One scenario envisions doctors delivering a limitless supply of livers, hearts and other organs to save the lives of countless transplant patients. In another, doctors unwittingly release a horrific plague upon unsuspecting millions.

In the controversial field of xenotransplantation, or the transfer of cells, tissues and organs from one species to another, the wildly divergent prophecies offer a glimpse of the potential glories and perils attached to none other than the common pig. Proponents view the quest for animal organs as one of the most realistic solutions to the human organ donor shortage, a deficit they say cannot be overcome by organs from living donors or cadavers alone.

"Xenotransplantation has appeared to me to be a potential solution to an enormous number of people who would die otherwise without an organ,” says Dr. David Sachs, a surgeon at Harvard Medical School and director of the Transplantation Biology Research Center at Massachusetts General Hospital.

Dr. Marlon Levy, the surgical director for transplant surgery at Baylor All Saints Medical Center in Fort Worth, Texas, calls a limitless supply of organs or cells the "Holy Grail” of transplantation. "And at least on the organ side of things,” he says, "the answer is using animal organs.”

Critics, on the other hand, joke that the future of transplantation is xenotransplantation -- and always will be. Others declare more soberly that the procedure poses the unacceptable risk of allowing potentially deadly viruses to accompany the transplanted animal organs, first into human patients and subsequently into the general public.
"In my opinion -- and I am not alone on this -- putting animal cells and tissues or organs into humans is kind of like playing Russian roulette,” says Alan Berger, executive director of the Sacramento, Calif.-based Animal Protection Institute and a member of the U.S. Secretary of Health's Advisory Committee on Xenotransplantation.

No matter what their position, most doctors and researchers admit the field faces other vexing questions, such as whether pig organs can evade initial rejection by the human immune system, and whether they will function properly afterward.

In 1963, in New Orleans, Tulane University surgeon Keith Reemtsma performed the first xenotransplants of the modern medical era, using chimpanzee kidneys. A pair of the transplanted organs worked for nearly nine months in one patient.

Since then, doctors have tried transplanting hearts, kidneys and livers from baboons, chimpanzees, pigs and sheep. All have ultimately failed, including a baboon heart that ceased functioning 20 days after it was transplanted into the famous California newborn known as "Baby Fae,” born with an underdeveloped heart in 1984.

Yet advocates aren't deterred.

"I think there's no other immediate solution” to overcoming the human organ shortage, says Dr. David Cooper, an associate professor of surgery at Massachusetts General Hospital and Harvard Medical School in Boston. Cooper says he has a "reasonable expectation that xenotransplantation might solve the problem in the next 10 years.”

Baylor's Levy is reluctant to adhere to any specific timeline but nevertheless forecasts eventual success as well. "And I think the challenge for us is to keep exploring any and all ways to eliminate the waiting list for solid organs,” he says.

Xenotransplantation isn't the sole avenue of research. Scientists are pursuing stem cell therapy, tissue engineering and bioartificial organs as other potential ways to assist faltering organs or grow new ones from scratch.

Dr. Robert Lanza, for one, views animal organs as a temporary solution until stem cell therapy and tissue engineering reach the bedside. The vice president of medical and scientific development at Advanced Cell Technology in Worcester, Mass., Lanza recently published a study with colleagues in which they used a combination of the two approaches to produce heart muscle, skeletal muscle and even miniature kidney-like organs in cows.

Others are trying to develop artificial organs, and a half-dozen companies are pursuing liver-assist devices to cleanse a patient's blood of toxins in emergency situations in a process akin to kidney dialysis. Some of the devices are technically considered xenotransplant procedures because they contain pig cells. (Pig-derived heart valves, on the other hand, have been used for decades to treat heart patients but are chemically treated so they do not contain living cells, and as a result can't be rejected.)

Although recent xenotransplantations have included injections of cow, pig and mice cells to treat conditions ranging from chronic pain to Parkinson's disease, the focus of the future has narrowed almost exclusively on pigs as potential organ donors.

The ease and speed with which swine can be bred have given rise to the notion of "organ farms,” but advocates tout other amenities as well. Over the past 30 years, Harvard's Sachs has bred a line of miniature swine that possess human-sized organs. And many pigs have been purged of common pathogens, a vital step in developing herds for xenotransplants.

Conversely, several factors have kept nonhuman primates from emerging as likely candidates. The kidneys of baboons, for example, are smaller than those of humans. And because most primates used in studies are caught in the wild, they may harbor a broader range of pathogens than animals bred in captivity. Some scientists also believe viruses from primates may cross over to humans more readily than pathogens from pigs, a contributing factor in the FDA's 1999 call to halt the use of nonhuman primates in clinical xenotransplant studies. HIV, now thought to have arisen in chimpanzees, provides a stark example.

Critics counter that the influenza pandemic of 1918 killed 20 million humans worldwide and featured a viral strain that originated and then mutated in pigs.

"There isn't any question that we have a higher degree of known viruses from primates,” Berger says. "But since pig haven't been studied as well, who knows?”

The focus on pigs also raises the question of whether its organs will function properly in humans, especially the multitasking liver. "We know that it [a pig liver] does a lot of good things,” Sachs says. "The question is, does it do everything?”

Many researchers say the medical use of nonhuman primates tends to raise more ethical qualms with the public than the use of pigs, which already have a long history as a human commodity. "Most people would agree that if you use a pig for bacon, then you should be able to use a pig's heart to save someone's life,” Sachs says.

This rationale is anathema to many animal rights advocates, who oppose both uses. "They think the public is less sensitive to pigs, so let's use pigs,” Berger says. "They're just trying to find the easy way to do this.”

Animal rights activists say continued efforts to improve xenotransplant survival times in nonhuman primates could require the sacrifice of countless more monkeys, chimpanzees and baboons. And eventually, such research could pave the way for the slaughter of thousands of pigs bred as human organ factories. The outcry has been particularly harsh in the United Kingdom, where observers say the public is more aligned against animal research.

Significant obstacles remain on the scientific front as well, especially the human body's rejection of anything perceived as foreign. Pig cells are studded with sugar molecules that provoke a particularly vigorous response from human antibodies. If an organ containing these sugar molecules were introduced into the human body, Lanza says, "it would turn black and reject within a matter of a few minutes and certainly within a few hours.”

With immunosuppressive drugs and other strategies, researchers have reached an average survival length of one month among primates that have received pig organs, and three months in some cases. "When we get to months to years, then it will be the time to start treating patients,” Sachs says, though he refuses to speculate when that might be.

Researchers have found at least one major cause for optimism. In January, the biotech companies PPL Therapeutics (associated with the company that cloned Dolly the sheep) and Immerge BioTherapeutics independently announced the creation of pigs that lack one copy of the gene whose protein product correctly positions the sugar molecule that causes the human immune system to react so violently. Breeding programs could eliminate both gene copies in the pigs' progeny and entirely remove the sugar molecule from the cell surface.

"If these pigs come to fruition, then we will have a pig that I strongly suspect we'll be able to get over these immunological problems ,” Cooper says. "That will be a big step forward.” The feat, experts say, is akin to removing a major roadblock to see what lies beyond it. No one yet knows whether its absence alone will substantially increase the survival time of xenotransplant recipients or whether other immune obstacles will remain.

Sachs says his group is pursuing another line of anti-rejection therapy called tolerance in which researchers try to fool a patient's immune system into recognizing a foreign organ as self and thus leaving it alone. Sachs says he's already found success with the approach in human-to-human transplants.

The concern over unleashing a lethal pig pathogen onto the public hangs over such recent successes like a storm cloud, however.

"To me, it's just a really scary Pandora's box,” says Betsy Todd, an infection control nurse in Manhattan. "This is not some sort of fantasy that these things can happen. We know that viruses can jump from one species to another.”

Simian herpes B, for example, is nonpathogenic in monkeys but can cause fatal brain swelling in humans. In 1998, the Nipah virus killed more than 100 Malaysian farmers who were apparently infected from handling pigs. Even more worrisome, experts say, is the possibility that pig retroviruses may recombine with other viruses or appear in unfamiliar forms and lie dormant for years.

"It's not a Chicken Little thing but you're only as good as the technology at the moment,” says Jonathan Allan, a virologist at the Southwest Foundation for Biomedical Research in San Antonio.

"All technology is not all knowing.”

Furthermore, Allan says a full organ transplant may provide a ready conduit for a virus that wouldn't normally have access to humans. "You're basically producing the most ideal setting for getting one pathogen from one species to another,” he says, perhaps allowing a brand new disease to emerge.

Eventually, if such a virus came into contact with other humans, he says, "you don't have to be a science fiction writer” to imagine dire scenarios.

Pig viruses known as PERV, or porcine endogenous retroviruses, have created the biggest stir so far. Like humans, pigs have apparently harmless retroviruses incorporated into the DNA of their cell nuclei. The unanswered question is whether such pig viruses could become harmful in a human cell. In 1997, a British medical researcher reported that these pig retroviruses could infect adjacent human cells grown in culture. The discovery led the FDA to hold public hearings and put a hold on xenotransplantation trials until researchers could document improved safety precautions. "We're not too worried about the patient,” Cooper says, pointing out that the patient would succumb without an organ transplant. "We're only worried about if the patient will become a public health hazard to those around him.”

Although the risk may never be eliminated entirely, researchers say they are taking three main approaches to make it as small as possible: diagnostic tests to establish a pathogen's presence, effective antibiotic or antiviral agents, and outright elimination of the pathogens through breeding.

"It's unlikely that we're going to find the perfect pig as transplant donor,” says Dr. Jay Fishman, head of infectious disease for the transplant unit at Harvard. "On the other hand, if we get all our pieces in order, we may be able to prevent the transmission of a particular virus from a particular herd.”

Sometimes luck helps. Immerge has discovered a subset of its inbred miniature swine that apparently doesn't transfer PERV to human cells.

"If it's in the pig organ but can't get into human cells, then the problem is solved,” Cooper says.

No so fast, others say.

"If you put PERV in a whole human and let it sit for 30 years, who knows what's going to come out?” Allan says. "If you unleash a virus in the population, you may not know you've done it.” But Cooper is unfazed.

"If you always waited for the unknowns to become known, you'd never advance in anything,” he says. "As long as we've solved all of the known problems, I think we should push ahead.”

Norman Daniels, a professor of medical ethics at Tufts Medical School, joined colleagues four years ago in calling for just the opposite: a moratorium on xenotransplantation.

"This is not a Luddite effort to eliminate technology or progress,” he says. "It's an attempt to manage the risks” for an unprecedented medical issue: receiving informed consent from those at risk of contracting any pathogen emerging from a patient's xenotransplant.

"So in this sense there's a public health issue that there isn't in other medical treatments, and that's what's at stake here -- a public health-public risk issue,” Daniels says. And even if researchers can obtain the informed consent of sexual partners, family members and friends of xenotransplant recipients, "how do you enforce it?” he asks.

"Once the genie is out of the bottle, it's flying around and no one can put it back it, and so my position is still to support a moratorium,” Daniels says.

Despite the risks, the lucrative potential of xenotransplantation has attracted the notice of analysts and biotech firms alike, with one 1996 estimate predicting worldwide revenues of $6 billion per year by 2010. But disappointing research results, mainly in the survival lengths for nonhuman primate recipients of whole organs, may be forcing a re-evaluation.

"You've seen a bit of a retrenchment in this field,” Levy says, with biotech companies re-examining where they want to go. "I suspect they wanted to be farther along than where they are now.”

Between 1992 and 2001, the FDA received 40 new applications for xenotransplantation clinical trials in humans, about one-fourth to treat liver failure. Half were withdrawn or on hold in 2001, with only 13 in effect. In one of the approved trials, conducted in 1997 and 1998, Levy and other Baylor researchers successfully used transgenic pig livers to cleanse the blood of two patients who later received livers from human donors. Both patients are still living, Levy says, with no evidence of PERV.

The apparent success of the clinical trials notwithstanding, "the sponsor, Nextran, hasn't wanted to throw more resources into this effort,” Levy says, with obvious disappointment.

"I guess I've had a glimpse at what could be and my natural inclination is to learn more,” he says, "and you couple that with the frustration from the number of patients dying on our waiting list and that's very frustrating.”

In the absence of more funding, Levy has switched his main focus to questions of safety. "And I think once those are answered, the field will feel more comfortable with moving forward,” he says. Levy's testing the 40 to 50 health care workers who were voluntarily involved in the two clinical procedures and came in contact with the patients to see if any have developed signs of a pig viral infection.

"I think vigilance is absolutely required but what we applied so far hasn't turned up anything,” he says.

Not yet, anyway.

During the summer of 1997, 17-year-old Robert Pennington had little reason to expect a life- threatening illness. "I've been healthy most of my life,” says the soft-spoken Texan. "I've always had a good immune system.”

But during the course of three weeks that summer, Pennington developed flu-like symptoms and became progressively weaker and more dehydrated. One day, he looked in the mirror and noticed that the whites of his eyes had turned yellow. By the time doctors diagnosed him with fulminate hepatic failure, or sudden liver death, his urine had turned the color of coffee. He slipped into a coma soon afterward.

In desperate need of a liver transplant, Pennington was moved to the top of the transplant list at Baylor University Medical Center in Dallas while doctors debated their options. Finally, Baylor surgeon Marlon Levy approached Pennington's grandparents, his legal guardians, and discussed a novel experiment designed to buy their grandson more time -- one that involved using a pig liver to cleanse his blood of accumulated toxins.

On Oct. 3, 1997, Pennington became the first patient in the world to successfully undergo an experimental xenotransplantation procedure in which doctors cycled his blood through a genetically altered pig's liver placed in a saline bath beside him.

"It was the main thing that was keeping me alive,” Pennington says with conviction. His doctors halted the procedure, known as extracorporeal perfusion, less than seven hours later when they found him a suitable human liver from a cadaver. A few weeks after the transplant, the U.S. Food and Drug Administration placed a temporary hold on all xenotransplant trials over concerns that pig retroviruses could jump to humans. One year later, Baylor doctors found similar success with a second patient, a woman.

Now 22 and living in Dallas, Pennington owns his own business selling watches, jewelry and car accessories. His doctors never found out why his liver failed, he says, but he hasn't had any major problems since the transplant, save a bout of dehydration a few months ago.

"I pretty much live a normal life,” he says, with daily doses of anti-rejection medication, vitamins and iron supplements some of his few concessions. His doctors have kept a close eye on him, first taking blood samples daily, then weekly. He now goes once a month for routine tests and undergoes more extensive tests every four to six months. "And they've never found anything abnormal yet,” he says.

Although Pennington believes xenotransplantation granted him a new life, he has become an advocate for human organ donation and is developing a Web site to encourage such donations after death. "I think the main thing is that if more people donated organs, then wouldn't have to resort to research with animals,” he says. Until that time comes, however, "they're going to have to do this to save lives. I'm all for it. It saved my life, so what else can I say?”