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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 // Fall 2005
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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.”

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Crossing the Line

Could a transplanted pig organ serve as a Trojan horse for a deadly disease?

A Brief History of Xenotransplants

Using organs from one species to treat another has long fascinated scientists.

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hed-dossier

1. Xeno: The Promise of Transplanting Animal Organs into Humans, by David K.C. Cooper and Robert P. Lanza (Oxford University Press, 2000). Excellent introduction to the history and science of xenotransplants from two top experts.

2. “Marked Prolongation of Porcine Renal Xenograft Survival in Baboons Through the Use of Alpha-1,3-galactosyltransferase Gene-Knockout Donors and the Cotransplantation of Vascularized Thymic Tissue,” by K. Yamada et al, Nature Medicine, Jan. 2005. First report, by David Sachs and his team, of results of life-supporting kidney transplants from Gal-knockout pigs to primates, using tolerance induction.

3. “Heart Transplantation in Baboons Using Alpha-1,3-galactosyltransferase Gene-Knockout Pigs as Donors: Initial Experience,” K. Kuwaki et al., Nature Medicine, Jan. 2005. Simultaneous report, by David Sachs and David Cooper’s teams, of the first Gal-knockout (non-life-supporting) heart xenotransplant results using chronic immunosuppression.

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