Are pigs the future of transplants?

Genetically engineered hearts are setting longevity records in baboon bodies

By Byron Spice

Pittsburgh Post-Gazette

December 28, 2004

Baboons transplanted with hearts from genetically engineered pigs survived for up to 6 months, a research step that scientists say bolsters the idea of someday transplanting pig tissue into people.

Not only did the baboons live longer than in previous tests of cross-species transplants, but they did so while receiving anti-rejection drugs at levels similar to those normally used in human patients, said Dr. David K.C. Cooper of the University of Pittsburgh's Starzl Transplantation Institute.

The findings by Cooper and colleagues at Harvard Medical School appear today in the journal Nature Medicine.

The animal experiments were performed at Massachusetts General Hospital using hearts from so-called "knockout" pigs that had been genetically altered so that they lack a gene necessary for producing a sugar called galactose.

The presence of galactose on the surfaces of pig cells triggers a devastating immune response known as hyperacute rejection when pig tissues are transplanted into another species. This process disrupts the blood vessel walls, causing them to burst.

Cooper, who left Harvard to join the Starzl Institute last February, said the baboons ultimately suffered organ rejection, but it occurred in the form of blood clots in small blood vessels.

"I think it's all part of the same process ... but it goes so slowly that you get clots forming" instead of the rapid disruption associated with hyperacute rejection.

In the latest experiments, eight baboons survived from two to six months with the knockout pig hearts. Two baboons that received hearts from pigs with low levels of an enzyme necessary for galactose production suffered hyperacute rejection within 20 minutes.

Cooper said baboons have survived for up to three months with pig hearts in previous experiments, but only when using levels of anti-rejection medications far higher than would be acceptable for a human patient.

The experiments were performed using hearts from pigs developed by Immerge BioTherapeutics Inc., a now-defunct company in Cambridge, Mass. But Revivicor Inc., a Blacksburg, Va., biotechnology firm owned by the University of Pittsburgh Medical Center and Highmark Inc., has developed its own version of the knockout pigs.

Only one other company, a small biotech firm associated with the Mayo Clinic, produces the same sort of knockout pig.

Though lack of galactose appears to have eliminated one hurdle in using pig tissues for cross-species grafts, or xenografts, the ultimate rejection of the organs indicates yet another barrier that must be cleared, Cooper acknowledged.

One possible answer is to give the pigs a human anti-coagulent gene, he noted. Revivicor already has produced a few such pigs and Cooper said he hopes to begin testing them in the coming year.

Once a member of Dr. Christiaan Barnard's transplant research group in Cape Town, South Africa, Cooper stopped performing human heart transplants eight years ago to devote his time to developing xenotransplantation.

"The biggest problem [in organ transplantation] is finding donors," he explained. "I don't believe we'll ever have enough human organs."

Though graft survival of six months is less than optimum, Cooper said, the duration is reaching a point where doctors might consider transplanting pig hearts or pig livers as "bridges" to keep patients alive until a suitable human organ becomes available. Similarly, pancreatic islet cells from pigs might be transplanted into diabetic patients and then periodically replenished.

Aside from rejection, one issue limiting xenotransplants is concern about introducing animal viruses or bacteria into humans. Pigs, for instance, carry a virus known as porcine endogenous retrovirus, or PERV. This virus may or may not be dangerous to humans, but as yet no one has been able to produce a PERV-free pig.

The National Institute of Standards and Technology last year awarded $1.9 million to Revivicor for a three-year, $2.7 million effort to develop a PERV-free pig through cloning. Revivicor is the former U.S. subsidiary of PPL Therapeutics, the Scottish firm that helped clone the sheep named Dolly in 1996.

(Science editor Byron Spice can be reached at bspice@post-gazette.com or 412-263-1578.)

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This article posted January 15, 2005.