Saving our bacon?

January 31, 1997

Human organ donor rates are declining and genetically altered pigs reared to provide organs for transplants to people offer real hope. But there are serious concerns about the dangers of passing on viruses. Do the medical benefits outweigh the risks? Robert Weiss (left), a microbiologist, and John Wallwork, a transplant surgeon, offer two perspectives on the debate.

The number of sick people who would benefit from a new heart or kidney greatly exceeds the availability of human organs, so there is much excitement about the possible substitution of organs from animals. I do not think the use of tissues or organs from baboons or other monkeys is a realistic option; each is a walking menagerie of microbes. That leaves pigs, which are the right size and can be bred under controlled conditions. Pig heart valves have already been implanted safely - but these are essentially inert tissue.

There is no great hurry to proceed with pig-to-human transplants. We are not even sure which organs would be beneficial. Hearts presumably would, but with kidneys it is an open question because they process blood wastes differently. Besides, immunologists have not yet solved the problem of how the human body tends to reject transplants from other species, although genetic modification of the pig promises to prolong organ survival from minutes to days or weeks - perhaps long enough to keep a patient going until a human organ becomes available. Long enough, too, to enable pig microbes to colonise sick patients.

Zoonosis means the transfer of infectious microorganisms from animals to humans. If that affected only the recipient of the xenotransplant, it would be easier to weigh the risk of some nasty consequence against the benefit of the transplant. No medical procedure is free of risk, and I think I would go for it if I were likely to die in any case. But suppose the infection spread from the xenotransplant recipient to his or her contacts, at home or on the bus? Suppose it developed into a widespread, unstoppable epidemic? Unlikely, indeed, but not unknown. New influenza strains are thought to have come from pigs. Aids was absent from humans 30 years ago, and HIV almost certainly originated as an extremely rare sporadic event from an animal to a human host.

Some zoonoses stop at the first infected human - rabies, for example; with others we cannot be so sure. Nor should we allow familiarity to breed complacency. Just because we have lived close to domesticated animals a long time does not mean that they could not pass on unknown viruses in unusual circumstances, such as inoculation or transplantation. A new epidemic form of disease in dogs is caused by a parvovirus that only recently jumped species from cats, possibly through the hypodermic needle of a distemper vaccine manufactured in cat cells. Only this month a new fatal, disease was reported in horses in Australia, caused by a distant relative of the measles virus, that probably spread to horses from fruit bats. Two people present at the equine postmortem have died from this virus - one from acute respiratory infection, one 15 months later from brain disease.

Cattle developed a form of leukaemia as a result of vets using the same needles to vaccinate against other diseases, so that the retrovirus causing leukaemia spread from cow to cow. Then there is the probable association between BSE and its variant Creutzfeldt-Jakob disease. In fact, more people have contracted CJD over the years through implanted human pituitary extracts of growth hormone than through cows, which brings us back to transplantation.

The pigs to be used for xenotransplantation must be made free of pathogens. That is easier said than done. Although most known ones can be eliminated, what about the unknown ones? In the past ten years, three novel human herpes viruses have been discovered yet we have only scratched the surface looking for herpes viruses in pigs, Apparently healthy animals may carry harmless viruses that are lethal to humans - for example Herpes virus B of macaques. Our recent studies indicate that pig cells harbour a retrovirus, a second cousin to HIV, that can grow in human cells in culture. It is too early to say whether that presents a danger to xenotransplantation, But this virus appears to be carried as part of the pigs' own genetic make-up, so it may be very difficult to eradicate it.

Transplant recipients have to be treated with immunosuppressive drugs to prevent rejection of transplanted organs. This makes them particularly susceptible to viral infections. They could become reservoirs for newly introduced viruses to adapt to propagate in humans generally. The genetic modifications being introduced into pigs in order to make their tissues appear more "human" and to protect against hyperacute rejection could make viruses more likely to transmit to humans. This is because the factors in human blood that trigger hyperacute rejection also destroy viruses that grow in pig cells. By dampening down rejection we may well increase the potential for human infection.

I do not expect a delay in human clinical trials of xenotransplantation to retard research or to result in lives lost that could have been saved. Pig organs transplanted into monkeys are still rejected within days or at best weeks, so there is much to be done by immunologists and geneticists to improve the technology of transplantation.

Curiously, the companies that tell investors that pig organs could be a billion-pound market appear to expect the research councils to pay for this vital research. Perhaps that will be no bad thing so long as those conducting the research are clearly seen to be wholly independent of commercial pressure to proceed with xenotransplantation quickly.

In the end we have to balance the benefits and risks, not only to the transplant recipient, but also to public health. Whereas transplant surgeons might deem it sufficient to follow the Hippocratic oath for their own patients, it behoves us microbiologists to consider a broader, social Hippocratic ethic for the population at large, at least to do no harm. The risk of xenotransplantation setting off a new human-to-human epidemic disease seems remote, but is by no means inconceivable.

We must therefore strive to minimise that risk, yet it is extraordinarily difficult to quantify such a "what-if" scenario. No doubt those eager to pioneer human xenotransplantation will label me a whingeing Cassandra, prophesying doom just when the possibilities appear so bright. Yet Cassandra was proved right.

Robert Weiss is professor of viral oncology, Institute of Cancer Research, University of London.


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