August 22, 2002

scientists react to breakthrough in pig-to-human transplants

PPL Theraputics, the company behind Dolly the Sheep, has successfully cloned the world’s first ‘double knock-out’ pigs. The animals were genetically altered to prevent human rejection of transplanted pig organs. This research has huge implications for cloning, ‘xenotransplantation’ (organ transplants from animals to humans) and research ethics.

Simon Best, CEO, Ardana Bioscience, said:

“This is a very impressive scientific achievement and it represents a major step forward in dealing with one of the major barriers in transplantation of organs from animals to humans. However, careful thought is still needed in assessing the risks of potential transmission of disease from animals to humans via transplantation.

“I am sure that this advance will further stir the debate about the balance of the risks and benefits of xenotransplantation. There is little doubt that increasing the availability of organs would be of huge benefit for the many thousands of patients on waiting lists for transplants.”

Chris Rudge, Medical Director for UK Transplant, the NHS organisation responsible for co-ordinating transplantation services across the UK, said:

“There is a worldwide shortage of organs for transplant and any research indicating a possible viable alternative source is of considerable interest. This would appear to be an exciting scientific development but it will be for the Department of Health to decide if or when any preliminary clinical trials can begin but, if so, it is likely to be a number of years away.

“Although this is a very interesting development there is still a lot of research work to be done before anyone knows whether this is likely to be successful in humans. There are very real concerns over the risks associated with the possible transfer to humans of infections from pigs. A Department of Health special committee called UKXIRA [UK Xenotransplantation Interim Regulatory Authority] is responsible for providing advice on any applications to start a programme of using animals organs in human beings.”

Professor Sheila McLean, Director of the Institute of Law and Ethics in Medicine at Glasgow University, said:

“This clearly is a major step forward and if widely applicable would certainly reduce the practical problems associated with xenotransplantation. However, there are many additional problems, such as the possibility of transmitting retroviruses.

“Of course, even reducing the risks of organ rejection does not address the ethical and legal issues which exist for animal to human transplants.”

Dr Susan Assinder, Senior Lecturer in Molecular Genetics, University of Wales, said:

“The number of patients needing organ transplants has skyrocketed in recent years while the number of donated organs grew only slightly. People die every day waiting for donor organs, so there is a clear incentive to try to match demand with supply from an alternative source. Pigs have had a lot of attention as potential transplant sources because their organs are the same size as ours.

“It’s clearly a very significant achievement. It is unlikely to be an automatic route to ‘rejection-free’ organs though, as there are additional rejection mechanisms that come into play. However, it is a major step on the way. The technology also has the potential to knock out specific genes to create pig models of human diseases.

“Interestingly PPL seem to have scooped the rivals on this. There was some argument when the single knockout was reported that PPL announced it in a press release in order to steal the thunder from a group in Missourri who were just about to publish in Science. They have taken a similar route this time, and this may lead to some discussion of the scientific ethics of reporting this kind of breakthrough via a Stock Market announcement rather than through a peer-reviewed journal.”

Dr Malcolm Alison, a research pathologist based at Imperial College School of Medicine, said:

“Transplanting organs from animals seems like a realistic prospect. The double knock-out technique removes special sugar molecules from the surface of the pig liver cells, so that the human immune system doesn’t recognise them as foreign.

“In fact, doctors already use pig liver cells to save lives. This ‘bioartifical liver support’, where a patient’s blood passes through a small reactor seeded with pig liver cells, removes waste chemicals from the blood that would otherwise build up inside the patient and eventually lead to coma and death. It’s used to keep people alive who have suffered liver failure, and can be used for up to 30 days before the patient gets a transplant. But you can’t keep someone wired to a liver support machine for the rest of their lives, and the pig liver cell cultures don’t live for very long. So transplantation seems like the obvious next step.

“People have always worried about the possibility of pig retroviruses transferring into humans if you did xenotransplantation. But bioartificial liver support has been used for some years, and there’s absolutely no evidence that anyone has been infected with a pig retrovirus.”

Dr Stephen Minger of the Centre for Neuroscience Research at King’s College London, said:

“While I welcome all research in this area, I have some concerns about the use of pig’s organs for human transplantation. PPL may have taken a large step forward in terms of inhibiting rejection of the transplanted organ but there may still be problems with pig retroviruses, which needs further investigation. This is one of the reasons that we are pursuing our work on human stem cells rather than relying on animal organs for human transplantation.”

Dr Graeme Laurie, Senior Lecturer at the Edinburgh Law School, said:

“The fact that we have reached this stage in cloning technology so quickly does not surprise me. It is one of the key features of modern science, and society’s response to its advances, that we find it impossible to resist doing things simply because we can.

“The promise of ‘wonder cures’, or a reduction in the serious shortfall in available organs for transplantation, makes this imperative very understandable, and I for one would not advocate attempts to ‘ban’ scientific developments of this sort, mostly because I do not believe that such a ban would ever be effective. This is not to suggest, however, that we should not have concerns, and indeed, very stringent regulation is what is called for.

“For me, the greatest ethical concern is the impact that it will have on animal rights. To be useable for transplant purposes these animals will have to be kept in super-sterile conditions, with highly artificial diets and serious limitations on their quality of life. This is not simply an extension of our current exploitation of animals for our own ends, but represents a potentially serious infringement of the respect that they are due.”

Professor Andrew George, Professor of Molecular Immunology, Imperial College London, said:

“This is an important step forward in this area, but I still feel that the biggest hurdle they have overcome was to produce the “single knock-out” pigs in December.

“In addition to organ transplants there could also be potential for using animal cells, where transplants of pancreas cells could help the many diabetes sufferers.

“I feel that they are being a little optimistic about the commencement of human clinical trials in two to four years – xenotransplantation has great potential, but before we apply it we must be confident about its safety.”

Professor John Fabre, Institute of Liver Studies, Guy’s, King’s and St Thomas’ School of Medicine, said:

“While scientifically exciting, the clinical relevance has been greatly overstated. Organs from these pigs will of course remain susceptible to new antibodies produced by recipients against hundreds of other foreign pig proteins, and to other strong rejection responses against these foreign pig proteins. It is likely that unacceptably high doses of immunosuppressive drugs would be needed to prevent rejection, even for a few months. The only way to test this is to perform xenografts from these pigs to nonhuman primates. Talk of clinical studies is premature to say the least.

“It is stated that animal organs are seen as the best solution to the problems of organ shortages. This is not necessarily the case. Alternatives are being actively pursued, eg human stem cells for diabetes, fully implantable pumps for hearts. In the case of liver, the complexity of the biochemical processes it mediates is such that liver grafts from distant species such as the pig are unlikely ever to be able to replace the human liver.

“The ethical issue of retroviral transfer from pig to man (which is in theory facilitated from organs of the double knockout pigs) remains a major one. The level of risk is not quantifiable, but even if very small, it carries potentially very grave consequences for the human species.”