Transplant Researchers Favor Miniature Pig for Donor Organs
Associated Press (August 7, 2001)
BOSTON -- Unlikely as it sounds, one solution to the shortage of organs for transplant could be the miniature pig, an animal that is already a lot like us and getting more so in the hands of genetic engineers.
The miniature pig is miniature in the same sense that professional basketball guards are short or the Earth is a small planet. It weighs 300 pounds -- one-third the regular size -- but otherwise is unmistakably all pig, a porky round creature that grunts and smells just like the barnyard kind.
However, the miniature pig's relatively dainty dimensions have caught the eye of scientists, who note that it is about the size of a really large person. This means it is filled with nicely proportioned innards, especially a human-size heart and kidneys.
For this and other reasons, the pig is regarded to be the most practical untapped source of needed body parts for sick and worn-out people. Perhaps 20 labs around the world are working to make pig parts fit for human transplants.
The goal: Clone and genetically modify pigs to "humanize" their organs. As that word implies, the animals are being changed in fundamental ways so they are less like pigs and more like people.
Researchers have already implanted some of these pig organs into baboons with modest success. Big scientific challenges still loom, but within five years, if all goes well, they hope to try them on people, offering redesigned pig hearts, kidneys and other organs to the desperately ill.
The idea of transferring whole organs from animals to people has intrigued doctors for a century. The most famous patient, 12-day-old Baby Fae, received a baby baboon's heart in 1984. But like all such operations, that one ended in failure, and the infant died 20 days later when her body rejected the heart.
Those attempts were crude, compared with the current round of genetic manipulation and immunological tinkering by biotech firms, pharmaceutical companies and academic labs racing to make xenotransplantation, as it is called, a medical reality. (The word comes from the Greek xenos, which means foreign.)
If it works, the result will be limitless organs for human use. The idea hardly seems farfetched to many transplant specialists, who watch thousands of patients die each year because of the shortage of human parts.
"I think it would be wonderful if we had a safe supply of organs that work as effectively as humans'," says Dr. Patricia Adams of Wake Forest University, immediate past president of the United Network for Organ Sharing.
According to the network, which manages the national transplant waiting list, about 77,000 Americans were in line for transplants last year, while 23,000 actually received them. The waiting list is growing five times faster than the supply.
Those numbers understate the shortage. Because transplant rules are so strict, many who could benefit never make it onto the waiting list. For instance, hospitals generally won't consider heart transplants for anyone over age 65, no matter how healthy they otherwise are.
So without enough organs from cadavers, many believe the best alternative is animals raised in germ-free barns near hospitals.
But oinkers?
"Although it seems illogical, most people agree that the alternative species that makes the most sense is the pig," says Julia Greenstein, president of Immerge BioTherapeutics, a Boston company created this year to develop pigs for transplants.
While a few champion the sheep or even the cow, agreement seems nearly unanimous among researchers that the pig is the xenograft donor of choice.
Certainly humans have nearer relatives that in some ways would be easier donors, because their tissue is less foreign to the human body. For instance, organs taken from chimps could probably survive with nothing more than immune-suppressing drugs, but the animals are endangered, and many would object to using humans' closest cousin for this purpose. While baboons are reasonably abundant, their organs are too small for adults.
Furthermore, taking organs from such closely related creatures could be risky. Apes and monkeys could carry viruses that are harmless to them but deadly to humans. The best example of this xenozoonoses is the AIDS virus, which probably evolved in chimps and is harmless to them but deadly to people.
So pigs' evolutionary distance from people -- somewhere between 50 million and 100 million years -- is one item in their favor. Of course, pigs have their own germs, and scientists take them seriously. But because the animals are so unrelated, many believe chances are slim their viruses would make people sick.
Supply certainly isn't a problem. Americans slaughtered 98 million last year. And their place on the food chain also probably means most wouldn't have ethical qualms about pigs for transplants.
"It is far more legitimate to have pig organs for human survival than pig meat for the supermarket. I think that's a slam dunk," says Harold Vanderpool, a bioethicist at the University of Texas Medical Branch who heads a xenotransplant advisory committee for the U.S. Department of Health and Human Services.
But the biggest advantage of pigs is the striking similarity of many of their organs. For instance, their hearts are plumbed almost identically to people's. Theirs beat 95 to 115 times a minute, ours 60 to 100. The pig kidney, lung, pancreas and possibly even the liver appear similar enough to humans.
Some companies are concentrating on standard pigs, which reach about 1,000 pounds, on the theory that their organs will stop growing once they get large enough to keep a human alive. They note that a young rat's heart, when transplanted into a mouse, never grows to full rat size. But whether the same will be true for people with hearts from young ordinary pigs is unknown.
The leading advocate of using the smaller organs of the miniature pig is Massachusetts General Hospital surgeon and immunologist David H. Sachs. "The miniature swine has the potential to donate an organ to any human being dying of organ failure," he says, "from a newborn baby to a sumo wrestler."
Dr. Sachs has been working with them for about 30 years. He started with two strains of naturally undersize domestic pigs that had escaped to the wilds high in the Rockies and Andes. By inbreeding, he developed a line that is 94% genetically identical.
Like others in the field, Dr. Sachs is working to overcome the single biggest drawback to xenotransplantation, which is the human body's dogged resistance to accepting foreign flesh.
If an ordinary pig organ is transplanted into a human, the body will destroy the blood vessels and kill it within hours. This hyperacute rejection, as it is called, occurs because pig cells are coated with a sugar known as alpha-1-galactose, or alpha-gal.
Every creature from bacteria up to New World monkeys has this sugar. But Old World primates and people don't. As a result, people have antibodies in the bloodstream that immediately latch onto this sugar, starting a violent attack.
"It's almost as though the body senses the organ to be a large microbe and goes out and destroys it," says Dr. Jeffrey Platt of the Mayo Clinic.
Antibodies kill the organ by triggering a cascade of enzymes called complement. One solution: Turn off the complement.
Scientists make pigs that carry a human gene that shuts down this process. While it prevents immediate rejection, antibodies still build up on the foreign sugar. The result is inflammation that kills the organ within weeks rather than hours.
So scientists would like to get rid of the antibodies entirely. Their approach is to eliminate the sugar that attracts them. Biotech companies are now working to produce "knock-out pigs," so called because the gene for alpha-gal has been knocked out of every cell in their bodies.
"Most of us agree it's an essential step forward, but it's not a solution," says Alan Colman, research director of PPL Therapeutics in Edinburgh, Scotland.
Besides getting rid of alpha-gal, it may be necessary to add four or five other genes, including some that prevent blood clots, he says. "That's just for starters. Whatever you do, it's difficult to fool the recipient about the fact the organ is foreign."
Dr. Sachs says not all this genetic engineering may be essential. Instead, it may be possible to stop antibodies from forming by training the human body to accept a pig organ as its own. The body's response to transplants is regulated in part by blood cells called T cells. These cells are programmed in the thymus gland, which eliminates any T cells that mistakenly target the body's own tissue.
Dr. Sachs reasons that if a xenotransplant recipient is given a pig thymus, too, it may convince the immune system that the pig organ is its own standard equipment. To do this, surgeons would first operate on the pig, attaching part of its thymus to the organ of interest. After it heals, this combination organ -- a thymokidney or thymoheart -- would be implanted in the patient.
The idea shows promise in animal-to-animal transplants, but if it fails, Dr. Sachs has another strategy. The thymus gets cues about what's foreign and what's not from the bone marrow. Perhaps giving the xenotransplant patient some bone marrow taken from the same pig that provides the organ will make the immune defenses tolerate the new tissue.
Will these combinations of genetic and immunological manipulation work? Dr. Sachs thinks so.
"I'm the first to admit that even after we solve each problem, there could be another one lurking," he says. "I can only say I don't know of another one right now. That's why I'm so excited." |
