs, but they leave the host susceptible to viruses, other infections and cancer.

In White’s trials, the first monkeys who received transgenic pig hearts had to be destroyed because they developed a gastrointestinal illness, probably from a viral infection that their depressed immune system could not fight off.

The anti-rejection drugs themselves also are toxic. Pittsburgh’s Ildstad cites studies on human-heart transplant patients indicating that one in 10 developed kidney failure because of drugs.

Many researchers thus are seeking ways to minimize the use of such drugs. One of the most promising involves training the host’s immune system to “tolerate” the transplant.

This approach is inspired by the fact that some human-organ recipients have been able to wean themselves off anti-rejection drugs. Immunologists theorize that the grafted organs held small amounts of the donor’s bone marrow stem cells--the immature white blood cells from which all other blood cells are derived.

Scientists believe that as these donor stem cells mature in the recipient’s body, they suppress the recipient’s immune reaction to the transplanted cells. In effect, they teach the body to tolerate the grafted tissue.

A team from BioTransplant and Massachusetts General Hospital has transplanted pig bone marrow in monkeys, using anti-rejection drugs only for the first 30 days. The marrow has survived for more than 300 days in some animals, giving them an immune system that is part monkey, part pig.

As a result, said Dr. David H. Sachs of Massachusetts General, the monkeys’ immune cells do not react to the pig cells as foreign. The team hopes that this technique can be combined with transgenic organs to lengthen a transplant’s life, he said.

Given this and other advances, researchers say, animal-to-human transplants seem all but inevitable.

Said Dr. Thomas E. Starzl, a transplant pioneer at the University of Pittsburgh: “I don’t think it is going to be possible to put the genie back in the bottle.”

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Shielding Organs From Rejection

When an animal organ is transplanted into a human, it undergoes an immediate trauma called hyperacute rejection that causes it to turn black and die, usually within hours. Hyperacute rejection is triggered by a sugar molecule, called alpha-gal, that studs the interior of the blood vessels within the organ.

NORMAL PIG

1) Interior of blood vessels in pig organs is studded with molecules called alpha-gals.

2) After a transplant, lymphocytes in the human immune system attack alpha-gals, clogging the vessel and cutting off oxygen flow.

GENETICALLY ENGINEERED

3) In genetically engineered pig organs, human proteins cloak alpha-gals so they are not attacked by lymphocytes.

Researched by THOMAS H. MAUGH II / Los Angeles Times