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
