Ecologist piece by Alix Fano, executive director of the Campaign for Responsible Transplantation.
ONE MAN'S MEAT
Falsified reports,incompetence,the possible introduction of AIDS and other new diseases, and not one single success story.All this lies behind the attempts to transfer the organs of one species into another, yet still the biotech companies continue to experiment, dollar signs in their eyes. Alix Fano wonders if they 'll ever get the message.
On 21 September 2000, The Daily Express landed on the news stands with an explosive story that caught the British public and much of the GM industry on the hop. The expose' was based on leaked internal reports describing xenotransplantation experiments on higher primates including cynomolgus monkeys and wildcaught baboons commissioned by Imutran, the British subsidiary of Novartis, and conducted by the controversial contract research laboratory, Huntingdon Life Sciences in Cambridgeshire. Now, although many people know that xenotransplantation experiments the process of transplanting organs, tissues and cells between different species takes place, few were aware of the horrors that were being perpetrated at Huntingdon in the name of science. The article not only highlighted extraordinary levels of animal suffering in the laboratories, but revealed glaring technical failures in the experiments conducted by the company, despite Imutran/Novartis's earlier claims that they were succeeding. These failures had been brought to the newspaper's attention by the British advocacy group, Uncaged Campaigns, whose 150page report, Diaries of Despair: The Secret History of PigtoPrimate Organ Transplant Experiments, was based on an extensive cache of leaked documents from an anonymous source. Imutran has taken legal measures to prevent Uncaged from disseminating the report. A court date was set for late November. The extent of the incompetence surrounding these experiments was staggering: the report revealed at least 520 errors and omissions in the conduct of studies, including organ weights not recorded, unlabelled and uncovered veterinary medications, inadequate surgery records, a quadruple overdose, the illegal reuse of animals, conflicting pathology reports, the accidental freezing of a kidney during transplantation surgery and a case of a swab being left inside a primate, which resulted in his death. In one particular incident, seven baboons appear to have been experimented upon despite a warning that they 'must not be worked on due to positivity for Herpes B' a virus lethal to humans.
READING BETWEEN THE LINES
Was this just pure incompetence, or is there an even more serious charge here? The documents demonstrated that, after five years of research, Imutran had improved the average survival time of monkeys with functioning pig kidneys from two to just four weeks. The success rate of heart xenotransplantation is even less tangible just 11 days according to the documents. As a result of these statistics, in April 2000, Novartis had set an 18month time limit to achieve major improvements in survival times. Uncaged Campaigns charges that Imutran/Novartis greatly exaggerated the success of their pigtoprimate experiments in published articles, by selectively using their 'best' data while ignoring data on average survival times and the overall health of the primate recipients. The 'success' of Imutran's pigtoprimate experiments should now be called into question based on the complete picture revealed by the leaked documents. What is so remarkable about this information is that the research was being carried out in a field that is so dangerous. Here was a corporate sponsored, government-sanctioned laboratory apparently overstating its success in a branch of science that will have extreme repercussions for mankind.
Was Imutran/Novartis really prepared to sanction shoddy and seemingly deceptive work in pigtoprimate organ transplantation a stepping block to pigtohuman organ transplantation merely to hit a deadline? The implications are highly disturbing, particularly as xenotransplantation hasn't had that great a track record. Since 1905, 82 humans have received whole organs from chimpanzees, baboons, pigs, goats and other animals, and all have died from infections and complications related to hyperacute rejection within hours or days of the surgeries.
Human and animal organs have evolved over the millennia to be able to deal with viruses, necessary immunities and other foibles and subtleties that each species requires. The trouble with xenotransplantation is that you just don't know what comes with each organ. Numerous published documents have warned of the dangers and unpredictability of animal viruses. The swine flu epidemic of 1918 killed 2040 million people worldwide. During 1998 and 1999, the novel Malaysian 'Nipah' encephalitis virus, which originated in fruit bats, jumped from pigs to humans, infected 269 people, killed 117, and led to the mass slaughter of one million pigs. The virus, which caused brain damage in dozens of victims, has resurfaced this year in several Malaysian villages.
In May 2000, a British farmer died after contracting a rare pig disease, streptococcus suis. It appears he inhaled the virus after it was breathed out by his pigs. A 1999 study by British scientists found that cancer-causing retroviruses are transmitted much more frequently and easily between different species in the wild than previously thought, adding concerns regarding the xenotransplantation of pig organs to humans.
In September 2000, scientists gathered at the Royal Society of London to determine whether polio vaccines made with chimp kidneys and contaminated with the simian form of HIV could have triggered the epidemic of the AIDS virus which has stricken 53 million people, most of them in Africa. If this theory proves true, it increases the odds that a potentially lethal microbe from another species could accidentally be introduced into the human population via xenotransplantation.
COMPOUNDING THE FOLLY
Despite these complex and largely unforeseeable cans of worms opened every time an organ is transplanted from one species to another, the scientists won't leave xenotransplantation alone. Pigs, they say, are source animals of choice because they breed quickly, have been extensively farmed, and have organs that are allegedly 'similar' in size to ours. Today, multinational biotechnology companies claim that they have bred 'germfree' pigs with human genes whose organs are less likely to be rejected by the human body. Soon, farms could be filled with cloned 'humanised' pigs living factories, genetically engineered to meet the world's growing demand for replacement organs. For there's money to be made. According to the United Network for Organ Sharing, a quasigovernmental organisation that coordinates human organ and tissue donation in the US, approximately 4,000 Americans die each year waiting for transplantable organs. Compared to the number who die from heart disease (726,974), cancer (539,577), pneumonia/influenza (86,449), AIDS (16,516), and by suicide (30,535), this may not seem high. But with over 60,000 Americans on transplant waiting lists (180,000 worldwide), a perceived chronic shortage of human organs and tissues, and a potential market in pig parts and expensive antirejection drugs worth $6$10 billion annually, the race to cash in on this market is officially on. Some researchers and biotechnology companies claim that putting pig organs into people may become a commercial reality within two years. Robert Michler, chief of transplantation at Ohio State University Medical Center in Columbus, believes that human trials should begin as soon as possible, as soon as 50 per cent of a group of baboons with transplanted pig hearts survive for three months a target set by the US Food and Drug Administration (FDA).
In August, scientists at BioTransplant, a Massachusetts-based xenotransplantation company, in collaboration with Massachusetts General Hospital, announced that they had bred a line of miniature pigs that could provide a 'safer source of cells, tissues, and organs for xenotransplants' because they allegedly do not transmit potentially harmful viruses to human cells. (Patents are being filed in the US and abroad to protect such allegedly lucrative 'inventions'. On 8 October 2000, The Sunday Times UK announced that BioTransplant had submitted an application to the European Patent Office for an 'embryonic pighuman hybrid', the uses for which have not been defined by the company.) BioTransplant researchers theorise that generations of inbreeding could have weakened the viruses and taken away their ability to infect. However, Porcine Endogenous Retroviruses (PERVs) a family of AIDSlike viruses that are harmless to their hosts but potentially lethal when transferred to other species are incorporated in the pig's genome and cannot be bred out. It has been estimated that hundreds of different endogenous retroviruses may be present in a given animal. BioTransplant admits that their minipigs still carry PERVs in their DNA, and thus in every organ, cell and tissue destined for transplantation.
Virologists like Dominic Borie and Robin Weiss have cautioned that endogenous retroviruses in pigs could recombine with human viruses and/or mutate into more infectious forms after transplant. Pigs may also contain other as yet unknown viruses. Daniel Salomon, a researcher at the Scripps Research Institute in La Jolla, California, has said that earlier studies, which suggested that PERVs have not infected people, 'may not have looked in the right places'. Patients injected with pig pancreatic islet cells to treat diabetes have had their peripheral blood lymphocytes (white blood cells) and blood serum tested for PERVs, and have been declared free of infection. But PERVs do not usually infect blood lymphocytes. They prefer epithelial tissues tissues that line the inside and outside of organs. Only biopsies of these tissues could reveal the presence of the pig virus(es), and such biopsies have not been done in humans. Baboon cytomegalovirus was, in fact, recently detected in stored tissue samples from a recipient of a baboon liver who died after a xenotransplant in 1992. A blood test will only pick up an active infection; but many infections (eg AIDS or 'mad cow disease') may remain latent in the body for years before they're ready to surface. So the fact that a blood test does not detect PERV in a patient's blood at a particular point in time, does not mean that that patient is not harbouring the virus. Moreover, most studies of xenotransplant patients have been retrospective, meaning that patients' blood was not sampled for PERVs periodically from the moment treatment began, as would be done in a controlled study. Most studies have also lacked a control group a group receiving a placebo transplant. Peter Collignon, an infectious diseases physician at Canberra Hospital in Australia, observes that, without a control group, there is no way to determine whether the treatment really worked. Indeed, the testing of xenograft patients that has been done to date has not established the technology's safety or its efficacy. One could go so far as to say that tests have been designed to conceal unfavourable outcomes. Many other questions and concerns remain, one of the most important being whether animal organs will ever be able to sustain human life. Will pig organs continue to grow at a 'pig rate' once transplanted into humans; will they become susceptible to human diseases; will they be able to carry out functions necessary for human survival? For example, unlike the human organ, the pig kidney lacks a mechanism for controlling levels of medicines, which could have a significant impact on a xenotransplant patient who requires several drugs. The porcine kidney cannot handle the high levels of uric acid found in the human bloodstream, which could lead to kidney stones or kidney failure; and it may not respond normally to the hormone vasopressin, which is released from the human brain. Such discrepancies could affect blood pressure, hydration and fluid balance. Human red blood cells are larger than those of the pig and there are incompatibilities in bloodclotting mechanisms, so that in a grafted pig organ, blood clotting, organ failure and death may occur from blockages in the tiny blood capillaries. A pig's heart normally pumps smaller amounts of blood per minute than required by a human, due to its horizontal posture. If the output of the heart is too low, multiple organ failure and death would result. In Transplantation Proceedings (1999, Vol 31, pp9058), M E Breimer describes physiological incompatibilities between humans and pigs, including differences in anatomy, physiology (regulation of blood circulation, hormone systems), immunology, complement and coagulation systems, pharmacology and metabolism.
Despite these seemingly insurmountable problems, pig research continues unabated. The prospect of commercial crossspecies transplantation has created huge financial incentives for multinational drug and biotechnology companies. Novartis (which also makes cyclosporine, the leading antirejection drug), Baxter Health Care and their many subsidiaries that dominate the field have already invested over $100 million in research.
Such enormous capital investment has prompted research collaborations between different companies and medical centres in an attempt to share risks and costs. Novartis is also sponsoring xenotransplant research at several American, European, and Canadian medical centres, to save on contract lab and research costs. Novartis is funding pigtoprimate xenotransplantation experiments at the Universities of Ohio State (Columbus), Pennsylvania (Philadelphia), Wisconsin (Madison), Stanford University, Massachusetts General Hospital and, in Canada, at the Universities of Western Ontario, Toronto, and Guelph. The Mayo Clinic in Rochester, Minnesota, which opened a large xenotransplant programme and pigbreeding facility last year, has forged an alliance with Baxter Health Care/Nextran, a New Jersey-based biotech company, to breed transgenic pigs whose organs would not be prone to rejection. Christopher McGregor, Mayo's director of cardiothoracic transplantation, has declined to say how much money Mayo has received from Baxter.
Despite these collaborations, there is fierce competition between each individual company or medical centre to be the first to successfully transplant pig organs into humans, driven by the desire to reap financial rewards, to gain publicity and to pacify anxious investors. Alexion Pharmaceuticals in New Haven, Connecticut, is developing stronger drugs to suppress the immune system. PPL Therapeutics, associated with the Roslin Institute in Scotland (famous for cloning Dolly the sheep and filing a world patent on the cloning of all animal species, including humans), is trying to breed transgenic pigs whose organs will not provoke hyperacute rejection when transplanted into humans because they lack a specific sugar called alphagalactosidase.
In March 2000, PPL announced it had cloned a litter of five female pigs using a double nuclear transfer technique. The company claims that pig cloning will ensure a plentiful supply of pigs for xenotransplantation.
However, cloning pigs for transplants is an expensive, technically difficult and inhumane proposition. Last May, BBC News Online reported that PPL was having trouble producing cloned pigs because none of the genetically modified embryos were surviving to term in their surrogate mothers. PPL acknowledges a 50 per cent postnatal loss of cloned animals. Cloned animals are typically weaker than their traditionally bred counterparts and may be prone to congenital abnormalities, chronic organ dysfunction, premature ageing (due to changes in chromosome structure), high infant and juvenile mortality and cancer (see Michael W Fox, Beyond Evolution, Lyons Press, 1999). Moreover, cloning pigs will not rid the animals of the numerous viruses, bacteria, and parasites they carry, which may lead to dangerous infections in humans.
Nevertheless, over the last several decades, US federal agencies have dispensed tens of millions of dollars to university researchers and private corporations for cloning and related xenotransplantation projects. The Commerce Department's Advanced Technology Program, established under the Bush Administration, has given multimilliondollar grants to corporations like Alexion Pharmaceuticals and Organogenesis Inc, and to PPL for their pigcloning projects. A B Cosimi, a researcher at Massachusetts General Hospital in Boston, received over $15 million from the National Institutes of Health (NIH) between 1992 and 2000 to study the immune response involved in xenograft rejection between pigs and baboons. A team of researchers at Duke University in North Carolina received almost $2.5 million from 1997 to 1998 to transplant pig hearts into monkeys and other animals in an effort to elucidate the 'immunological barrier to cardiac xenotransplantation'. In 1997, the NIH published an announcement on the Internet soliciting 'applications [from domestic and foreign researchers] to enhance [the] ability to transplant organs and tissues across species barriers (xenotransplantation)'. The NIH even promotes xenotransplantation in articles designed for children on its website under the guise of 'science education'.
CHANGE OF OPINION?
But not all US companies continue to be enthusiastic about xenotransplantation. In August, Geron BioMed, a US biotech firm, announced that it was cutting back funding for its Scottish subsidiary's xenotransplant research programme, Roslin BioMed, citing concerns about public health risks. Geron stated it would redirect its efforts to cultivating human stem cells for research and transplantation. Ian Wilmut, Roslin's chief scientist, said he was disappointed by Geron's decision but understood concerns about 'unknown [pig] viruses being released into the human population'. Shortly after the Geron announcement, PPL Therapeutics, which is a Roslin offshoot, distributed a press release stating that it was not abandoning its xenotransplantation research pro gramme, least of all because of virus fears, leading critics to question the motives behind the company's sudden retraction. In April 2000, the US FDA suspended cellular xenotransplant experiments in which foetal pig brain cells were injected into the brains of stroke patients. Thomas Fraser, president of the Charlestown, Massachusetts-based company Diacrin, admitted that one patient developed seizures a week after a transplant and another had minor brain swelling and muscular fatigue. The company said it would try to determine whether the pig cells or the equipment used to deliver them to the brain were to blame for the 'side effects'.
A study published in the British journal Nature on 17 August 2000 raised further questions about the safety of cellular xenotransplants. Salomon et al showed that when insulinmaking pig pancreatic islet cells were transplanted into mice with deficient immune systems, PERVs jumped the species barrier, migrated from the site of transplantation, and infected mouse tissues such as the spleen, liver, salivary gland, skin, small bowel and lung. Given this chain of events, the pig virus would likely be present in saliva, faeces, broken skin and coughedup lung secretions. Salomon and colleagues concluded that pigtohuman islet xenotransplantation could result in patients becoming exposed to infectious PERVs that might be able to replicate.
It is unlikely, however, that Salomon's study, or any other, will be heeded by US regulatory officials or companies investing in xenotransplantation. After all, reports in 1997 and 1998, stating that various strains of PERV from different breeds of pigs infected human cells, didn't seem to raise enough of a red flag for anyone to actually halt xenotransplantation research. Andr* Jestin and his colleagues at the French Agency for Food Safety in Ploufragan found that the complete genomes of, amazingly, 11 types of PERV are expressed in pig organs, including the heart, liver, pancreas and kidneys.
Jestin believes that controlling these viruses, or eliminating them via genetic engineering, will be much harder than anyone thought. Porcine pseudorabies virus has been detected in Swedish diabetes patients treated with porcine cells in 1997. And in August 1999, Science published the results of a Novartissponsored study of 160 patients in nine countries exposed to living pig tissue over a 12year period. Some patients in the study reported persistent rashes and strange fevers. But most worrisome was the finding that 30 patients who had their blood 'filtered' through pig spleens tested positive for PERV DNA; 23 patients had pig cells circulating in their bodies 8.5 years after treatment; and four patients, injected with pig cells, produced antibodies against PERVs, leading the authors to admit that 'PERV infection [could not] be excluded'.
WHO WILL ACT?
So where do we go from here? At a public meeting in January 2000, Dr Phil Noguchi, director of the US FDA's Division of Cellular and Gene Therapies, acknowledged that xenotransplantation is 'fraught with danger'. FDA documents have openly stated that '[X]enotransplantation may facilitate the transmission of known or as yet unrecognised agents to humans'. New pig viruses, like 'Nipah', and strains of PERVs, are continually being discovered. A pig virus, contracted via xenotransplantation, could spread to other humans undetected, causing an AIDSlike plague. Yet there are currently 12 FDAapproved xenotransplant clinical trials ongoing in the US. Most, if not all, are industrysponsored, and involve the use of pig cells to treat diabetes and neurological diseases, and whole pig livers and cells to perfuse ('filter') the blood of patients with acute liver failure. The FDA (which has also sanctioned the sale of unlabelled and untested genetically engineered foods) has refused to enact even a temporary moratorium on such trials, claiming that it will monitor patients closely to ensure public safety. Sound familiar? In the 1980s, the FDA allowed thousands of people to receive HIVtainted blood and blood products, resulting in thousands of cases of HIV infection and the deaths of over 10,000 haemophiliacs. Clearly, governments have chosen to ignore the P r e c a u t i o n a ry Principle in the xenot r a n s p l a n t a t i o n debate. They have also completely ignored alternatives to xenotransplantation, including prevention of disease, use of human tissue for transplant and increased human organ donation. Each and every day in the United States, 6,000 bodies full of human organs are buried or burned. That's two million each year, many times the number of organs required for all types of transplants. In 1998, the General Accounting Office found that the US is doing a poor job of retrieving organs for transplantation. Many nations, including the Netherlands, Austria, Spain, Belgium and Singapore, have seen organ donation rates soar after the passage of 'presumed consent' laws, which assume that citizens will donate their organs after death unless they 'opt out'. Although a majority of Americans (85 per cent) support organ donation, the feasibility of such a law has not been considered. Meanwhile, in the wake of the Huntingdon scandal on 22 September 2000, Uncaged Campaigns called for an independent judicial inquiry into the information contained in the leaked documents, as well as a ban on animalbased xenotransplantation research in the UK. On 26 September 2000 Novartis announced it was closing down operations at Imutran. However, the announcement added that the company was merging with USbased BioTransplant, perhaps hoping to leave a scandal behind and transfer its operations to the US, with its notoriously lax animal welfare and biotechnology regulations. Novartis, which had been collaborating with BioTransplant to breed lines of pigs with human genes, will own 67 per cent of the company and retain the rights to commercialisation of research from the new merger. In return, BioTransplant will receive royalty payments from Novartis sales. Elliot Lebowitz, BioTransplant CEO, revealed that commercialisation of xenotransplantation could generate 100 million dollars in annual revenue for his company. The work continues.
Alix Fano, MA, is executive director of the Campaign for Responsible Transplantation (CRT) and author of a chapter on xenotransplantation in the book, Redesigning Life? The Worldwide Challenge to Genetic Engineering, (Zed Books, February 2001). CRT, an international coalition of physicians, scientists and 90 publicinterest groups, is promoting a ban on xenotransplantation and advocating for safer, more costeffective and humane alternatives. Check out www.crtonline.org to learn more, sign an online petition and get involved