The numbers are grim. According to the United Network for Organ Sharing, more than three times as many people in the United States were waiting for heart, kidney and liver transplants than received them in 1999; over 5,500 people died waiting for organs. And many more patients could benefit from organ transplants than ever make the waiting list, either because they are too sick or too healthy to qualify. According to one estimate, 45,000 Americans could benefit each year from heart transplants, but only 2,000 or so human hearts are available.

One promising solution to this medical predicament is to harvest organs from suitable animals and use them for human transplant. It may sound outlandish, but several biotech and pharmaceutical heavyweights, as well as some smaller biotech firms, are gearing up to do just that (see table, next page). In preliminary experiments, these companies have already implanted animal cells in human volunteers to treat such diseases as Parkinson’s and epilepsy. Researchers plan to start whole-organ clinical trials in the next two to three years.

The use of animal organs in human transplants is not exactly new. You may remember “Baby Fae,” the 12-day-old California infant who, in 1984, received a heart transplant from a most unusual donor-a baby baboon. This controversial experiment marked the first time most people had ever heard of “xenotransplantation,” transplanting tissues or organs between species, and Baby Fae’s very public death only 20 days after her surgery chilled the climate for xenotransplantation work. Still, medical researchers quietly pressed ahead, and their efforts may soon pay off.

The animal of choice in the new generation of experiments? Pigs. That’s because pigs are both plentiful and easy to raise, and “the similarities to man are amazing,” says Julia Greenstein, CEO of Immerge BioTherapeutics, a joint venture between Swiss drug giant Novartis and Charlestown, MA-based BioTransplant.

But transplanting tissues from pigs to people does present a few problems. The most critical is “hyperacute rejection,” an immune reaction that causes organs from pigs to turn black and cease functioning within minutes of transplant into humans. The cause of this reaction is a sugar called alpha-gal that laces the surface of every pig cell. Since human cells don’t make this sugar, the immune system produces antibodies against it and kills all cells bearing it.

For whole-organ transplants to become reality, a strategy is needed to deal with the troublesome sugar. That’s why companies such as Princeton, NJ-based Nextran are genetically engineering pigs to make proteins that help repress the immune reaction that the sugar causes. Nextran, owned by pharmaceutical giant Baxter, has already used the livers of such pigs to keep patients with acute liver failure alive until donor organs were found. In these early human tests, the pig livers remained outside the body, but “it’s just a prelude to going into a human,” says University of Pittsburgh transplant surgeon John Fung. The company plans to apply for permission to conduct preliminary human trials of such xenotransplants by the end of next year.

Other companies, including Immerge, PPL Therapeutics and Advanced Cell Technology, are combining this strategy with efforts to completely eliminate the guilty pig sugar. To do this, they must “knock out”-disable or remove entirely-the gene for the enzyme that makes the sugar. There is some concern, however, over whether pigs can survive without the sugar. “Chances are the pigs will be healthy, but no one’s 100 percent sure,” says immunologist David Cooper of Massachusetts General Hospital’s Transplantation Biology Research Center.

Even if the pigs do survive, genetic modifications alone might not be enough to conquer transplant rejection problems, even with antirejection drugs. So PPL, Immerge and Advanced Cell Technology are pursuing additional strategies for blocking rejection. Each hopes to fool the human immune system into thinking that a new pig organ belongs in the body, usually by infusing or implanting pig bone-marrow cells into the recipient several weeks before a transplant operation. The idea is to use antirejection drugs to keep the marrow cells alive long enough for the human immune system to start thinking of the pig cells as “self”-reducing the patient’s dependence on very large doses of the powerful drugs after the organ transplant. Fung is skeptical, though: “Trying to get animal organs to be accepted using approaches that haven’t worked in human organ transplantation requires a leap of faith.”

Omaha, NE-based Ximerex is even more ambitious, trying to completely eliminate the need for antirejection drugs by “introducing” individual pigs and transplant recipients prior to surgery. A patient’s bone marrow cells would be infused into a pig fetus, educating both the pig and human immune cells to think of each other as self. After the pig’s birth, hybrid pig/human bone marrow would be put back into the patient. One drawback: patients would have to wait four to five months between bone marrow sampling and transplant operations. Ximerex president William Beschorner doesn’t think the obstacle is insurmountable: “The typical wait for a human transplant is well over a year. It would not be a major problem for most patients.”

Each of these companies hopes to begin clinical testing of heart and kidney xenotransplants in the next few years. Although Cooper is generally optimistic, he sounds a note of caution. “It’s like peeling an onion: every time you pull off one layer, you find another problem underneath.” The thousands who die each year waiting for new organs hope those problems are solved soon.