THE HEART OF THE MATTER

Transplanting animal organs into humans creates ethical problems as well as medical complications. Making pig and human tissue compatible, using new genetic techniques, could reduce both and save thousands of lives. Martin Redfern reports

JEFF GETTY was living on borrowed time. As a late-stage Aids patient, he had a T4 cell count (the level of the type of immune cells in the blood that are attacked by the Aids virus) which had fallen to just 70 - about 20 times lower than normal. But 38-year-old Jeff was not the sort of person to give up hope. A self-described yuppie with a keen interest in cars and good living, he had once had a good job and a home in San Francisco. In 1985, on learning he was HIV-positive, he left work and began campaigning on behalf of those with Aids. His most recent and most difficult fight was to win approval for himself to become the first Aids patient to receive a bone marrow transplant from a baboon.

The idea was that the monkeys are almost completely resistant to infection with HIV. It gives them symptoms no worse than flu and they then become immune. So if Jeff could be given the immune system of a baboon, he too might resist the disease. It was a long shot, but he felt he had nothing to loose and lobbied hard for the experiment to win ethical approval.

Last October he succeeded but was too ill with secondary infections for the operation to take place. When it did, in December, what was left of his own immune system had to be "conditioned", as the doctors euphemistically put it. Essentially this means destroyed with drugs and radiation so it will not reject the transplant.

The doses given to leukaemia patients before a bone marrow transplant would have so damaged Jeff's weakened immune system that they might have killed him, so the cautious doctors gave him a far lower dose, injected the baboon cells and waited to see what would happen. To their surprise and relief, he began to feel better. His T4 cell count rose to a higher level than it had been for three years and, in January this year, he was able to leave hospital and resume his hobbies of sailing and weight training.

But there was another surprise. Each weekly blood test failed to detect the presence of any baboon-derived cells in his blood. It looks as if the transplant failed to take. But Jeff's doctors cannot understand why he seems so well. Did the conditioning destroy a lot of the virus? Was the remission simply spontaneous or brought about by Jeff's positive mental attitude?

Dr Suzanne Ildstad of the University of Pittsburgh, leading the team of surgeons treating Jeff, is reluctant to admit defeat. "Jeff has been very courageous in volunteering to be the first patient," she says. "A great deal of information has already been learnt, and that alone makes this a success rather than a failure."

Jeff Getty's was a unique experiment but it is unlikely to remain that way for long. Already, Dr Ildstad and her colleagues are planning an application to win approval for a second test on another patient. But Aids is just one area where animal transplants may be important in the future. Far more numerous and, on existing knowledge, more likely to succeed are transplants of whole organs: kidneys, liver, hearts.

About 20,000 hearts have been transplanted in the world and hundreds of thousands of kidneys, but there are too few donor organs to go round. As anti-rejection drugs and surgical procedures improve, so the demand for organs will grow. In Britain alone nearly 1,000 people are waiting for a heart transplant, many more for kidneys. The potential for transplants of any new organ within the US is probably 100,000 a year, but only a quarter of those will ever receive one. Improving road safety and the wearing of seatbelts has meant a decline in the supply of donor organs. In the US, doctors now have a legal obligation to ask the relatives of any suitable donor for permission to use organs; but surveys have shown they fail to do so, afraid at increasing distress. In many European countries, the law has been changed to allow the use of organs from everyone who has not specified to the contrary. Such legislation is being considered in Britain. Even so, demand seems always likely to exceed supply - a situation that has already led to questionable practices, with poor people in Turkey and India being offered money for donating one of their kidneys.

Meanwhile, surgeons have looked around for alternatives to human organs. Artificial organs are still bulky and unreliable. Living ones grown from a patient's own tissues are still far in the future. Attention has therefore turned towards animals. Last month the Nuffield Council of Bioethics published a 150-page report on how Britain might approach such "xenotransplants". It concluded that animal organs may be able to supplement significantly the present inadequate supply of human organs, and that careful research to that end should proceed. But the report also highlights complex questions of ethics and safety.

The first problem is which animal to choose. To minimise rejection, or the need to use powerful drugs to suppress it, it is essential to pick something as closely related to humans as possible. It is also crucial, however, that the chosen organ is large enough. Most monkeys and apes are smaller than humans and are slow to breed and mature. They are also intelligent and their use as forced donors raises ethical issues.

The Nuffield Council on Bioethics' report also highlights the risk of infections carried by monkeys moving into humans. Viruses, too, may be a problem. Ebola, which caused a frightening outbreak of haemorrhagic fever among humans in Zaire last year, must have a natural host - perhaps a monkey - in which its symptoms go unnoticed. Who knows what diseases may be harboured invisibly by other animals, only to appear in humans after transplants?

There have been over 20 attempts so far at transplanting organs from monkeys, usually baboons, into humans. Most have been unsuccessful in the long term; all have been controversial. The first in Britain was at the Harefield Hospital in 1975, where a 13-month-old baby was kept alive for 16 hours using a baboon heart. Two years later, the South African surgeon Christian Barnard tried unsuccessfully to transplant a baboon heart into a human.

On 26 October 1984, a 14-day old baby girl, known as Baby Fae, was given the heart of a baboon. The surgeon was Dr Leonard Bailey of the Loma Linda Hospital in California. Though Fae was not the first human to receive an animal heart, she was by far the youngest. The operation attracted huge publicity, and criticism both ethical and medical. Doctors were said to have made little attempt to find a suitable human heart and, as was revealed afterwards, hadn't even matched her blood group. The hope had been that her own immune system would be too immature to cause rejection.

Baby Fae had been born with no left ventricle, the heart chamber responsible for pumping blood around the body. One baby in 12,000 is born with the defect, and is usually allowed to die soon after birth. Leonard Bailey rejected several potential baby patients because their tissue types were too different from the baboons' hearts available. Even so, he had to use such a quantity of anti-rejection drugs that Fae died of kidney failure 20 miserable days after the operation. When asked how closely-related baboons were to humans, Leonard Bailey admitted that his religious beliefs led him to suppose that humans are not related to animals at all.

In 1992, baboon organs were in the news again. Surgeons at the University of Pittsburgh transplanted a baboon liver into a man dying of liver failure as a result of hepatitis-B infection. Human transplants are not normally given in such cases, since the hepatitis virus would probably infect the new liver, too, and cause it to fail. But baboons appear immune to the virus. In this case, the patient showed little sign of rejection and the smaller monkey liver grew to human size before the man died of an unrelated illness 71 days after the operation.

Humans are not the only receivers of donor organs. Hearts have been transplanted between different sub-species of goat and in all manner of combinations between sheep, pigs, baboons and chimps. Most bizarre of all were claims made in 1986 that an American neurosurgeon had performed 50 transplants in which the heads and bodies of apes had been exchanged. The reported aim was research to eventually provide terminal cancer patients with new bodies to support their healthy brains. The experiments were widely condemned, but they show how far things might go without regulation.

At first sight, pigs might seem a poor substitute for human or even ape donors. They are far more distantly related to us, and they appear to have a very different body structure. But they are about the right size, and so are their organs. A 75kg pig has the same-sized heart as a 75kg human, with the same pumping capacity. Indeed, John Wallworth - director of the transplant programme at Papworth Hospital, near Cambridge - has described pigs as being effectively horizontal humans. They are also easy to keep in captivity, breed prolifically and grow quickly - so it is on pigs that most attention is now focused. Rival groups in Britain and the US are now competing to be the first to carry out a successful pig transplant into a human.

The most difficult aspect of any transplant, even between humans, is rejection. Our immune systems recognise chemicals called antigens on the surfaces of foreign cells, as if they were invading organisms. They then send out chemicals called antibodies, and whole cells - killer cells - to attack them. Doctors can control this to some extent by matching the tissue type of donor and recipient. There will still be differences, but these can be controlled by drugs that suppress the immune system. Such anti-rejection drugs have improved dramatically in recent years, following the introduction of one called cyclosporin. But used in excess, they can make the patient highly susceptible to any passing infection and can also cause kidney damage.

With transplants between unrelated species, there is an additional problem. If an untreated pig heart were to be transferred directly into an untreated human, the immune reaction would be so violent that the heart would turn black in 15 minutes and be virtually destroyed in 30. This is due to chemicals, called complement, that rally to support the immune system. Where they find antibodies clustered around a foreign organ, they start to dissolve the membranes of all the organ's cells so they burst open. Human organs do not trigger this violent attack from complement because they are coated with a layer of protective protein. The breakthrough needed to prepare pig organs for transplant into humans is to "humanise" the pigs; to coat their cells with human protective protein.

Pioneering this process in Britain has been Dr David White of the Cambridge company, Imutran. He and his scientists have now succeeded in introducing the genes for two human protective proteins into pigs. To do so, they first had to construct an artificial chromosome into which they could pack the genes. (They used a chromosome that came originally from yeast). They then gave sows the same treatment used to give a human mother a test- tube baby. Egg cells from the sow's ovary were fertilised in a laboratory dish and the fertilised cells injected with the artificial chromosomes. These were implanted back into the sow, where they developed into healthy piglets which were normal except for the protective human proteins on the surfaces of their cells. Dr White is keen to point out that the pigs are not human pigs - they are, he says, just ordinary pigs with extra proteins.

On the other side of the Atlantic, Dr John Logan and his colleagues at the New Jersey biotechnology company DNX, have introduced three human proteins into pigs. They have also tried using un-humanised pigs' livers as temporary filters to clean poisons out of patients' blood. In the first patient, violent immune reactions meant that five pigs' livers were needed. Dr Logan believes humanised pigs could help avoid such numbers in th future, and could even offer the chance of a permanent transplant.

Hearts from genetically engineered pigs have already been transplanted into baboons. They were not actually substituted for the baboons' hearts, but connected to their blood circulation via blood vessels in the neck. An untreated pig's heart would have lasted no more than 30 minutes. Even at first, the genetically engineered ones lasted 30 hours. Since then, John Logan in New Jersey and John Wallworth in Cambridge have achieved typical survival times in monkeys of 40 days; some have lived for 60 days. That may not seem a very long extension to life, but it is as good as human heart transplant surgeons were achieving in the late 1960s, and could easily be long enough to keep patients alive until a suitable human organ became available. Surgeons believe that, with more experience, pigs' hearts could offer a new lease of many years of life to thousands of people.

But how would it feel to have a pig's heart beating in your chest? Psychological studies have shown that people who receive a human transplant may suffer feelings of guilt, a return to adolescent psychology, or delusions that they have inherited aspects of the donor's personality. Typically they go through three stages after their operation. To begin with they feel the new organ is still a foreign body that seems to stick out, or at least intrude into their consciousness. Some say they feel they are carrying something fragile which must not be damaged, or that the organ is their "baby". They then begin to talk less about the new organ and feel it is at least partially incorporated into their bodies. Finally, they become completely unaware of the new organ, and don't mention it unless asked.

Transplants from animals could easily produce extreme reactions during the first stage, ranging from guilt to revulsion. On the other hand, some people may prefer to have a pig's heart rather than that of a dead human being beating inside them, just as they prefer the thought of roast pork to cannibalism.

Bodies such as the British Union for the Abolition of Vivisection are strongly opposed to the use of animals as organ donors. Even the doctors and scientists involved in the project stress that the decision is for society as a whole to make. But some, including John Wallworth, feel it would be unethical to withhold animal organs if they prove safe and effective as transplants. "We have ham sandwiches, after all," he says. "If it shows clear benefit to patients in alleviating suffering, I see no problem at all." Immunologist David White agrees, adding: "We've been using insulin from pigs to treat diabetes, and heart valves from pigs for lifesaving heart surgery, for generations now. I see this as just an extension of accepted medical practice."

The latest report from the Nuffield Council on Bioethics supports that view, and emphasises the strong reasons - practical, ethical, and for reasons of safety - in using pigs rather than primates. In a few years' time, people with pigs' hearts may be healthily walking the streets.

! Martin Redfern is an executive producer with the BBC World Service science unit.