Collaboration key for xenotransplants

WASHINGTON, DC — Prospects for successful xenotransplantation — therapeutic transplants of animal organs and tissues into humans — are improving. But workers in the field caution that there is still a long way to go before organs from animals will be able to fix the perpetual shortfall in the supply of human transplant tissues.These were the key conclusions at the 11/12 March 2002 Advisory Committee on Xenotransplantation (SACX) meeting at the US Department of Health and Human Services (DHHS), at which brought committee members were brought up to date on recent studies.Established in 1999, SACX meets quarterly, and will eventually put together reports on the state-of-the-art, safety issues and informed consent, destined for the desk of DHHS Secretary Tommy Thompson, a Bush appointee. The most cheering news discussed at the meeting was the recent production of transgenic piglets lacking a gene that triggers immune system rejection in humans.Pigs have long been regarded as a particularly suitable potential source of transplants. Their organs are similar in size to those of Homo sapiens and much is known about their biology because of their well-established economic importance. A major hurdle was overcome with the publication in 8 February Science of a study reporting knockout piglets missing a gene for the cell-surface sugar α-galactose, thought to be a chief trigger of rejection (Science 2002, 295:1089-1092).But that's just the beginning; the next step is to breed pigs homozygous for the knockout in order to obtain animals completely lacking the sugar, and to perform exhaustive tests for immune responses. Nor is it clear that preventing α-galactose reactions alone can foil complex process of tissue rejection. "But to even knock out a gene in a large animal, and such a critical gene, is a major step forward," suggested Megan Sykes, professor of surgery and medicine at Harvard Medical School and an expert member of SACX.Daniel Salomon, associate professor of molecular and experimental medicine at the Scripps Research Institute, La Jolla, California, and another SACX expert, is also happy about the transgenic pigs. The implication, he proposed, is that for the first time, a reliable technology has been created for not only for knocking out genes in pigs, but probably for inserting new genes as well. That technology, he said, will lead to more complex strategies and more immunologically compatible pigs.Preventing immune system reactions between donor and recipient is the biggest problem facing all transplantation research, but preventing infection is also critical. Infection continues to be a risk for human-to-human transplants. The US Centers for Disease Control and Prevention recently reported that three transplant recipients had last year contracted Chagas disease — a potentially fatal parasitic infection that is rare in the US — from a Central American donor.Xenotransplantation raises infection questions of a different kind. The lesson of HIV — believed to have been transmitted to people from nonhuman primates — suggests that organisms that live harmlessly in their natural animal hosts might be virulent in humans. Pigs carry porcine endogenous retrovirus (PERV), and much recent investigation has focused on whether it could transfer to people and make them sick, with results that have been mildly encouraging, although not conclusive. "The more work we do, the more we understand this virus, the more comfortable we are that we can detect it and that its risk remains fairly low," said Salomon. Sykes reported that recent research has suggested that not all pigs can transmit PERV to human cells. That means it might be possible to develop a supply of nontransmitting pigs for xenotransplantation.Replacement of whole organs is not the only aim of xenotransplantation; in fact, cell and tissue transplants are likely to be successful sooner. Organs are vascularized, and donor endothelium comes into contact with the recipient's antibodies and other immune system components, a problem not found with cell transplants. "There's a future for whole organ transplants, but the first type may be a cellular transplant," Sykes noted."I think pig islets and pig neural cells are the two best candidates for the next wave of truly successful beneficial tissue transplants," suggested Salomon, who summarized the prospects for this approach at the recent SACX meeting. The next wave will likely consist mainly of neural cells for treating Parkinson's disease, Huntington's disease, and other degenerative neurological conditions, plus spinal cord injuries, Salomon predicted. Cell transplants for treating Alzheimer's disease are a theoretical possibility, but much less likely, he said.Pancreatic islet transplants exhibit potential as a way of treating diabetes, especially porcine islets. "And there are other types of cells, like hepatocytes, that are being explored, not only as cellular transplants, but also as artificial organs for perfusion of blood outside of patients - sort of as a bridge while they're waiting to regenerate their own livers or waiting for transplants," Sykes reported. This extracorporeal functioning is not, strictly speaking, xenotransplantation, but it's an example of competing approaches, some of which focus on hardware. The most successful is the totally implantable artificial heart, although recent recipients have mostly died within a year.There is talk about growing transplantable organs from stem cells, but that approach is so new that Salomon doesn't regard it as competition for xenotransplantation. "Stem cells have been talked around big time, there's a lot of hype, but that's a field in its infancy. It's nowhere near where xenotransplantation is at this point. It's very exciting, but very primitive," he pointed out.Sykes concurred that xenotransplantation continues to be the best near-term solution to the shortage of organ and cell transplants, but noted candidly that the obstacles remain formidable.Xenotransplantation, she said, needs help from colleagues in other fields — especially those who understand areas such as coagulation and the complement system. "Carbohydrate interactions is another one. There are whole families of new cellular receptors that recognize carbohydrate disparities. They've been largely unexplored, and they're probably of major importance to the xenotransplantation field. Somehow we have to get people from other disciplines thinking about how this evolving science would impact xenotransplantation."

Collaboration key for xenotransplants

Non-rejecting pigs advance xenotransplantation but input from other fields is needed to optimize future progress.

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