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Cloning

Cloned pigs hype driven by greed not need

Biotech company PPL Therapeutics plc has claimed another major breakthrough in developing pigs for transplantation into humans (1). But PPL's glowing predictions for their technology appear to be based more on a commercial desire to attract investors than any real scientific 'advance'. It's alchemy, 21st century style.

We've heard it all before. In 1995, Cambridge-based Imutran Ltd claimed they would be ready to start clinical trials of genetically engineered pig organ transplants by the end of the following year (2). The prediction was based on the biotech company's apparent success in modifying the porcine organs so that they avoided the initial, violent immune reaction that rapidly destroys pig organs when they are transplanted into humans. It's called hyperacute rejection (HAR). Of course, the predictions proved inaccurate, but Imutran got their investment anyway: Sandoz - who have since merged with Ciba Geigy to form Novartis Pharma - bought the company in 1996, mesmerised by Imutran's over-confidence and revenue predictions of $11 billion per annum.

But by 1998, Nature magazine was observing:

"In the cold dawn of the 4th International Conference on Xenotransplantation last Autumn in Nantes, France, it was clear that optimism resulting from progress in overcoming HAR had given way to the realization that many other factors playing a role in organ rejection are still far from understood." (3)

Seven years, millions of dollars and thousands of animals later, the prospects for xenotransplantation are as remote as ever. Documents leaked from Imutran in 2000 to Uncaged Campaigns, a British bioethics pressure group, showed that some five hundred higher primates were subjected to severe and undeniably cruel transplant experiments in a controversial research campaign that was more Battle of the Somme than Blitzkrieg (4). The lesson: the immunological obstacles to such distant cross-species transplant are far more complex and inscrutable than capital-hungry biotech companies like to let on.

Subsequently, and with other approaches to organ development and assistance developing rapidly, the United Kingdom Xenotransplantation Interim Regulatory Authority (UKXIRA) concluded in typically understated style:

"It seems, therefore, that the likelihood of whole-organ xenotransplantation... being available within a clinically worthwhile time frame may be starting to recede." (5)

This was, as New Scientist observed earlier this year, "a diplomatic way of saying that the technology was dying on its feet" (6). One scientist sitting on the UKXIRA also noted that the meagre survival times that Imutran had achieved involved "very extreme" attempts at immunosuppression which, apart from having severe animal welfare consequences, "really bear no resemblance to reality in moving to man" (7).

Essentially, PPL's cloned GM pigs merely take a different route to the same place that Imutran had reached in 1994. Even the extent of PPL's success in avoiding HAR is questionable. The sugar (alpha 1,3 galactose) that PPL claim to have removed from pig cells through the deletion of the relevant gene is not the only one involved in hyperacute rejection. To complicate matters further (complications being a inevitable but often concealed element of biotechnology), removing the genes that stimulate the production of the alpha gal sugar simply creates another problem: other sugars become exposed that bind with the human antibodies that trigger rejection (8). It's perfectly possible, therefore, that PPL's cloned pigs are even less suited for human transplant than Imutran's tried, tested and failed GM pigs.

The only doctors that are likely to be seriously involved in PPL's cloned pigs are spin specialists. More PR than ER.

At Christmas 2001, PPL announced through a press release the birth of five cloned piglets lacking one copy of the alpha gal gene. A familiar public relations strategy emerged: give the pigs cute seasonal names; gloss over the biological complications; exaggerate the potential benefits of the 'advance' and downplay the suffering endured by the animals.

An article in trade magazine PRWEEK reviewed the "campaign" and sheds light on the real agenda (9).

PR company Hudson Sandler were employed by PPL Therapeutics with a "crucial objective: "to make existing and potential investors of the commercial potential of the project - estimated by Hudson Sandler to run to a possible £7.5 billion." The "most important" measure of success for the PR campaign "was the effect the announcement would have on investors and PPL's share price."

Hudson Sadler were still at the helm for the recent announcement, dealing with "Financial PR enquiries". The news release is strongly targeted at investors, with PPL claiming that they intend to have "spun-out" (i.e. sold off) the xenotransplantation programme by the end of the year (10). It appears that it is easier for PPL to portray their activities as commercially viable by using PR agencies rather than the more objective and rigorous approach traditionally used in science: publication of peer-reviewed articles.

Even conservative commentators such as Professor Patrick Bateson of the Royal Society have been highly critical of PPL's news management techniques:

"This announcement, which no doubt will boost the company's share price, could be considered premature before other scientists have had a chance to look at the claims." (11)

But accuracy is far from the only victim in this affair. It's animals who are paying the heaviest price. The PPL press release refers in passing to a fifth piglet that died shortly after birth "of unknown causes". Do PPL know more than they are letting on? Also carefully concealed is the number of failed attempts to produce the double knock-out piglets. PPL states that it has produced a further 60 single knock-out piglets since the first litter was born at Christmas 2001. The shine was taken off that announcement when days later, it emerged that Dolly the cloned sheep was suffering from premature arthritis, adding further evidence to a catalogue of strange and disturbing ailments suffered by cloned animals. Mice with an analogous gene "knocked out" all developed cataracts and went blind (12). The sense of precision and reliability conveyed by PPL in describing their experiments masks the fact that tinkering with genes inevitably causes unpredictable ripple effects throughout an animal's biology. Many questions require urgent answers: how many pigs and piglets have PPL killed in order to produce these animals? What is the health status of these piglets?

It is perhaps significant that these experiments are taking place in the US rather than at PPL's premises in Scotland. Animal experiments are virtually unregulated in the US, while in the UK proposals to vivisect animals are supposed to pass a cost-benefit test. (Though in reality the Government places very little weight on the suffering of animals and fails to question the claims of 'benefits' put forward by researchers.) The upshot of the lack of any pretence at ethical deliberation in the US is that companies wishing to perform the most extreme animal experiments will gravitate to the American 'lowest common denominator'.

Pigs are highly intelligent animals, possibly more so than dogs. The confines of the laboratory environment, the psychological traumas caused by early maternal separation in the breeding process and the bleak, sterile surroundings of the facilities required for the production of "source" pigs spell a level of suffering that those exploiting them refuse to acknowledge. But the most intense abuse is endured by the "surrogate humans" used to test the pig organs.

The PPL announcement refers coyly to a collaboration with the University of Pittsburgh's Thomas E. Starzl Transplant Institute. Here "organs and cells from these double knock-out pigs will be used in pivotal transplantation studies aimed at testing for elimination of hyperacute rejection and long term survival of these xenografts."

In plain English, this means that they propose to subject higher primates to the most invasive and traumatic experiments imaginable.

Despite the UK Government's bias towards commercial biotechnology, such experiments would now be very unlikely to receive a licence in the UK.

But, firstly, this will depend on whether PPL can entice anyone to fund this research. Major pharmaceutical firms do not give a damn about animals, but they are not too keen on wasting money on research that is unlikely to reap financial benefits in terms of marketable product. One seriously hopes that no company is foolish or callous enough to invest in these experiments. Imutran's approach -which in any case failed to stop the prevent the next wave of rejection following HAR - involved the use of three or more immunosuppressants at doses many times higher than usable in humans, plus the removal of the spleen. The effects were catastrophic. The clinical signs recorded by technicians as the primates died remain injuncted for the time being, but what little information that has emerged into the public domain gives a glimpse of genuinely horrific suffering.

The toxic effects of the immunosuppressants and the ensuing vulnerability to infections caused:

• whole body shaking
• infected and weeping wounds
• gangrene
• internal haemorrhaging
• weakness
• vomiting
• diarrhoea
• abdominal and scrotal swelling
• spasms
• cancer

In a published paper, Imutran scientists reveal what happened to one animal:

"...cervical abscess eroding the internal jugular vein leading to haemorrhage and collapse of the animal."

Another primate was transplanted with a piglet heart - into its neck. For several days as it died, it was observed holding its neck which was "swollen red" and "seeping yellow fluid."

This gruesome research cannot even predict what will happen should pig organs ever be transplanted into humans.

Baboons, for example, have different immune systems to humans and they react differently to immunosuppressant drugs. Certain pig viruses which could spread into humans do not affect baboons. Any survival times eked out in baboons or other non-human primates are unlikely to translate to human reality.

One basic consideration does not appear to have been taken into account: the primates used in this research start off healthy, while any human recipients of pig organs would already be seriously weakened.

Yet more problems exist with biological differences between pig and primate organs. For instance, pig erythropoetin, produced in the kidney, differs from the primate version. It is necessary to stimulate the production of red blood cells. But pig erythropoetin doesn't work in primates, leading to fatal anaemia. Comparisons between pig hearts and human hearts reveal several major anatomical differences, some of which stem from the fact that the pig is a horizontal animal, unlike the human. Facile remarks concerning the similarity of size between pig and human organs conceal the complex reality.

Lurking in the shadows is the constant threat of introducing new viruses into the human population through xenotransplantation. One group of viruses which is of particular concern - because they can infect human cells - are the endogenous retroviruses, cousins of the HIV virus. Normally, cross-species transmission of such viruses is very difficult. But xenotransplantation would be like rolling out the red carpet, as it potentially circumvents all the usual barriers to place a live reservoir of viruses in a severely immunosuppressed patient. Coupled with the genetic modification process which some virologists believe could pre-adapt pig viruses to human infection, and the risk is all too real. Once again, we must take the biotech firms' confident predictions of "control" over viruses with a hefty pinch of salt. There are likely to be many, many viruses in existence which we don't even know about yet.

The hype over xenotransplantation hides mammoth biological obstacles and extreme cruelty to animals. It may also lead to complacency on the part of the public with regard to human organ donation, which everyone agrees will always be superior to organs from another animal (13). Commercial xenotransplantation companies will clearly try to emphasise the purported human benefits of their research. But the truth of the matter is that financial greed is not necessarily identical with human need.

Copyright, Dan Lyons, 28.08.02

About the Author

Dan Lyons is director of Uncaged Campaigns, the leading critic of xenotransplantation in the UK. He has an honours degree in Politics and Philosophy and is conducting research into the ethical and political theory implications of xenotransplantation towards a PhD qualification.

He is currently involved in legal proceedings initiated by Imutran and its parent company Novartis Pharma resulting from Uncaged Campaigns' publication of a report authored by Mr Lyons, Diaries of Despair, based on documents leaked from the company.

Those proceedings have lasted almost two years now. Mr Lyons, who is a Defendant in the case, has recently been granted legal aid in a bid to establish the public interest justification for publication of the Imutran documents and overturn the interim injunction preventing publication of the information.

For further information please see www.xenodiaries.org.

References:

1. News Release: "World's first cloned double knock-out pigs lack both copies of gene involved in hyperacute rejection in humans", PPL Therapeutics plc, Thursday 22nd August 2002.
2. Nuala Moran, "Pig-to-human heart transplant slated to begin in 1996", Nature Medicine, Volume 1, Number 10, October 1995: 987.
3. "Briefing: xenotransplantation", Nature, Vol 391, 22 January 1998: 323.
4. Lucy Johnston & Jonathan Calvert, "Terrible despair of animals cut up in name of research", Daily Express, Thursday 21 September 2000: 18-19. See also www.xenodiaries.org and M Jennings et al, "RSPCA Report: Non-Human Primates in Xenotransplantation Research in the UK", RSPCA, 21 June 2002.
5. "United Kingdom Xenotransplantation Interim Regulatory Authority, Third Annual Report," Department of Health, 2001: 18.
6. "Waiting for a miracle: time is running out for organ transplants from animals", New Scientist (editorial), January 12, 2002: 3.
7. Professor Herb Sewell speaking at the UKXIRA Open Meeting, February 2001.
8. S.A. White and M.L. Nicholson, "Xenotransplantation", British Journal of Surgery, 1999, 86: 1499-1514.
9. Andy Allen, "Cloned pigs enthral City and medics", PRWEEK, 18 January 2002: 14.
10. See Footnote 1.
11. Quoted in "Cloned pigs raise transplant hopes", BBCi, Thursday 22 August 2002. http://news.bbc.co.uk/1/hi/sci/tech/2210306.stm.
12. R.G. Tearle et al, "The alpha-1,3-galactosesyltranferase knockout mouse - implications for xenotransplantation, Transplantation, 61, 1996: 13-19
13. As noted by the Government-appointed Kennedy Committee in its 1996 report, "Animal Tissue into Humans", Department of Health: 84-85. "The risk of reduction [in the human organ supply] would seem to depend on an over-emphasis on the likely success [of xenotransplantation]..."

Uncaged Campaigns 30.08.02