The future is sow

In Grafton, scientists are experimenting with pig organs that one day could be transplanted into humans

by Nancy Rappaport

They look like pigs. They smell like pigs. But the 30-or-so hogs at the Tufts University School of Veterinary Medicine are not what scientists would call the "total pig."

For one, the North Grafton barn in which they mill about isn't connected to a pen or a field but to a stainless-steel surgery suite. And a woman dressed in a baseball cap and jeans tending to the 300-pound pigs is not a farmer but a senior research technician at Midas Biologicals Inc., which is working at the core of a growing scientific, ethical, and social debate.

For these are genetically-engineered animals with altered organs that potentially could be transplanted into humans in desperate need of organs such as livers, kidneys, hearts, or lungs or even bone marrow.

"What they're doing is they're making an animal model that is humanized -- a pig with organs that aren't totally pig," says William Myers, chairman of surgery at University of Massachusetts Medical Center.

These so-called "transgenic" animals -- born with organs that contain human genes -- might be the key to solving both a critical shortage of human organs and the tendency for human beings to reject foreign organs. Thus, advocates contend, the still-extremely-experimental procedure has the potential to save the lives of thousands of people.

Opponents, meanwhile, maintain that xenotransplantation -- meaning, the implantation of animal organs into humans -- is morally wrong and medically irresponsible. They object to what they see as scientists playing God with non-free-thinking animals. Of major concern is the possibility that xenotransplants could unleash deadly animal diseases onto the human population.

"It's Frankenstein science," says Lisa Lange, national spokeswoman for the People for the Ethical Treatment of Animals (PETA), a group opposed to xenotransplantation. "The UK banned it because of the very real possibility of starting a new epidemic that would make AIDS look like the flu. You're playing Russian roulette with the human population."

MIDAS BIOLOGICALS, which occupies rented space at Tufts University, is one of only a handful of companies in the United States working with new technology to create a population of transgenic animals for human transplantation. The company currently produces the animals for New Haven-based Alexion Pharmaceuticals, where, officials say, the organs are currently being tested on primates. Xenotransplantation has only rarely been attempted on humans -- and with deadly results. However, scientists say that the first viable animal-to-human transplant may be as soon as five years away.

"In the meantime, there's a lot of work to be done," says Karl Ebert, a former professor of reproductive physiology at Tufts who started Midas Biologicials in 1996. Scientists agree that there is not yet enough known about the physiology and immunology of transgenic organs or the risk of spreading animal infections, such as retroviruses, to humans. "A lot of studies have to go on before that can happen," Ebert says.

Currently, experiments involving transplanting organs into non-human primates have been unsuccessful, Ebert says. "They die fairly quickly. If we can get to six months, that's a major breakthrough. Right now we're working on a period of weeks."

One major obstacle: organs from one species cannot be transplanted into another without triggering "hyperacute rejection," in which the body's white blood cells, the lymphocytes, recognize the organ as foreign and produce antibodies to attack it. In human-to-human transplantation, doctors use immunosuppressive drugs to try to combat this problem.

Using a technology that involves the microembryotic injection of recombinant human DNA (the altered DNA), scientists like Ebert place human genes into pig embryos that are then implanted into a surrogate mother pig. By introducing the human gene into the embryo, in theory, the human body would accept the animal organ as human, and this would suppress the rejection process.

In the short term, xenotransplantation is viewed as a bridge solution -- a way to keep someone alive until a human organ becomes available.

"It can be a temporary stopgap for humans until they get an appropriate organ by allowing them to survive for some point in time," Ebert says. "More importantly, xenotransplantation might be totally acceptable and replace the human organ entirely."

FOR PEOPLE SUFFERING from life-threatening organ disease, an organ transplant is often the only "cure." Because of a critical shortage of human donor organs, animal-to-human transplants may be their only hope for survival, according to the United Network for Organ Sharing (UNOS), in Richmond, Virginia, the organization that oversees organ donations. "We're cautiously optimistic about xenotransplantation," says UNOS spokesman Bob Spieldenner. "We see it as having definite benefits; a lot of lives could be saved, but it still needs a lot of research. There are still a lot of ethical questions and other things to be solved first."

There are currently more than 58,000 patients in the US waiting to receive an organ transplant, he says. While 55 people receive an organ transplant each day, another 10 die before available organs are located and transferred to the hospital or before transplants could be completed. Last year, 20,000 people received transplants and 4000 others died waiting for them.

Meanwhile, animal-rights groups such as PETA, which has operated a human-organ donor drive since 1986, argue that possibilities to recruit human donors have not been exhausted.

Spieldenner of UNOS suggests that improvements to the registration process could go a long way in increasing the donor bank. While becoming a donor is as easy as signing an organ donor card, family members are always asked for permission, making it imperative that people make their wishes known while they are still alive. The number of people who need transplants has increased over the years as well, but the number of donors is up only slightly due, in part, to increased seat-belt use and more stringent motorcycle helmet laws.

So, if animal organs could be used even as a bridge, it might be enough to give someone time to survive and stay relatively healthy until a human organ became available, Spieldenner says. Livers are given what's known as "most urgent status" and the wait could be as short as a couple of days. For other organs with less medical urgency, like a kidney, the wait could be as long as three years, he says.

But once they receive a transplant of a human organ, a recipient's survival rate is generally very high, Spieldenner explains. For liver transplants, there is an 81 percent first-year survival rate. For kidney transplants, the chances for survival are as high as 97 percent if the organ comes from a living donor. "We have people who've received transplants and been around for another 20 years," Spieldenner says.

SINCE THE FIRST crude experiments with xenotransplants were attempted in the early 1900s, chances of survival have been grim. But during the past several years a number high-profile transplants using pig or baboon organs -- both preferred for their similar structure to human organs -- were completed with what scientists consider mixed results. In 1984, a newborn known as Baby Fae received a baboon heart that functioned for 20 days in the first neonatal cardiac xenotransplantation. In 1992, a patient at Cedar Sinai Medical Center in Los Angeles lived for 32 hours after receiving a pig liver. Scientists at University of Pittsburgh transplanted baboon livers into two humans who lived up to 70 days. In 1995, an AIDS patient who received bone marrow from a baboon died several hours after the operation due to complications from the HIV virus.

Other experiments using animal tissues have had more promising results. Pig brain cells are presently being injected into human brains to treat Parkinson's disease. And pig livers are being used outside the human body as a method for liver dialysis.

Myers, of UMass, was part of a team of top researchers of xenotransplantation that made important advances in the fight against immunological problems associated with such procedures. "We had patients who were in desperate need of liver transplants who took pig livers and used them as a form of liver dialysis to help patients survive until suitable organs became available. We've had some very dramatic results with this procedure," says Myers who tells the tale of one man's survival: "He was by all means brain dead. We were able to bridge him over to a liver transplant. He did great. This work encouraged us that xenotransplantation could be used as a bridge."

But as replacement for human organs? "Possibly," Myers says. "Do the benefits of xenotransplantation outweigh the risks? Absolutely not. At least, not right now."

ONE MAIN REASON is the risk that both animal diseases and unknown pathogens could be transmitted into the human population. Animals, including baboons and pigs, are known carriers of viruses that may be innocuous to animals but deadly to humans. HIV is an example of an animal virus that many researchers believe was transmitted to humans from monkeys.

"Retroviruses pose the most ominous of threats and might be more of an immediate concern," says Dr. Phil Nogouchi, director of the Food and Drug Administration's division of gene therapies. "However, like HIV, there might be viruses that take years to manifest," he says. "The secondary risk is that we don't know the effectiveness of the organs or how long they will last. Animals have shorter life spans than humans. The function might be adequate for animals, but will it be adequate for humans?"

The FDA, along with a handful of other government agencies, is in the process of updating a series of broad, voluntary guidelines for transplanting organs from animals to humans. The FDA is developing a national registry that could be used to follow and monitor transplant recipients for a number of years, analyzing long-term effects of xenotransplantation. Along with that is a proposal to collect patient and animal tissue samples to be held in an archive so that if a new disease were to emerge, public-health threats could be readily traced and identified.

"Xenotransplantation is an issue we struggle with constantly," Nogouchi says. "We appreciate the need for alternative sources of organs, but on the other hand, it could be so dangerous in terms of potential spread of disease that it's not warranted. Whether it's safe or unsafe, we just don't know."

One of the reasons that pigs are being used in many transgenic experiments is that, in addition to being developmentally similar to humans, pigs have very few known diseases that would be detrimental to humans, as opposed to baboons, which are known to carry a variety of diseases, Ebert says.

"Is it a risk? There's always a risk when you don't know what viral components are and how they get activated," he says. "There may be some risk in that, but if you needed a heart and you couldn't get one, you would take one."

John Lynch of Auburn admits that in the months before finally receiving a life-saving liver transplant in December, he would have gladly accepted any liver, even from a pig.

"I would have taken anything that was available to keep me alive," says Lynch, a former Worcester paramedic who contracted the Hepatitis C virus in the line of duty more than a decade ago.

"But now, in retrospect, I don't know what I'd feel like if it was an animal liver," Lynch says. "I now think about the 19-year-old who died and I got her liver. I haven't gotten to that point of being able to think of her and what she was like. I definitely would have had a harder time adjusting if it were an animal."

Len Murphy of Ayer, who has been on the list to receive a liver since January, called the thought of using a pig liver in humans "grotesque."

"I have a dog and I love that dog. I wouldn't want anyone to hurt her," says Murphy, who discovered he had Hepatitis C virus in 1971 during a physical to update his insurance coverage. "To do that to a pig, it just doesn't seem right. It sounds ghoulish to me."

Murphy, who is considered a low-priority transplant candidate because he has not become seriously ill thus far, says he hopes he never receives a transplant, even though it is the only treatment for his condition. "If an organ became available for me today I'd say, `Nah, give it to someone else.' But today I'm sitting comfortably in my house," he says. "I can tell you philosophically I hate to have something else have to suffer because of me. If you keep pigs in a pen and start putting weird organs in them, I don't like the idea. I also don't like the idea of waiting for someone to die so I can have their organs. But if my 13-year-old son needed an organ, my attitude would be different. I'd do whatever I could. Right now I'm against it. Science looks wonderful from one vantage point but very scary from another."

XENOTRANSPLANTATION stands to be a boon for the science and pharmaceutical industries, but the animals are very rarely considered in the equation, PETA's Lisa Lange says. "They're not test tubes with tails or commodities to be harvested. They feel pain, anxiety, fear -- all of this needs to be taken into consideration. Thousands of animals are dying."

It is true that all of the animals that pass through the barn door at Midas Biologicals will ultimately give their lives in the name of science, Ebert says. But they are given toys, including bowling balls and chains, to play with during their time in the barn and anesthetics to ease any pain associated with the procedures that occur in the surgery suite.

"A pig is born to make pork, but our pigs are born to make something special," Ebert says. "They are taken care of a hell of a lot better than your average farm pig. To make sure the animal is the best it can be they have to be raised in an environment that's cleaner than you'd experience in most hospitals yourself."

While many people may object to the use of higher primates in such experiments, others don't take issue with the use of pigs, since they are traditionally bred en masse and slaughtered for food.

"If it were a chimpanzee, I'd have to think very seriously about it. A pig, we're accustomed to mass producing them for food. Baboons raise issues of how far down you have to go to get to animal with `inherent dignity' that needs protection," says Robert Veatch, professor of medical ethics at the Kennedy Institute for Ethics at Georgetown University. "What's striking in xenotransplantation is that the value to humans per animals sacrificed is higher than other research involving animals. I've endorsed it in principle," he says. "The benefits are potentially enormous in terms of the people that may be saved."

Occasionally, someone may take issue with xenotransplantation on the grounds that it is inherently wrong to mix species, but those views are usually held by religious fundamentalists, Veatch says. "Most mainstream groups aren't concerned. I have found no mainstream religious group that would oppose it. The only people who would oppose are those who think the theory of evolution violates some religious belief," Veatch says. "I've heard some of those folks say you're creating a monstrosity." Mainstream Catholicism, Protestantism, and Judaism would have no objection on principle, he says.

Even if the medical and ethical questions associated with xenotransplantation can be resolved, Veatch maintains, one issue remains: the ethical dilemma that would be created if xenotransplantation proved successful.

"If xenotransplantation is perfected we'll face a huge cost of transplanting all of the organs to all the people in the world who need them," Veatch says. "As long as it's an exotic, experimental type of an idea, where you do it in an extreme case, that's one thing, but if perfected, the cost would be astronomical; we could put our entire medical budget into it. There would be no limit to the organs that could be transplanted. You'd face another ethical question of who gets to have a xenotransplant. There are 50,000-plus people who need one in the United States alone, plus everyone else in the world. So who should get them? Where do you draw the line?"