GM pigs could fill transplant gap

LONDON — It might sound like tomorrow's medicine, but legend has it that the first documented case of xenotransplantation dates back to 1682, when bone from a dog was successfully used to repair the skull of an injured Russian aristocrat. The potential for use of animal organs and tissue to benefit humankind remains as controversial today as it was then. But after decades of failed attempts to successfully marry the two, new signs of progress are beginning to emerge in the ability to achieve successful transplantation between different species.PPL Therapeutics, a biopharmaceutical company that helped to create Dolly the sheep, has announced a breakthrough in its quest for a solution to one of the many obstacles facing the routine use of animal organs — that of hyperacute rejection. The company, a commercial offshoot of the Roslin Institute, Edinburgh, has bred five cloned pigs that have had a specific gene responsible for human rejection of pig organs knocked out. This, the company claimed, marks a major breakthrough in the development of xenotransplantation because it provides a possible solution to organ rejection, the downfall of most previous attempts to transplant animal tissue. And the fact that the genetically engineered pigs — born on Christmas Day 2001 — are also clones could potentially allow a ready supply of organs to be produced.The knock-out gene — alpha 1,3 galactosyl transferase — is responsible for making an enzyme that adds a sugar to the surface of pig cells which is recognised by the human immune system as foreign. This prompts the immune system to respond, causing hyperacute rejection of the transplanted organ or cell within minutes of implantation. Since the early 1960s, when transplant pioneers experimented with chimpanzee hearts and kidneys in sick children and adults, this has been the primary cause of failure. By switching off the culprit gene, it is hoped it might now be possible to 'blind' the immune system to the fact that foreign material has been introduced.But organ rejection is just one of the difficulties facing this new branch of transplant medicine. A potentially greater problem is the risk of animal viruses crossing the species barrier and infecting humans. Studies have already shown that a pig virus — porcine endogenous retrovirus — can infect human cells in the laboratory. A second company, Immerge BioTherapeutics Inc, claims to have produced cloned piglets that have the same gene switched off as in the PPL pigs, but has also selectively bred them to minimise the risk of viruses being transmitted to humans. The company claimed that preliminary research showed that cells from the line of pigs it selected — a breed of miniature pigs — do not have the capacity to spread the virus to human cells.Inevitably, these developments have attracted widespread media attention, not least because pigs score highly in what some call the 'Yuk Factor'. They believe overcoming the scientific obstacles is one thing, winning public support for the use of pig organs in people may be quite another. Even though pig tissue is already used in a variety of medical applications — such as heart valves and skin grafts – its' use is in a discreet form and is not common knowledge among the general public. Substituting an entire organ is a much more overt deployment of animal tissue.As well as organ replacement, the technology paves the way for other therapeutic procedures. PPL said it anticipates the first application will be the testing of insulin-producing islet cells from the cloned pigs for the treatment of diabetes — first in primates, then in humans. Similar cell transplantation procedures could also be used against diseases such as Parkinson's and Alzheimer's.But after decades of speculation and promise, how viable is mass-production of animal organs and cells for human use and what's the next big problem to overcome? According to Andrew George, a reader in molecular immunology at Imperial College of Science, Technology and Medicine in London, the threat of animal viruses infecting human patients is by far the biggest difficulty. "There are several obstacles but this one is potentially an absolute show-stopper. It's a very difficult question — the recipient of a transplant is potentially going to benefit but at a risk to the rest of society," he said. "There are lots of experiments being done to get an idea of the risk but at the end of the day that risk will always be there. So it's a question of how much risk is acceptable but even then the first few patients who have this will have to be incredibly closely monitored. My own view is that the risk is actually going to be very low and at the moment experiments are showing that we should be able, by careful breeding, to reduce them to a very low level."In terms of the practical applications, George believes the potential to harvest animal organs to order — instead of emergency transplants of donated human organs — will provide vital time to plan for the procedure. "At the moment, if a transplant organ becomes available the patient is operated on with very little preparation. But if you can time it then you can start preparing the recipient in order to accept the graft. For example, you could pre-administer pig cells in such a way as to make the immune system tolerant or blind to the graft. By giving it in advance you would be trying to turn off the immune system. It's about educating the immune system to do what you want it to do and this instance you want it to turn off when it sees this foreign material."In theory, George considers that a limitless supply of viable animal organs might mean pig hearts can one day be offered as an alternative, for example, to coronary bypass surgery in patients with severe heart failure. Another use could be to use pig livers as a bridging transplant for patients who may have suffered liver failure as a result of paracetamol poisoning, although long-term use of porcine liver tissue is not viable at the moment because its biochemical composition is too dissimilar.Similar benefits would be gained in islet cell transplantation because although scientists have shown human-to-human transplantation is possible, it can take several donors for each patient to produce the quantities needed. "While this research is looking good, it's difficult to say how we would ever get enough human donors to satisfy all the diabetic patients in the world," George warned. For the time being, and even allowing for smooth scientific progress, routine use of pig organs in humans remains a decade away, he suggested. By then, if the current organ donor shortage continues, medicine might be glad of them.

GM pigs could fill transplant gap

Genetically modified pigs could provide organs for transplant that are not rejected by the immune system.

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