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| Archive : Fall 2005 |
How to Handle Rejection:
One sugar-free pig, one celebrated baboon heart attack and several million T-cells tricked into tolerance.
That's Some Pig
 By Allan Coukell
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S ometime in the 1600s, a sword-wielding Tartar cracked open the head of a Russian nobleman
named Butterlijn. Desperate for something to repair the wound, an enterprising surgeon borrowed a suitably sized piece of bone from the skull of a dead dog. Butterlijn recovered. But when word of the remarkable achievement reached the archbishop of the Orthodox Church, he threatened the nobleman with excommunication. Butterlijn fled.
This story, even if apocryphal, marks an early episode in the long, strange and mostly unsuccessful history of xenotransplantation—the practice of introducing animal tissues and organs into humans. Yet after hundreds of years of failure, modern medicine may finally be close to solving the transplant problem. The need has never been greater.
At any given moment, some 89,000 patients in U.S. transplant centers require an organ, according to the United Network for Organ Sharing; many die waiting. And the list grows daily. So scientists dream of organ farms and an endless supply of healthy hearts, kidneys, livers and lungs. It is a vision David Sachs has been pursuing for more than 30 years. But bridging the species barrier has been harder than he expected. As a young immunologist at the National Institutes of Health in the 1970s, Sachs was aware of efforts to use chimpanzee kidneys to save the lives of patients with advanced renal failure. But to Sachs, the ideal cross-species donors were pigs, not primates.
Despite the close genetic similarity between chimpanzees and humans, pigs offer the advantages of being plentiful, fast-breeding and easy to keep. Their hearts, kidneys, lungs and livers are about the same size as human organs. And while there would be ethical objections to using humans’ close primate relatives as organ donors, it seemed to Sachs that few would mind using pigs, millions of which are butchered annually for bacon.
Scientifically, though, there are issues. Over millions of years, human beings have evolved a system of immunological defenses exquisitely adapted to repel foreign invaders. The same system that identifies and destroys bacteria and viruses also attacks any other living matter the body recognizes as "nonself." Pigs are certainly nonself.
When transplant recipients reject human organs, it is normally because the body—specifically a type of white blood cell, called a T-cell—has recognized the foreign tissue. To minimize the difference between donor and recipient, doctors check for blood-group compatibility, as they do for transfusions. They also consider tissue type, using as markers a set of molecules called MHC proteins. The closer the MHC match, the less likely it is that the transplant will be rejected. But once T-cells recognize a foreign MHC protein, they set off a cascade of responses that, unless it’s suppressed by drugs, results in the failure of the organ.
Unfortunately, pig organs are rejected much more swiftly than human ones. A pig kidney transplanted into a primate will almost immediately begin to darken and turn black. "You look inside and you see bleeding, hemorrhage, thromboses everywhere," says Sachs, now director of the Transplantation Biology Research Center at the Massachusetts General Hospital. "Often the organ is dead before the surgeon completes the procedure."
The reason for this violent reaction remained a mystery for many years. Scientists knew it was caused not by T-cells but by circulating antibodies. (Antirejection drugs, which mostly reduce T-cell activity, are useless against this kind of rejection.) But it was only in the early 1990s that the culprit behind the response—a type of sugar called alpha-1,3-galactose, commonly known as Gal—was identified.
Most mammals, including pigs, "express," or manifest, Gal; it is found on the surface of nearly every cell and in the lining of blood vessels. But old-world primates, including humans, do not express this sugar and thus react strongly to it. This discovery launched a race to produce Gal-free pigs, whose organs might not be summarily rejected.
It was around this time, in 1993, that Jennifer Searl got sick. A petite 12-year-old with light brown hair and green eyes, Searl was a scrappy soccer player who, her mother had noticed, was looking a little pale. She was on her way to summer camp when the results of a blood test explained why: Her kidneys had failed.
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Photo: Getty Images
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