Genetically altered pigsare now being reared to provide organs for human transplants. But The THES has learnt that these potential donors could be the trigger for a devastating epidemic. David King reports.
In these days of Aids and BSE, it is hardly possible to open a newspaper without being confronted with one of humankind's most ancient terrors: the threat of plagues. But the latest danger comes not from the ranks of our ancient foes - tuberculosis, malaria and cholera - but, paradoxically, from the cutting edge of medical technology itself. All over the world, there is mounting excitement among transplant surgeons, and the biotechnology companies who aim to supply them, about the possibility of xenotransplantation - transplanting organs from pigs or baboons into humans.
Advocates argue that the supply of human organ donors is unable to keep up with the demand for transplants and that thousands of people are dying on the waiting list each year. Last year an Aids patient had a bone marrow graft from a baboon, which failed to take, but most attention has focused on pigs, genetically engineered to prevent their organs being immediately rejected by the human immune system. One of the three leading companies pursuing research in xenotransplantation is based in Britain; Imutran, in Cambridge, has said that actual transplants are no more than a year away.
Unprecedentedly for a medical development still at the research stage, and potentially capable of saving thousands of lives, there have already been public campaigns of opposition, such as that by the group, Doctors and Lawyers for Responsible Medicine. The main issue troubling the critics is the possibility that the foreign organs might contain viruses which could start new epidemics. As Paul Layman of DLRM points out, the risk is not just to the individual patient, but to the population at large. Earlier this year, Jonathan Allan, a virologist who has served on US government committees dealing with the subject, called for a ban on the use of baboons in transplants, because he believes they are too close to humans and carry viruses which might infect us.
Although the risks are thought to be lower with pigs, it is in fact impossible to screen out viruses which are unknown. Such viruses often cause no problems in their normal host species, but may cause devastating disease if they hop into humans. It is widely believed that Aids arose in this way, by transfer from African monkeys to humans.
Now The THES has discovered unpublished research that shows that such risks are far from hypothetical. Robin Weiss, professor at the Institute of Cancer Research in London has shown, for the first time, that a pig retrovirus, (the class of viruses which includes the Aids virus) is capable of infecting human cells in the laboratory. Once the virus went through one life cycle in human cells it was then able to infect a wide range of other human cells. Other labs in Britain and the US are rumoured to have similar results. Imutran says it is aware of the findings and is assessing their significance.
An unusual feature of the retroviruses is that when they infect cells they can become integrated into the cell's chromosomes. They are then inherited along with the rest of the genes. Such viruses are often incapable of multiplying in their normal host organism.
However, if cells containing these viruses are transferred to another species, the viruses can sometimes multiply in the new host, a phenomenon known as xenotropism. This possibility is made more likely when the new host's immune system is suppressed, as is essential with transplant patients.
Opinion is divided about the risk of an epidemic from such viruses. Andre Menache, president of DLRM, thinks it is so grave that animal to human organ transplantaion should "be abandoned in favour of safer alternatives". But although Weiss is concerned, and believes vigilance is necessary, his view is that, if xenotransplants can be shown to work, they should be allowed to go ahead. For although Weiss's research has shown that the pig virus can multiply in human cells, no one knows whether it actually causes human disease or whether it can be easily transmitted between people. Most retroviruses, like HIV, are only transmitted sexually, or through body fluid exchange, although one is transmitted via insect bites.
The main argument consoling these scientists, and even someone like Jonathan Allan, who has been outspokenly critical of transplants from baboons, is the evolutionary distance between pigs and humans, and the long history of intimate contact between the species. As Allan points out, with thousands of years of close contact, including, undoubtedly, exchange of body fluids during the slaughter of pigs, if a pig virus were likely to cause serious disease in humans, it would have happened by now. "On the other hand," he muses, "perhaps it has, and what we're calling a human virus now was once a pig virus." Allan thinks the chance of problems is a hundred to a thousand times lower with pigs than baboons. But, as he says, 'If they're doing 10,000 xenotransplants a year, that evens up the odds rather, doesn't it?" Weiss's results also point to a further risk, which no one is prepared to quantify. In addition to pig retroviruses, a xenotransplant patient might have their own harmless human endogenous viruses. If two retroviruses infect the same cell, they can "recombine" with each other to produce a hybrid virus, with potentially new properties. These are undoubtedly rare events, but they do happen: in a 1992 gene therapy experiment Robert Donahue and his colleagues showed that two defective retroviruses, which were each incapable of multiplying on their own, unexpectedly recombined to produce a virus which caused cancer in the monkey into which it was injected. A real worry is that a new virus could be produced in xenotransplant patients which, like HIV, did not produce symptoms for several years. In that time, it might be passed on to many people and be impossible to contain.
Companies like Imutran say they take these dangers seriously. But, in concert with prevailing bioethical opinion, they believe the medical benefits outweigh the risks. Given strict regulation and monitoring of transplant patients for signs of disease, they think we should be able to manage the risks. In Britain, a Department of Health committee chaired by Ian Kennedy of King's College, London, is due to report soon and expected to agree with the Nuffield Foundation's recommendation to set up a national committee of experts to oversee trials of the new technique. In the US, however, it looks likely that regulation will be delegated to committees in each hospital where trials are to take place. Such a prospect alarms Jonathan Allan, who argues that voluntary guidelines are "possibly the least successful method of policing these transplant procedures." A particular problem with local committees, he says, might be their susceptibility to desperate pleas from patients in need of transplants. Even the panel which approved the baboon bone marrow transplant might have been swayed by the lobbying of the patient and Aids activists.
Perhaps the crux of the problem is how our society deals with such risks. Do we choose to avoid them altogether, or do we go ahead and try to manage them and mitigate any harmful consequences? There is a lot of money riding on xenotransplants. Only the future will tell whether we are making a disastrous mistake if we allow them to go ahead.
David King is editor of GenEthics News.