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Pig organ transplantation brought one step closer

The Lancet
Volume 359, Number 9301 12 January 2002

by Helen Frankish

Rival teams of scientists announced last week that they had succeeded in cloning "knockout" pigs, which lack one copy of a gene that prompts the human immune system to reject transplanted pig organs. The researchers say this is the first step towards creating pig organs that are suitable for transplantation into human beings.

Researchers removed the gene for -1,3 galactosyl transferase, an enzyme that puts a sugar molecule on the cell surface of pig cells. The presence or the sugar molecule triggers "hyperacute rejection" and has been the biggest hurdle in pig-to-human transplantation.

PPL Therapeutics (Edinburgh, UK) announced on Jan 2 that five piglets without the -1,3 galactosyl transferase gene had been born on Christmas day at its US laboratory in Virginia. Meanwhile, scientists at the University of Missouri, in collaboration with Immerge BioTherapeutics, a joint venture between Novartis and BioTransplant Incorporated, announced the following day in Science that in September and October, 2001, they had created four cloned pigs also lacking the gene (www.sciencexpress.org).

"This was really the step we believed was technically the most difficult and clinically most important", David Ayares, vice president of research at PPL, told The Lancet. "Until we get over the hyperacute rejection step we won't be able to see what additional changes we believe we are going to have to add." Ayares thinks they will also have to add complement inhibitor genes and genes involved in restoring normal coagulation to prevent long-term organ rejection.

Some experts are concerned, however, that viruses present in pig tissue could be passed on to humans, such as the porcine endogenous retrovirus. According to Jonathan Allan (Southwest Foundation for Biomedical Research, San Antonio, TX, USA), human beings and primates are protected from other animal viruses by antibodies that neutralise the viruses. But Allan says that removing the gene that causes hyperacute rejection will also take away the body's natural defence mechanism against porcine viruses.

"When the retrovirus buds from the cell surface as it replicates, it takes a piece of the cell membrane with it, which happens to have the -gal on it", Allan explains. "Once you take away -gal, the antibodies are not going to neutralise the pig virus, so you've taken away one of the most important means of self-defence. Anything you do to blunt the immune system will also improve the chances of a viral infection."

Alix Fano, director of the Campaign for Responsible Transplantation (New York, NY, USA), a group opposed to xenotransplantation, believes there are alternatives. "If all the private and public money that has been poured into xenotransplantation--over $1 billion--had been poured into disease prevention and increasing the pool of human organs for transplantation, we would have reduced the number of people on transplant waiting lists by now." Fano also believes that legal measures, such as presumed consent laws, passed in countries such as Singapore, France, Belgium, and Italy, could increase the number of human organs available for transplantation.

"In my opinion, xenotranplantation is about profits--it's about making money", adds Fano. "It's not about altruism or caring for human health because if we did care we would be doing things that are more therapeutically effective, less expensive, and less dangerous."

Analysts estimate the xenotransplantation market is worth US$5 billion, and competition is intense among the rival biotechnology companies. PPL was criticised by some scientists for trying to get "one up" on its rivals, by announcing its results the day before Immerge BioTherapeutics was due to publish its results in a peer-reviewed journal. "I think it's shameful to do that", comments Allan. PPL scientists have now submitted their findings to a peer-reviewed journal.

Dolly the sheep develops arthritis

Dolly the sheep, the first mammal to be cloned from adult cells, has developed arthritis at the comparatively young age of five and a half, Ian Wilmut (Roslin Institue, Edinburgh, UK), one of her creaters has revealed. Arthritis is not unknown in sheep, whose average lifespan is 12-14 years, but Dolly has developed it at an unusually young age, and in two joints not normally affected. However Wilmut said it was not known whether Dolly had developed arthritis as a result of the cloning process, or whether it was "an unfortunate accident".

Ayares admits they had "an inkling" that other groups were "nipping at their heels", but he says that Immerge BioTherapeutics' results had no effect on the timing of their announcement. "As we're a publicly traded company, we're legally bound to release any stock-sensitive information as soon as we have it." Indeed, following the announcement, shares in PPL on the London Stock Exchange soared by 40%. These were to fall by 15% the following day, when it was revealed that Dolly the sheep, the first mammal to be cloned from differentiated adult cells, has developed arthritis (see panel).

The future of xenotransplantation is still uncertain, and PPL, despite being one of the most successful companies in this field, has only limited funding. It is therefore seeking $15 million in investment to fund its xenotransplantation research.