New Scientist
January 12, 2002
Comment: Editorial, Pg. 3

Waiting For a Miracle
Time is Running Out for Organ Transplants From Animals

IT HAS become an unwritten rule of the biotech business that all newly cloned animals must have PR-friendly names. On this score, at least, the latest cloned piglets didn't disappoint. No sooner had little Noel, Angel, Star, Joy and Mary - born on Christmas day - squealed their way onto the front pages than a rival team of cloners was unveiling an equally cutely named litter of four.

Suddenly, the race to turn pigs into organ donors seemed to be hotting up. "We are looking at four to five years for clinical trials to begin in humans," announced Alan Colman of PPL Therapeutics, the company that created the quintuplet. At this point readers averse to a little cold water being thrown should turn the page. It would be wonderful if biotechnologists could make the kidneys, lungs, hearts and livers of pigs compatible enough with the human immune system - and sufficiently free of pig viruses - to make good the desperate shortfall of transplant organs. But the commercial hype surrounding xenotransplantation often obscures the fact that the obstacles to success are still colossal.

Despite the blanket publicity these animals achieved, they are not the first cloned pigs nor even the first pigs to be genetically redesigned to make their organs more human-like. What they are is the first GM pigs created via the cloning process - a technical advance, but hardly proof that pigs can be turned into organ donors.

We've been somewhere like this before. Remember Astrid, the first genetically modified pig created for research into organ donation ? A couple of years after her birth in 1992 her creators predicted human trials within three years. The trials didn't happen. In 1998, we were again told about an imminent clinical trial involving pig kidneys. That didn't happen either.

In fact, so far the only recipients of organs from Astrid's offspring - or from other "humanised" pigs created in her wake - have been a string of previously healthy laboratory monkeys and baboons. Their dismal fate suggests that xenotransplanters have made no real progress for about five years. In the early 1990s, the big obstacle to transplanting pig organs into primates like ourselves appeared to be the violent immune response known as hyperacute rejection, in which grafted tissues are starved of blood. So naturally enough, the genetic changes in the first generation of humanised pigs were designed to overcome this reponse.

And mostly they do overcome it. The problem is, the organs still don't survive. True, most of the monkeys and baboons given these organs are able to live for days or weeks, instead of the hours they might survive with ordinary pig organs. But no matter how many immunosuppressive drugs the monkeys have pumped into them, none of the modified pig organs has lasted much more than a couple of months. What scientists hadn't bargained for was a second powerful immune response, known as acute vascular rejection. It gets going more slowly than hyperacute rejection, but the end result is just as ugly - a surge of blood clotting factors and an oxygen-starved organ.

Whether the new genetic change made to the latest batches of cloned piglets will make much of a difference is unclear. But even if it does help, few experts think it will be sufficient to completely halt this form of rejection. The immune system is like a well-drilled army. Penetrate one line of defence and a second line quickly moves in. In all likelihood far more genetic tinkering will be required to stop the army in its tracks. And by then advances in artificial organs and stem cell research aimed at patching up natural organs may have made donor pigs redundant.

Whatever happens, expect the latest cloning triumphs to trigger a new phase of xenograft research, coupled with renewed concern about the ethics of using pigs this way. Such worries miss the point. When it comes to animal welfare, the bigger problem is the large number of primates that have to die in what even animal experimenters concede are grisly circumstances.

In its last major report, UKXIRA, the panel of experts set up by the British government to monitor xenotransplantation research, concluded that the "evidence of efficacy has not advanced at the rate predicted" and that the "likelihood of whole-organ xenotransplantation being available within a worthwhile time frame may be starting to recede". It was a diplomatic way of saying the technology was dying on its feet. The question now is whether Noel and her siblings can help scientists create the big advance in organ survival necessary to resuscitate it. They need a breakthrough fast. The patience of those bankrolling the research will not last forever. Nor will the public's willingness to tolerate the continued loss of primate life.

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