Could these priceless pigs help save thousands of human lives each year?

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The Independent Online
FOR MORE than a decade, a small group of scientists working in a clutch of anonymous portable cabins outside Cambridge believed they were on the track of a solution to the worldwide shortage of transplant organs.

Led by the brilliant Cambridge University immunologist David White and the heart surgeon John Wallwork, director of transplant surgery at Papworth hospital, they bred pigs that had been genetically modified to overcome the problem of rejection and provide a source of "farmed" organs for transplant into humans.

The potential of the new technique, if it worked, was enormous. Throughout the Western world thousands of people die each year waiting for donor organs and thousands more never make it on to the waiting lists. In Britain, almost 5,500 people are waiting for an organ and 2,500 transplants were carried out last year.

A report by the US investment bank Salomon Brothers estimated that worldwide there were 45,000 human organ transplants in 1994 but that with an unlimited supply of pig organs this could grow tenfold to 455,000 by 2010 with a total value of $6bn (pounds 4bn) a year.

In 1995 the team, which had formed a small biotechnology company called Imutran, became the first in the world to transplant pig hearts into monkeys. A pig's heart would normally be rejected within minutes, but the monkeys were still alive 60 days later. The scientists could barely contain their excitement and, at a celebratory press conference, they said they expected to carry out the first human transplant within a couple of years.

A second series of transplants using kidneys a year later convinced them that they had overcome the first big hurdle of rejection.

Excitement spread to the global pharmaceutical industry and in 1996 Imutran was bought by Sandoz Pharma, now part of the Swiss multinational Novartis, for an undisclosed sum.

Then disaster struck. The Government had set up an inquiry into xenotransplantation (animal to human) under the chairmanship of Ian Kennedy, professor of medical law and ethics at King's College London. There were concerns about the ethics of using animals for transplantation and about the risks of transmitting animal viruses into the human population.

The Kennedy report concluded that it would be ethical to proceed with the first human trials only if the risks to the patient and the population were reduced to "tolerable margins", the pigs were properly looked after and the cost of the research, in terms of its impact on other medical or surgical treatments, was acceptable.

The chief fear was that a virus might spread from pigs into the human population, in the way that Aids was thought to have spread from monkeys in central Africa. BSE (mad cow disease) had shocked scientists by spreading from sheep to cows and then to humans. In the Doomsday scenario, it was feared that a small scientific experiment in Britain might trigger a worldwide epidemic.

Professor Robin Weiss, formerly of the Institute of Cancer Research, was the first scientist to warn of the risk of transmission of pig viruses. He warned that four pig retroviruses had been identified and laboratory studies had shown that two had the potential to infect humans. Retroviruses cannot be bred out of the pigs because they are inserted in the DNA of the cell and genetic modification of the pigs could make viral transmission more likely.

The Government responded by banning experimental pig-to-human transplants until research had been done to show they were safe. It also established the Xenotransplantation Interim Regulatory Authority, to which all applications for permission to conduct trials have to be made.

After a two-and-a-half-year hiatus, yesterday's study, conducted with the Centre of Disease Control in Atlanta, Georgia, and published in Science magazine, provides strong evidence that the risk of viral transmission is small.

Among 160 patients world-wide treated with living pig cells, in skin grafts and other procedures, none had been infected with a pig virus. Of the 160, 36 were on immunosuppressant drugs so could have been presumed to be at greater risks. In some patients living pig cells were circulating in their body more than eight years after treatment, which demonstrated that pig tissue could "survive in the human body for long periods with no ill-effects," according to the statement issued by Novartis.

Dr Corinne Savill, chief executive of Imutran, said: "We think it is good news and we are very pleased." Two further, so far unpublished, studies have failed to find any viruses in the serum of the genetically altered pigs or in monkeys thathave received transplanted organs from them, she said.

Professor Weiss remains cautious. He said: "The possibility remains that, say, one in 1,000 xenograft recipients may become infected ... The concern then will be the potential for onward transmission .... Lest we dismiss this as ridiculous we should bear in mind that the worldwide pandemic of [HIV] may be attributable to a single cross-species event."

For the individual the potential benefit is likely to be greater than the risk but for the community at large the risk-benefit equation is much harder to quantify, Professor Weiss said. "The ethical and technical problems of maintaining vigilance over xenotransplantation should not be underestimated," he added.

Dr Savill said that any patient who underwent an experimental transplant would be closely monitored and subjected to regular checks. "We would never stop working with regard to safety ," she said. But an application to conduct the first clinical trials was still years away because further work had to be done to overcome the problems of rejection.

Trials in monkeys have demonstrated that the first and most powerful immune response, known as hyperacute rejection, which prevents transplantation between species, has been overcome by the genetic modification of the pigs. The second and third stages require further development of drugs to suppress the immune response.

Sir Roy Calne, the transplant pioneer of Addenbrookes Hospital, Cambridge, and an adviser to Imutran, said the rejection problem was more difficult than the safety issue. "It is like a race with a series of high opaque hurdles," he said. "You don't know where the end is and you don't know what the next one will be until you have got over the last. Hyperacute rejection was the first hurdle and the transgenic technique seems to have solved that.

"Then there was the worry about retroviruses and safety, which was not such a big one for me because man and pigs have lived in close proximity for many years. I have read the paper very carefully and there seems no evidence of infection in humans. Now there is the question of how we are going to cope with the rejection of pig tissue. I suspect that is a fairly large barrier myself."

Sir Roy added that the prize, if success could be achieved, would be immense. "If we could do it without hurting patients it would completely revolutionise transplantation. But there is a big `if' there. We don't know where the end of the hurdle race is. We can now approach the next hurdle with a bit more confidence."

The Experts' View


Dr Vivienne Nathanson, head of science, policy and ethics at the British Medical Association

"The questions that need to be answered are whether, emotionally, people would be happy with animal transplants, and what will be the attitude of those who are against the use of animals?"


Baroness Warnock, former professor of philosophy at Oxford University and chairman of the 1984 government inquiry into test-tube babies

"The success of organ transplants is not tremendously high, and it is an enormously expensive procedure. I have no difficulties in having an organ from another animal as long as research has shown there are no dangers of becoming infected."


Canon John Polkinghorne, chairman of the science, medicine and technology committee of the Church of England

"In the production of xenograft (animal transplants), both humans and animals may be the subjects of harm and suffering. This must be kept within acceptable limits. We do not believe that our basic humanity will be violated by the introduction into human bodies of non-human genetic material."


Claire Rayner, chairman of the Patients' Association

"We have been using animal products for millennia. It won't cause the animal any particular harm as I understand it. And my guess is that they will probably be getting very good care during their lifetime because of what they'll be used for."


Professor Peter Bell, chairman of the research board at the Royal College of Surgeons

"The use of pigs as donors is a debate that has to take place. Some doctors will not want to use them and they are entitled to do so, but we will have to talk about the alternatives. The artificial heart is very much in its infancy. The alternative would be to get people to give their organs en masse. But, so far, they don't seem inclined to do that."


Angela Bolton, 26, a patient at the Royal London Hospital in east London, spends four hours on dialysis three times a week. She is waiting for a kidney

"The main thing is safety. That would really be something that I would have to know - that it's safe - and I'm sure that a lot of the other patients would need to know."