There is no longer any doubt that dormant virus from donor tissue can infect the host in cross-species transplants. Angela Ryan reports on the latest in this gruesome saga.
The Organisation for Economic Cooperation and Development (OECD) and World Health Organisation (WHO) are drawing up plans for an international watchdog to monitor the safety of xenotransplantation clinical trials, which are already underway in the United States . The scheme will monitor the risks of pathogens spreading from animals to humans, with the potential to create new pandemics. An international network of experts will be assembled to provide rapid responses to adverse events. Delegates said that the challenges of monitoring the consequences of xenotransplantation required a 'new paradigm'.
The news comes amid reports of pig endogenous retrovirus (PERV) crossing from pig cells to mice . Scripps Research Institute (La Jolla, CA) announced they had found PERV infection two months after transplanting pig pancreatic islets into immune deficient mice. The islets continued to make infectious virus particles and other mouse tissues in non-transplant sites such as the liver and spleen, were infected with PERV. In addition, PERV also infected isolated human cells in culture. Daniel Salomon, associate professor of Scripps department of molecular and experimental medicine said, "If you transplant pig tissues - at least as pig tissues exist today - there's a real possibility that you're going to move PERV from these pig tissues to humans".
The Roslin Institute announced that its parent company Geron Biomed will abandon the development of pigs for xenotransplantation. Gerons president and CEO Thomas Okarma admits that PERV transmission "is a huge problem and one of the major stumbling blocks to successfully commercializing xenotransplantation".
Other companies, such as Imutran, are proposing to use cloning to generate PERV-free animals, after first knocking out or disrupting crucial PERV genes. However, chief scientific officer for Biotransplant Julia Greenstein said "Rationally knocking out PERV is a major technical hurdle as there are around 50 copies of PERV in the pig genome and the majority are not full length or absolutely correct in sequence. It is not clear whether knocking these out genetically is really achievable".
Imutran received a major vote of no confidence at the end of last year when its parent company, Novartis, announced plans to merge its xenotransplant research with that of Biotransplant . Imutran is devel-oping a line of genetically modified pigs with 'humanised' organs , but Novartis was dissatisfied with the thirty-nine day average survival time of pig to monkey heart transplants so far achieved. Moreover, Imutran received very bad publicity after evidence of excessive cruelty to animals came to light in its UK transplant center at Huntington Life Sciences. It is blaming animal rights activists for the closure, and plans to pump $30 million into its new collaboration with Biotransplant over the next three years.
Biotransplant submitted a patent claim for the creation of hybrid human-pig pluripotent stem cells for use in therapeutic cloning which has since been rejected on ethical grounds. Novartis is hoping Biotransplant will improve the survival time of pig organs in monkeys so as to enable clinical trials to go ahead . It will set up a company in Massachusetts, where there is a more relaxed regulatory climate.
Another fatal blow for xeno-transplantation came this month from UK Xenotransplantation Regulatory Authority (UKXIRA) which expressed serious doubts over the prospects of successful pig to human transplants at its third annual public meeting in Westminster earlier in February . The expert advisory committee were given documents detailing Imutran's experiments on pig-to-primate organ transplants, that had been leaked to anti-vivisection group, Uncaged Campaigns, and exposed in the Daily Express last year. They revealed extensive animal cruelty in Imutran laboratories at Huntington Life Sciences, as well as significant lack of progress. John Dark, a Newcastle heart transplant surgeon and member of the authority, said the research yielded "disappointing" results and had "lead up a blind alley". Virologist Professor Robin Weiss (Windeyer Institute of Medical Sciences) was scathing about Imutran's approach to investigating the danger of viruses crossing from pigs to humans. He said it was extraordinary that despite his advise the company had only searched for one class of pig viruses, in a study of patients who had been exposed to living pig tissues. He said the problem of pig viruses was the most persistent obstacle to the technology.
The Authority was also critical of Novartis's decision to transfer Imutran research from the UK to the US, avoiding animal welfare regulations. Dr Maggy Jennings, a senior RSPCA official, said "serious and substantial" animal suffering and death had occurred at Huntingdon. Dan Lyons, Director of Uncaged Campaigns, grasped the nettle and said "pig organ transplants are cruel, dangerous and don't even work."
Xenotransplantation research has focused on pig organs and tissue as their biochemical profile is similar to that of human organs. However, associated problems remain significant and include hyperacute rejection, delayed rejection and cell-based immune rejection as well as novel infections that may be transmitted from donor to recipient and spread throughout the human population . There are multiple animal retroviruses and other harmful agents found in animal donor organs and cells. Furthermore, nothing is known about the survival and longevity of pig derived xenografts as no primate hosts have ever survived beyond the first month after transplant.
When xenotransplantation was first attempted during the 1960s there were no survivors and researchers concluded rejection was an insurmountable problem. Today, despite considerable investment, rejection remains an insurmountable problem while the danger of creating new viruses is now known to be inevitable. There is every reason to abandon this line of research and development immediately .
*Note added by the Editor