Without an organ transplant, he would survive only hours, and the odds of finding a viable liver that soon were slim. So his grandparents (who are also his guardians) consented to a radical experiment. Under the direction of Dr. Marlon Levy, surgeons excised the liver of a genetically altered pig named Sweetie Pie and placed it next to Robert in a saline bath. Then, after inserting tubes into vessels in the boy’s neck and groin, they began cycling his blood through the pig’s organ. “We could tell right away that it was working,” his grandmother recalls. “The blood leaving Robert’s body was grayish, but it looked normal as it went back in.” The liver was still going strong six-and-a-half hours later, when the Baylor team obtained a human donor organ and implanted it. “I was amazed when I heard what had happened,” Pennington says. He’s turning 20 years old this month, and hoping to start an Internet business.
The technology that saved Pennington’s life could very well revolutionize medicine in the coming century. Researchers on both sides of the Atlantic are now racing to breed pigs whose cells, tissues and organs could be transplanted permanently into humans, without being destroyed by the immune system. Xenotransplantation, the transfer of organs between members of different species, may someday rescue thousands of the people who now die each year waiting for accident victims to give up hearts, lungs or livers. The procedure could also generate big revenues for surgeons and biotech companies–$6 billion a year by 2010, according to some estimates. But where proponents see boundless opportunity, critics see a catastrophe in the making. They fear the new practice could unleash new plagues, by transferring obscure pig pathogens into the human population. And they argue that no effort to save an individual justifies such risks.
Physicians have tried for centuries to rejuvenate ailing patients with animal organs. As you’d expect, they’ve fared best when borrowing from closely related species, such as baboons or chimpanzees. Humans have survived for up to 71 days on baboon livers, and for as long as nine months on kidneys taken from chimpanzees. But neither of these animals shows much promise as an organ supplier. Baboon organs are too small to sustain people for long periods. Chimps are too scarce, and too nearly human, to be routinely slaughtered for spare parts. And any primate can harbor deadly infectious agents. As Harvard microbiologist Ronald Desrosiers explains, “The closer one gets to humans in the evolutionary scale, the greater the risk of transmission.” Considering that the human AIDS viruses originated in chimps and monkeys, even enthusiasts now agree that we’ll have to tap our more distant relatives for “donations.”
That’s where pigs come in. They resemble people in weight and physiology. They’re also plentiful and easy to breed and maintain. And as nonprimates, they provoke fewer ethical and safety-related concerns than chimps or baboons. Animal-rights activists oppose using any mammal as an organ factory–“The fact is, we should not live by the suffering of fellow creatures,” says Wendy Higgins of the British Union for the Abolition of Vivisection. But given that we already slaughter tens of millions of pigs for food each year, the prospect of killing tens of thousands more for medical purposes isn’t likely to spawn much popular outrage.
Physicians are already using various pig components–heart valves, clotting factors, islet cells, even brain cells–to treat human maladies. Moving whole organs from pigs into people is vastly more complicated. But researchers at Imutran of Cambridge, England, and Nextran of Princeton, N.J., are making headway. And despite all the controversy, health agencies seem content to let them proceed with caution. The U.S. Food and Drug Administration has authorized a number of experiments like the one that saved Pennington, and the British government has set up a regulatory authority to handle xenotransplantation issues. With luck, says Imutran chief operating officer Corinne Savill, the first attempt at a permanent heart or kidney transplant could occur within five years.
The technical obstacles are daunting. As Drs. David Cooper and Robert Lanza observe in their forthcoming book, “Xeno,” success will require “overcoming one of the human body’s oldest and strongest survival mechanisms.” Unless it’s blocked by anti- rejection drugs, the immune system will destroy even a reasonably compatible human donor organ within weeks. Its reaction to pig organs is far more violent. Pigs’ blood vessels are covered with galactose, or “Gal,” a sugar molecule that also happens to decorate many of the parasites and bacteria we encounter from day to day. We spend our lives generating antibodies to Gal–and when those antibodies encounter pig tis- sue, they know just what to do. They bind to Gal molecules, prompting the body to release an assortment of toxic proteins known collectively as “complement.” Our own tissues can neutralize these proteins before they cause damage. But human complement can turn an unarmed pig organ to mush within minutes.
No antirejection drug can stop this “hyperacute” reaction, but researchers at Nextran and Imutran have found a clever way around it. Their trick is to outfit pigs with the same “complement regulatory proteins” we use to shield our own tissues. By injecting a small assortment of human genes into one- and two-cell pig embryos, the scientists can occasionally produce an animal that makes these protective proteins naturally. These designer pigs still carry the Gal sugars that set off the complement cascade in humans. But because their tissues stand up to complement, they can survive brief exposure to our blood. With the advent of such pigs, says Dr. Christopher McGregor of the Mayo Clinic, “hyperacute rejection has disappeared off the radar screen” as an obstacle to xenotransplantation. For someone like Pennington, who needs an organ to sustain him for a day or two, that’s significant.
Unfortunately, hyperacute rejection is just the first of many obstacles to permanent transplantation. It’s followed within days or weeks by “acute” rejection, during which the recipient’s antibodies attack the foreign organ directly, destroying the cells that line its blood vessels. No one has yet succeeded at stalling that event in animal studies, but researchers are pursuing several approaches.
In one technique, the recipient’s blood is withdrawn and passed through a machine that separates blood cells from plasma, the watery fluid that carries antibodies and other noncellular constituents. The plasma is then mixed with synthetic Gal sugars that act as decoys, attracting anti-pig antibodies and pulling them out of circulation. When the treated plasma is returned to the body, it remains pig-tolerant until the depleted antibodies regenerate. Researchers have also tried injecting fake Gal directly into the bloodstream. Using these tricks and others, they can now keep pig hearts working for several weeks in baboons. “If we can get survival into the three- to six-month range,” says Nextran vice president John Logan, “we’ll be ready to think about human clinical trials.”
And ready to argue endlessly about the risk of spreading contagion from pigs to people. Nextran is taking elaborate precautions to keep its pigs free of known pathogens. Their water is disinfected, their air cleansed by filters, their feed composed solely of pasteurized plant products. Anyone entering the pigs’ compound has to scrub and dress for surgery. The animals are monitored for any sign of disease, and they’re screened regularly for more than 30 infectious agents, ranging from influenza to anthrax. As Logan points out, that’s more than you can say for any human organ donor.
Pigs, however, harbor some viruses that hygiene can’t eliminate. The so-called PERVs, or porcine endogenous retroviruses, are viral fossils–sequences of viral DNA that are now permanently integrated into pigs’ chromosomes. PERVs are passed along through heredity, not through pig-to-pig contact, and they aren’t known to cause any illness. In a recent study, Imutran researchers tested cells from 160 people previously treated with living pig tissues and found no evidence of active PERV infection. “Good news,” says Savill.
Critics dismiss the study as inconclusive at best, since it didn’t involve the transfer of entire organs. “You’re going to have pig cells floating around in immunosuppressed humans for 20 to 30 years,” says Jonathan Allan, a virologist at the Southwest Foundation for Biomedical Research in San Antonio. “The viruses buried in their chromosomes could become active at any time. I’m not trying to scare people into thinking they’re typhoid Marys because they’ve been hooked up to a pig liver. But there are lots of questions that haven’t been answered.” PERVs are known quantities, which we can test for and monitor, but they’re not the only potential sources of trouble. “The real worry is not all the viral agents you know about,” says Desrosiers. “It’s the even larger number you know nothing about. How do you test for something if you don’t know it exists?”
Obviously, you don’t. You either decide that some risks are not worth taking, or you take the plunge and hope for the best. Transplant surgeons are understandably eager to move ahead. “If mankind had not been able to take carefully calculated risks,” says Dr. Goran Klintmalm of the Baylor Institute of Transplantation Sciences, “Columbus would never have sailed to the New World, Marco Polo would never have left Venice.” Worldwide, only a third of the 180,000 people now in line for human organs will receive them. In the United States alone, 11 people die waiting every day. No amount of public awareness can fill that gap, for most cadaver organs are unusable. Pigs may well be the answer, but the ethical calculus is more complicated than the surgeons allow. The recipients of pig organs may win nothing more than a few months of misery–and even if they win years of good health, the hazards may prove decisive. If a virus of pig origin started killing people, says Allan, each “success” could end up costing hundreds of lives. The actual risks are incalculable at the moment, but the technical hurdles are falling fast. So let us hope for the best.
