Xenotransplantation
"The shocking truth behind Britain's most high-profile animal experimentation project...The secret papers show horrific animal suffering despite claims to the contrary. They also reveal researchers have exaggerated the success of work aimed at adapting pig organs for human transplant."http://www.uncaged.co.uk/xeno.htm
Uncaged Campaigns has achieved an astonishing legal success by winning the right to publish the Diaries of Despair report and over a thousand pages of confidential documents that describe in unique detail harrowing experiments involving the transplant of GM pig organs into five hundred higher primates. A second leak of related documents, from the Home Office, are included in the published dossier. Visit our dedicated website at www.xenodiaries.org.
Contents
- Xenotransplantation news
- Introduction
- Xenotransplantation in a nutshell
- Virus Transfer - what the experts say
- Comments on Draft Report of the Infection Surveillance Working Group
- Comments on "Draft Guidance Notes on Biosecurity Considerations in Relation to Xenotransplantation"
- Alternatives to xenotransplantation
- Xenotransplantation links
Xenotransplantation News
Meanwhile, campaigners have achieved a surprise partial victory in Australia where the Government have agreed to impose a 5 year moratorium on animal-to-human organ transplant trials. Several of the submissions and representations in the moratorium drew heavily on Uncaged's Diaries of Despair Report and documents.
For the xenotransplantation news archive click here.
1. Introduction
We would particularly like to draw the reader's attention to sections 4 & 5 of our coverage of xenotransplantation. Both sections consist of comments on documents recently put out for consultation by working groups of the United Kingdom Xenotransplantation Interim Regulatory Authority. The first document, which examines recommendations for infection surveillance, has been published in the renowned independent journal Bulletin of Medical Ethics. This recognises the high standard of expertise that Uncaged Campaigns brings to the debate on xenotransplantation. Together, the two documents cover some of the most important issues surrounding xenotransplantation, particularly the danger of viruses crossing from xenografted pig cells and tissue into the human population. We demonstrate that xenotransplantation will always pose a threat to public health.
The two documents are also valuable insofar as they describe and analyse the ethical framework which is supposed to underpin UK Government policy on xenotransplantation. That ethical framework is a cost/benefit assessment. We conclude that the real, definite costs to animals and the potential costs to public health clearly outweigh the rather speculative benefits that may accrue to transplant patients, taking into account the relative likelihoods of a virus outbreak and successful xenotransplantation, the existence of alternative strategies to xenotransplantation (which affects the calculation of any marginal benefit to be gained from xenotransplantation), and other factors.
If you have any comments, praise or criticism, or if you would like to participate in our campaign to stop xenotransplantation, please contact us at info@uncaged.co.uk. We hope you find the material informative and stimulating!
2. Xenotransplantation in a nutshell
Genetic "Engineering"
Organ Rejection
Xenotransplants bring far more violent responses such as hyperacute rejection, an extremely strong reaction which destroys the new organ within minutes. It is thought that introducing human genes into pigs may avert this hyperacute response, but the pig organ will still face other rejection processes which scientists believe will be stronger than those faced by human organs. Finally, even if the pig organs survived there is strong evidence to suggest that they will fail to function adequately within the human body.
Uninvited Guests
"Nothing could be worse than if in trying to save our lives we inadvertently engineered a plague."
New Scientist Editorial 8th August 1998
Xenotransplantation research is being conducted not by charities or universities, but by commercial pharmaceutical and biotechnology companies. The main UK researcher is owned by Novartis, a multinational drug company which also supplies the major anti-rejection drug Cyclosporin. One estimate suggests a potential market of US$6bn for genetically manipulated animal organs, with $5bn for sales of the associated drugs. Public health, and the lives and wellbeing of hundreds of thousands of animals are being jeopardised, ultimately, for the sake of profit.
Pigs As Spare Parts Factories
Genius Or Madness?
BSE shows us the dangers of meddling with nature. Nuclear weapons show us the dangers of unleashing forces which we cannot control. Xenotransplantation is fraught with dangers known and unknown: our concern for those suffering from organ failure must not lead us to make a terrible and irreversible mistake.
3. Virus transfer - what the experts say
"It is well established that most new emerging human infectious diseases generally have their origins in other species. A direct method of establishing new infectious human disease would be to implant infected tissues from a nonhuman species into humans thus allowing viruses direct access to human tissues... Seldom, if ever, have we had as much knowledge to prevent a future epidemic. What is lacking is the wisdom to act upon that knowledge."
Dr Jon Allan, Virologist, Southwest Foundation for Biomedical Research, Texas, USA.
"If we go ahead with xenotransplantation, it will be a step in the dark"
Professor Tony Minson, Virologist, Cambridge University.
"If you are putting your bets on containment, it’s a lost cause... It is odd that a small number of people in the government are making unilateral decisions about something that could have such long-term consequences for the public."
Dr Jon Allan.
"If you have a pig transplant, you may die of leukaemia in twenty years time."
Dr David White. Founder of Imutran Ltd., biotechnology company at forefront of development of xenotransplantation.
"There are lots of viruses in pigs. One problem is that pigs have a kind of retrovirus (a retrovirus is the same family of viruses as HIV) which cannot be eliminated from the pig because it is inherited in the pig’s own DNA yet can come out as an infectious virus. What we have shown is that up to three strains of pig retrovirus can propagate in human cells, in culture, therefore there is a risk that they could infect humans and might cause disease in humans."
Professor Robin Weiss, Virologist, Institute of Cancer Research, London.
3rd November 1999
4. Comments on Draft Report of the Infection Surveillance Steering Group of the UKXIRA
1. Introduction
Before referring specifically to the Draft Report, I would like to reiterate our organisation's overarching ethical position on the subject of xenotransplantation.
Uncaged Campaigns believes that xenotransplantation is intrinsically immoral in terms of its exploitation of nonhuman animals. Animals such as pigs (and humans, for that matter) have vital interests in avoiding deliberately-inflicted suffering, fulfilling their desires and instincts, and not being killed. Their incarceration, the frustration of their natural instincts as a result of their housing conditions, and their destruction all represent fundamental abuses of their moral right to have their vital interests respected.
The prospect of xenotransplantation threatens to extend our society's abuse of animals. Therefore it represents a retrograde step in the progress of our civilisation. We appear to becoming more barbaric and more violent. The goal of extending human life in the face of naturally-occurring disease does not justify the exploitation and killing of other animals, notwithstanding the potential costs of xenotransplantation to both human recipients and the wider population.
Therefore, in our considered opinion, the entire exercise of drawing up systems for infection surveillance is premised upon a morally unjustifiable position: that xenotransplantation is acceptable.
However, we are aware that the UKXIRA's deliberations are supposed to be based upon the ethical conclusions of the Kennedy Report. (1) While we regard the moral positions adopted by the Kennedy Report as mistaken, illogical and arbitrary, (2) we will suggest that the central conclusion one must inevitably draw from the Draft Report, taking into account the Kennedy moral framework, is that xenotransplantation should still not proceed.
2. The decision-making framework
This was the core ethical position adopted by the Kennedy Report:
"We conclude that the use of the pig for xenotransplantation may be ethically acceptable. We conclude further, however, that the acceptability lies in balancing the benefit to humans against the harm both to the pig and to humans."
[Recommendation 9, Para 4.30]
It is this "balancing" or cost/benefit process which is supposed to underpin the UKXIRA's on-going deliberations. We emphasise this point because some comments made by UKXIRA members lead us to fear that this ethical basis is being ignored. (3)
The Draft Report of the Infection Surveillance Steering Group obviously has important implications for the cost/benefit analysis insofar as it indicates further potential costs to be borne by xenograft recipients and the wider population. It is our opinion that a complete and unbiased assessment of these costs will lead to the conclusion that the costs of xenotransplantation outweigh the benefits, and that therefore the xenotransplantation project should be abandoned, to quote one of the options mentioned by Professor Herb Sewell at last year's Annual Meeting.
3. Can we really expect to control viruses?
The key aim of the proposed surveillance system is to minimise the risk to public health from xenozoonoses through the rapid recognition and control of outbreaks.
Our first, broad observation is that controlling microbiological phenomena is an uncertain and risky affair in general. The risk posed by viruses, especially retroviruses, presents particular difficulties in terms of detection and treatment. The Kennedy report acknowledges:
"Viruses are difficult to treat with drugs and can mutate rapidly to resist the immune system; thereby infecting humans more readily... A further major problem lies in the inability to identify even known viruses. Infection with viruses can be difficult to detect. Even where the virus is known and a test has been developed, the test may be insensitive or give false positive results." (p. 33)
The problems of detection and treatment with unknown viruses are even more unfathomable. It is generally acknowledged that unknown porcine viruses exist. (Kennedy, p. 74)
Recipients of xenografts will be quite ill in the first place, and the administration of immunosuppressant drugs is likely to increase the range of symptoms they experience. In these circumstances, it will be difficult to identify a particular symptom as being the result of a xenozoonosis, further compounding the inherent complications of detection.
The limits of knowledge were exemplified by the recently announced results of tests on the tissue of a baboon liver recipient who was found to have been infected with a virus from the animal seven years after they had died. It had been thought that the herpes virus that had infected him was incapable of infecting humans. (4) The fact that this incident involved a primate and not a pig should not be used as an excuse for complacency for it demonstrates the unpredictability and mysteriousness of viruses in general.
The recent "Nipah" virus outbreak in Malaysia is an extremely worrying event in terms of its implications for the safety of xenotransplantation. The virus, which passed from pigs to humans, had never been seen before, and killed over a hundred of the two hundred and fifty or so people it infected.
Currently, the main virus of concern is the porcine endogenous retrovirus (PERV). One particularly worrying aspect of PERVs is that they may infect a recipient and then remain latent for many years. Even if a retroviral infection could be identified after it emerged after several years, it may be too late to stop the virus from spreading around the general population. If symptoms emerged initially in a non-recipient (because the original recipient had died before they had showed symptoms or the virus had been detected, for example), identifying the source of the outbreak as a xenotransplant would be even more difficult.
Confident assertions of "control" over microbiological phenomena, particularly viruses and retroviruses, are dangerously deluded, in our opinion. To quote Dr Jon Allan: "If you're putting your bets on containment, it's a lost cause." (5)
4. Adequacy of proposed surveillance regime
Apart from the intrinsic difficulties with attempts to survey and control infections, there are a number of additional practical difficulties with the draft proposals.
Many recent newspaper headlines have focussed on the proposal to require xenograft recipients to abstain from having children. This is perhaps the least one would expect from such recipients, and it is probably the easiest requirement to monitor, relative to other requirements. Obviously though, the patients who perhaps have most to gain from a xenograft - younger recipients - would have most to lose from a subsequent ban on reproduction. In the case of young male recipients, ensuring that they do not father any children will be particularly problematic.
The stipulation that recipients must agree to use barrier contraception consistently and for life will be very difficult to enforce in practice. With the best will in the world, it will be inevitable that some recipients will fail to comply with this requirement "consistently and for life".
Questions of consent and enforcement become even more difficult and dubious around the requirement for recipients to have their current and future sexual partners registered and monitored by health authorities. In particular, is it really ethical and practical to expect future sexual partners to be bound by arrangements made by their partners before their relationship started? We think not.
The lifelong monitoring system for recipients envisages a testing frequency of once a year after one year, with the frequency of sampling reviewed after two years. Given the possibility of any xenozoonotic infection remaining latent before emerging after a number of years, the proposed sampling frequencies appear to be inadequate. The practical difficulties of ensuring that recipients comply with these requirements several years after transplantation are also worrying. There will inevitably be a tendency towards complacency in this situation. Ironically, should xenotransplantation become fairly effective (though we believe this is unlikely, especially in the case of organs), this will proportionately increase the difficulties in ensuring lifetime monitoring of recipients.
If no "untoward events" appeared in initial small-scale clinical trials, then the Steering Group envisages a relaxation of the surveillance programme. Indeed, such a relaxation "would have to be the case before xenotransplantation could be used a routine therapy." (6) (The Draft Report does not explain why this would be the case.) We firmly believe that any proposals to relax surveillance requirements would lead to public health being jeopardised to an even greater extent. Given that the risk of xenozoonosis is acknowledged to be small, the likelihood of an untoward event occurring is likely to increase in proportion with the numbers and survival rates of any recipients. To propose to relax surveillance requirements under such circumstances is illogical and dangerous in the extreme. The potential for any infection to remain latent exacerbates the long-term hazard of xenozoonosis.
The proposed post-xenotransplantation surveillance scheme for contacts is disturbingly inadequate. Once again, the potential for latent infection underlines the need for consistent monitoring for life. The current scheme is far too reactive, relying as it does on the identification of xenozoonotic "untoward events". Reacting to infections that may cause symptoms after being latent is like shutting the stable door once the horse has bolted. In such cases, the so-called "incident control team" will be superfluous.
Aside from doubts over effectiveness, the prospect of introducing rapid emergency legislation, including detention for testing, in the event of a xenozoonotic outbreak threatens to breach basic human rights to liberty. Although prospective recipients in a life and death situation may agree to submit to such measures in the instance of an "untoward event" (although problems will arise regarding how valid consent could be obtained in such circumstances), imposing such restrictions on contacts and partners could be extremely problematic.
5. Consent and public health
Transplant patients are who are being asked to agree to these measures are going to be in a fairly desperate situation. We acknowledge the emphasis that the Draft Report places on the need for extensive and unbiased information to be supplied to potential recipients. However, we are sceptical as to whether information provided to such patients would really be objective. Although the UKXIRA could check on materials intended for presentation to the patient, subtle underlying biases and pressures are bound to creep into the interactions between the prospective patient and the "independent" information-giver. (We have placed the word "independent" in quotes because we feel that such a person, with the best will in the world will have underlying prejudices in favour of xenotransplantation, or will feel indirect pressure from xenotransplantation teams to bring about a positive response to proposals to conduct xenotransplantation.)
Additionally, one must strongly question whether it is possible, in such a situation, for potential recipients to really give the matter cool, rational consideration: therefore it is debatable whether valid consent is possible.
Given the risks posed to society in general by xenozoonosis, for xenotransplantation to fulfil just one of the necessary ethical conditions, some satisfactory mechanism for democratic assent to xenotransplantation procedures must be obtained. Although approaches to this question are beyond the scope of the Draft report, such issues are central to the overall ethical acceptability of xenotransplantation. We believe that such issues have not been adequately addressed by the UKXIRA or the Government.
The infection surveillance scheme outlined by the Steering Group in the Draft Report is designed to minimise the risk not only to recipients and contacts who may have actively consented to surveillance requirements, but also to society in general. It is this risk to the general public which poses particular ethical, legal and practical problems. Given this universally acknowledged risk to society, one would expect that society, acting through the instrument of government, should be able to enforce the necessary measures to protect itself. The conclusion, therefore, that society cannot act collectively to try to protect itself through a surveillance scheme, (7) raises, in our view, further insurmountable ethical obstacles to xenotransplantation. Relying on voluntary consent to compliance is not only unsafe, but removes the right of society as a whole to defend itself.
The practical reasons why we believe voluntary consent to be an inadequate safeguard can be summarised as follows:
- The lifelong compliance and numerous additional conditions set out in A5.2 are complex, demanding and certainly vulnerable to human error. It would not be credible to expect all patients to comply with all these conditions, even with the best will in the world. Indeed, the Draft Report acknowledges this when it admits that legislation will "probably" not be needed, and that patients will "normally" perceive the need to attend regular check-ups. (8)
- Patients will be aware that they retain the right to withdraw from post-operative surveillance schemes at any time. (9)
- In practice, expecting recipient's contacts to comply with surveillance requirements will be even more difficult. Changes in patients' future relationships will complicate this situation further. Although the Group suggests: "Patients may need to be counselled about telling future sexual partners about their status as xenotransplant recipients," this cannot go anywhere near far enough to give us confidence that all such contacts would submit to the necessary requirements.
- The higher the degree of success for xenografts, the more likely it will be that recipients and contacts will fail to comply with life-time monitoring and other conditions.
A lack of confidence in voluntary consent leads us to conclude that xenotransplantation does indeed give rise to a public interest justification for the introduction of legislation to ensure compliance with surveillance requirements.
Having said that, the Steering Group's conclusion is understandable in the light of the serious potential breaches of human rights that would be contained in legislation to "protect" public health from xenozoonoses.
Therefore, the controversy over the question of whether to introduce legislation to enforce surveillance requirements brings sharply into focus the significant and serious social dangers posed by xenotransplantation, and the practical difficulties inherent in attempts to minimise the risk to public health. If it is unethical and impractical to enforce, through legislation, the (inadequate, in our view) surveillance requirements necessary to try to minimise the danger posed to society in general by xenotransplantation, then we must acknowledge that xenotransplantation is unethical, purely in terms of its social costs.
6. Financial costs of infection surveillance
The infrastructure that the Draft Report suggests is necessary to implement the required level of infection surveillance is complex and vast, including as it does several specialist teams at both local and national level and extensive microbiological testing programmes. The cost of setting up such an infrastructure is not an issue that appears to have been addressed, but it will obviously be very expensive. In an era of limited resources for health care, and bearing in mind the limitations and flaws described above and the highly experimental nature of xenotransplantation, we strongly believe that allocating precious funds to such a project would be a tragic waste of money. Furthermore, we strongly believe that such funds could be used far more effectively to improve health care services and benefit the public if it were invested in improving the quality of delivery palliative care and the efficiency and availability of existing medical technologies, including, perhaps, allotransplantation. Ultimately, the only possible beneficiaries of such an infrastructure, we believe, would be the biotechnology companies who hope to sell xenotransplantation therapies in the future to the NHS.
7. Scope for human error and practical limitations
As in any human endeavour, there is room for human error to creep in. Human error has caused disasters in many situations. The complex nature of the surveillance infrastructure and the ineffable aspects of viral phenomena it is intended to monitor exacerbate the danger of human error occurring, or problems arising simply through lack of knowledge, which will compromise the effectiveness of the surveillance regime and expose the public to health risks. Given the potentially disastrous consequences of a xenozoonosis, the comment from French virologist Claude Chastel - that xenotransplantation could lead to "a new infectious Chernobyl" - seems apt.
Although this may seem far-fetched, one must bear in mind that HIV/AIDS may have arisen from a single zoonotic event. Once the species barrier is crossed, it is without doubt impossible to be confident that any viral infection could be contained. The BSE/CJD disaster should also be a salutary reminder of the potential for both human error and ignorance to lead to public health being endangered. Present talk of very small risks in the case of xenotransplantation is very reminiscent of estimates of the risk of nvCJD at the beginning of that crisis.
Generally speaking, we believe that there will be manifold practical difficulties in implementing the various requirements of the infection surveillance regime. We believe that the Draft Report is dangerously over-optimistic in this regard.
8. Conclusion: The decision-making framework revisited
We would like to express our appreciation at the work of the Infection Surveillance Steering Group in putting together the Draft Report. We believe that it is an extremely useful document because it provides the launch pad for a serious discussion of one particular area of social costs inherent of xenotransplantation. These costs can be summarised as follows:
This analysis of the document demonstrates quite clearly that on grounds of social cost alone, the xenotransplantation project should be abandoned and research into xenotransplantation stopped immediately. We believe that there are irrefutable arguments in favour of legislation for the purpose of banning xenotransplantation.
- In practice, no xenotransplantation infection surveillance programme can be expected to provide adequate safeguards to public health. (See Section 3.)
- In practice, recipients of xenografts will be unable to fulfil all the necessary conditions "consistently and for life."
- The likelihood of close contacts, especially future contacts, complying with necessary requirements is even more remote.
- Any success that xenografts might achieve will increase the chances of non-compliance and xenozoonosis because of complacency and the frequency of operation increasing the probability of a xenozoonotic event occurring.
- Latent infection pose extreme difficulties for detection, control and treatment. Unknown viruses are similarly problematic.
- The proposal to relax surveillance requirements in the event of routine xenotransplantation is incredible.
- In practice, it will be difficult to obtain valid consent from recipients.
- No proposals have yet been made to obtain consent from society in general, which is necessary given the social risks of xenotransplantation.
- It would be impractical and a breach of basic individual human rights to enable society to protect itself from the threat of xenozoonosis by enforcing surveillance requirements through legislation. This is a very serious ethical and practical cost of xenotransplantation.
- In practice, voluntary compliance with surveillance requirements by recipients and contacts is unreliable and inadequate as a safeguard to public health.
- The cost of setting up and running the surveillance infrastructure will be prohibitive and not an effective allocation of scarce health care resources.
- It is highly likely that human error will occur at various points in the surveillance infrastrusture, further compromising public health.
However, these social costs are not the only ones to be taken into account. The case against xenotransplantation proceeding is further strengthened when we take into account the suffering, exploitation and destruction of animals and incorporate these into our cost/benefit analysis. While some may argue that it is worth continuing to research xenotransplantation in the hope of overcoming its practical difficulties, to do so would not only be an example of wishful thinking, but it would also completely ignore the on-going suffering of animals inherent to such an approach. Such ignorance is unacceptable and contrary to the guiding ethical principles of the UKXIRA.
Therefore, we strongly urge the UKXIRA to act in accordance with the bioethical framework that should underlie its regulation of xenotransplantation, and recommend to the Secretary of State for Health that the technology be outlawed immediately.
Researched and written by Dan Lyons, Uncaged Campaigns.
Footnotes
1 UKXIRA First Annual Report, p.9.
2 Uncaged Campaigns submission to consultation period following publication of "Animal Tissue Into Humans": The Science & Ethics of Xenotransplantation. See also M. Fox & J. McHale, "Xenotransplantation: the ethical and legal ramifications", Medical Law Review, 6, Spring 1998, pp. 42-61.
3 According to a report at www.healthscout.com October 26 1999, "U.K. Animal Organ Patients May Face Child Ban - Proposals meant to prevent animal viruses from crossing to humans", by Nicolle Charbonneau, David Cook says that xenotransplants are inevitable. This seems to be a rather prejudicial statement.
4 C. Norton & C. Arthur, "Transplant of baboon liver gave man virus", The Independent, 1 October 1999, p.13.
5 Quoted in D. Butler, "Last chance to stop and think on risks of xenotransplants", Nature, Vol. 392, 22 January 1998, p. 322.
6 See Annex Five, p. 31.
7 Ibid.
8 Ibid., p. 34.
9 Ibid., p. 36.
5. Comments on "Draft Guidance Notes on Biosecurity Considerations in Relation to Xenotransplantation"
Submitted to the United Kingdom Xenotransplantation Interim Regulatory Authority (UKXIRA), January 2000. Author: Dan Lyons. Copyright Uncaged Campaigns.
1. Introduction
The Draft Guidance Notes on Biosecurity Considerations in Relation to Xenotransplantation (hereafter referred to as the Biosecurity Draft) suggests a regulatory scheme designed to "minimise the possibility of infectious disease transmission in xenotransplantation." (1) Undoubtedly, the risk of infectious disease transmission (xenozoonosis) is one of the most important factors in the cost/benefit assessment that, in theory, determines whether xenotransplantation should continue to be researched. The reason for this salience is the undeniable possibility that a xenotransplantation procedure could introduce a novel infectious organism into the human population which could then cause a pandemic of catastrophic proportions. Together with the draft document produced by the UKXIRA's Infection Surveillance Working Group, the Biosecurity Draft proposes a set of procedures intended to manage the risk of xenozoonosis. Both documents are invaluable contributions to the consideration of this risk insofar as they encourage deliberation of the threat of xenozoonosis and allow us to assess how great that risk is, and whether that risk can be managed in an adequate manner by the proposed regulatory schemes. Thus, both draft documents have crucial implications for the future of xenotransplantation.
The Biosecurity Draft, which is to be considered here in a response written by Dan Lyons on behalf of Uncaged Campaigns, raises further ethical issues because of the consequences it brings for source animals. While benefits or risks to humans are, at this stage, hypothetical, the costs to animals are definite, and already being suffered. The reality of these costs gives them a unique quality in the consideration of xenotransplantation, and merits particularly deep and urgent thought.
The aim of this document is to assess the issue of xenozoonosis and the adequacy of the Biosecurity Draft's proposed regulations with a view to determining whether xenotransplantation is ethically acceptable according to the cost/benefit framework.
Chapter 2 briefly discusses the context of the Biosecurity Draft: historical instances of the cross-species transfer of viruses and the potential for such microorganisms to be transmitted from animal to humans in the event of xenotransplantation procedures taking place.
Chapters 3 & 4 make specific comments on sections of the Biosecurity Draft, focussing particularly on the adequacy of the remit of the discussion contained in the Draft and remarks concerning the suitability of pigs as source animals.
Chapter 5 discusses the danger posed by viruses that cannot be eliminated through biosecurity measures, such as porcine endogenous retroviruses and unknown viruses. By characterising this risk it is possible to estimate the level of public health protection likely to be afforded by biosecurity.
Chapter 6 assesses the efficacy of biosecurity systems in terms of the exclusion of specified pathogens from source animals, and the impact of those systems on animal welfare.
2. Viral zoonoses and xenotransplantation
To put the risk of xenozoonotic viral infection into context, it is worth recounting some of the many examples of viral diseases which have crossed the species barrier. Outbreaks of Ebola and Marburg virus (these are filoviruses) in Africa have led to mortality rates of up to 90%. The original source of these infections is thought to be bats (2), but an outbreak of Marburg virus in a laboratory in Germany in 1967 came from the blood and tissue of African Green Monkeys originating from Uganda (3). It is widely suspected that HIV (a retrovirus) infection in human beings and the subsequent disease AIDS emerged as a result of the transmission of a simian immunodeficiency virus (SIV) from primates to human beings (4). It is estimated that 23 million people worldwide are now infected with HIV, a virus that is spread relatively conservatively through sexual transmission (5) and the exchange of certain other bodily fluids such as blood.
Medically-induced zoonosis has also occurred. During the 1950s, millions of people were exposed to a monkey parvovirus, SV40, in contaminated polio vaccines produced from monkey kidney cells. SV40 DNA has been found in patients with a rare form of cancer (6). The AIDS epidemic itself may have been accidentally introduced through the culturing of a polio vaccine in chimpanzee kidney cells (7).
Sin Nombre is a little-known, fatal hantavirus which attacks the lungs and is usually carried by rodents: it has broken out at least twice in the 1990s in the southwest of the United States (8). In Australia, two new dangerous viruses have affected human beings: Lyssavirus from the black fruit bat, and Morbilli, a relative of the measles virus that killed 14 horses and three humans (9).
Most significantly, pigs themselves appear to have been a source of deadly new epidemics: the human "Spanish" influenza epidemic of 1918 that killed between 20 million and 50 million people across the globe was probably, it is believed, a mutation of a pig influenza virus that was spread from American pigs by US troops during World War One (10). More recently, the Nipah outbreak in Malaysia involved the transmission of a highly lethal, hitherto unidentified Hendra-like virus from pigs to humans. Other infectious agents that transfer between pigs and humans have lately been identified, including porcine hepatitis E virus (11) and wasting syndrome-associated circovirus (12).
With thirty new diseases - most of which have transmitted from nonhumans to humans - having been discovered in the last twenty years, some commentators have been led to assert that "newly emerging viruses are now the biggest threat to mankind [sic]." (13) The advent of HIV/AIDS alone reinforces the case that new zoonotic viruses are, at least, a serious threat to human health.
The record of zoonosis related above demonstrates that different kinds of viruses can and do cross the species barrier, sometimes to catastrophic effect. Virologist and advisor to the FDA, Jon Allan, expresses the potential of virus transfer in xenotransplantation like this:
"It is ... well established that most new emerging human infectious diseases generally have their origins in other species. A direct method of establishing new human infectious disease would be to implant infected tissues from a nonhuman species into humans thus allowing viruses direct access to human tissues." (14)
Normally, the body is afforded protection from pathogenic microorganisms by natural barriers such as the skin, mucus linings and the highly acidic environment of the gastro-intestinal tract. Xenografting bypasses these barriers, directly introducing stowaway viruses to human tissue with unparalleled efficiency: viruses that are normally blood-borne or sexually transmitted, and thus quite difficult to contract from nonhuman animals, would now have the chance to infect human tissue. Thus xenotransplantation enhances the chance of zoonosis occurring.
3. Comments on Introduction of Biosecurity Draft
In their Introduction, the Biosecurity Steering Group (BSG) states:
Xenotransplantation carries the potential to introduce infectious agents into the human population. The risk and the cost to animals must be weighed against the potential to save many human lives. It is outwith the scope of these notes to discuss the ethical issues involved but they try to address some of the important areas of concern and outline systems for managing the infectious disease risks associated with this technology.
This passage raises deep concern about the conceptual framework which has guided the work of the BSG. In particular, the BSG's position - that ethical issues fall outside the scope of the notes - must be reformed. We acknowledge that it is understandable that the BSG should investigate methods of "managing the infectious disease risks associated with this technology". However, given the terms of reference of the UKXIRA and the ethical framework laid out by the Kennedy Report (15) (echoed in the second sentence of the passage quoted above), we believe that the BSG is fundamentally mistaken in failing to discuss the "ethical issues". It is absolutely vital that the ethical implications of biosecurity considerations should be discussed. Questions such as potential efficacy of biosecurity systems and the welfare implications for animals feed directly into the cost/benefit analysis that must determine whether xenotransplantation per se is ethically acceptable and, thus, whether it should continue to be pursued.
By failing to address this fundamental question in these notes, one is left with the suspicion that the BSG refuses to address the cost/benefit implications in case they raise doubts about the overall ethical propriety of xenotransplantation. Judging from remarks made at the Open Meeting, UKXIRA members know that they ought to be open-minded about whether xenotransplantation should proceed, but in practice the regulatory deliberations are based on an assumption that xenotransplantation is ethically acceptable and therefore inevitable. (I refer once again to remarks attributed to Dr David Cook (16), and I also highlight the language used in the document which talks of what "will" happen rather than what "might" or "would" happen.) We fear that a prejudicial attitude pervades the UKXIRA which prevents it from carrying out its duties in accordance with the terms of reference and the ethical framework set out by the Kennedy Report.
4. Comments on Section 1.1 "Species"
The BSG refers to the choice of pigs as source animals "because of the appropriate size of their organs." Although this is outside the main thrust of the document in question, it is worth remarking in passing that there are physiological and biochemical disanalogies between pig organs and human organs that are potentially insuperable: considerations of size are relatively banal! For example, one study published in 1998 identified eight major anatomical differences between human hearts and pig hearts (17). Also, the BUAV/CIWF report "Animal organs into humans" highlights a number of discrepancies between pig kidneys and human kidneys (18).
The reason for raising this issue is that it is a relatively neglected topic (compared to immunology and xenozoonosis) that has an important bearing on the cost/benefit assessment. Attention to this issue, we believe, raises further serious doubts about the likely effectiveness of xenotransplants, which lightens the "benefit" side of the scales relative to the costs.
Regarding immunology, I think that there may be an error in the text of the draft document. The notes state: "The development of genetic engineering has led to the production of transgenic pigs whose tissues are less liable to acute rejection after transplantation into a human host." (my emphasis). However, to the best of my knowledge, the genetic manipulation of pigs has been intended to overcome hyperacute rejection. There are subsequent rejection processes which are sometimes referred to as acute vascular and acute cellular rejection. As far as I am aware, Imutran/Novartis are experimenting with different combinations of immunosuppressant drugs in primates to dampen these acute rejection processes. The results of these experiments appear to be more equivocal than those investigating hyperacute rejection. It is very important not to overstate the experimental success of xenotransplantation research in case we form false impressions of its likely effectiveness.
5. The limits of biosecurity measures
In a crucial statement, the BSG claims that a combination of hysterotomy derivation of the dams of source animals and the maintenance of qualified pathogen free conditions (QPF) conditions will "provide animals of sufficiently high microbiological cleanliness and also ... be acceptable from the point of view of animal welfare." We believe that this is a disturbingly complacent statement that is entirely erroneous from both public health and animal welfare perspectives, and is guided by a subjective view based on a notion of what is practically achievable rather than what is actually safe or ethically acceptable.
Before commenting on the animal welfare implications of the BSG's draft document (see section 6.2), we would like to offer observations on the issue of microbiological cleanliness, focussing for the time being on organisms which cannot be eliminated through the maintenance of "biosecure" conditions, such as porcine endogenous retroviruses. We believe that consideration of these matters clearly demonstrates that the BSG's claim that its biosecurity measures will "provide animals of sufficiently high microbiological cleanliness" is unsupportable.
5.1 Porcine Endogenous Retroviruses
The first area of concern surrounds porcine endogenous retroviruses (PERVs). PERVs appear to be closely related to gibbon ape leukaemia virus and feline leukaemia virus (FeLV). (19) In what are probably the most illuminating and significant research projects yet to have been conducted into the danger of PERVs, three classes of infectious type C PERVs have been shown to be capable of infecting human cells. (20) At least one of these PERVs will be present in "most if not all" porcine xenografts because PERVs cannot be eliminated by biosecurity methods. (21) The PERVs can infect both pig and human cell lines, indicating that PERVs have the potential to replicate in pig transplants and human cells in immunosuppressed xenograft recipients. Moreover, once the PERV has inserted itself into human cells and started to replicate, it seems to become insensitive to attack from the human immune system, in particular human complement. (22) One research group has concluded:
"Release of infectious virus from PAEC [pig primary aortic endothelial cells] occurred without mitogenic stimulation, suggesting a serious risk of retrovirus transfer after xenotransplantation." (23)Summarising the threat of PERVs, virologists Jonathan Stoye and John Coffin have written: "Transplanting an organ carrying endogenous xenotropic provirus is equivalent to injecting a patient with live C-type virus..." (24) (C-type viruses can cause cancer. (25)) The inevitable presence of infectious, human tropic PERVs in tissue or cells for xenotransplantation is, on its own, reason enough to reject the BSG's judgement that source animals will be of "sufficiently high microbiological cleanliness."
Commenting on the discovery of infectious PERVs in March 1997, Jon Allan urged: "Public health officials should resist the transplant community's clamor for animal organs in light of this data." (26) Stoye had also recommended that the best way to rule out the threat posed by such PERVs would be to eliminate them through breeding them out: "under the circumstances there seems to be no alternative." (27) However, knowledge has since emerged which demonstrates the practical impossibility of eliminating infectious PERVs. Therefore, given the lack of an adequate alternative to dealing with the threat posed by PERVs, under the circumstances, we believe that there is an unacceptable risk to public health associated with xenotransplantation.
There are further observations that highlight the potential dangers posed by PERVs. A research team at the Paul Ehrlich Institut in Germany, lead by J Denner, has produced evidence that infectious, human tropic PERVs are immunosuppressive for human lymphocytes. They conclude:
"This implies that xenotransplantation may result in a trans-species transmission of endogenous retroviruses derived from the donor animal. In analogy to HIV and SIV high-titer virus replication may cause an AIDS-like disease in the immunosuppressed human transplant recipient. Two additional points have to be considered: First, human anti-complement proteins produces by transgenic animals will also protect the virus and, second, the virus may be transmitted to other humans and thus increase its pathogenic potential." (28)Endogenous retroviruses in pigs are believed to pose no less of a risk to human health than primate endogenous retroviruses. Bearing this in mind, the results of a retrospective analysis of two baboon liver recipients' tissues are sobering: researchers detected baboon endogenous retrovirus (among others) in several types of tissue. According to the researchers, this discovery "underscores the potential infectious risks associated with xenotransplantation." (29)
Another suggestive observation was made as a result of an accident in an animal experiment. Two apparently harmless mouse leukaemia viruses (MuLVs) formed a new infectious virus through recombination, resulting in lymphomas in three of ten exposed immunosuppressed macaque monkeys within a year. Commenting on this, Dr Jon Allan said: "These results should compel public health agencies... to regard animal to human transplantation as a melting pot for retroviruses that might result in recombinant viruses with altered [i.e. increased] pathogenicities." MuLVs are closely phylogenetically related to PERVs and other C-type retroviruses. (30)
At the UKXIRA's Workshop on Porcine Endogenous Retroviruses, Professor Robin Weiss recounted another precedent of cross-species retroviral transfer: a ("presumably") endogenous retrovirus in a species of mouse that transferred to gibbons and became an exogenous gibbon to gibbon infection. (31)
PERVs in transgenic tissue may give rise to an increased risk of PERV transmission and infection. Robin Weiss has advised that viruses harboured in genetically-modified pig cells could coat themselves in the same chemicals - human regulators of complement activity (RCAs) - that have been induced to protect the graft from human complement attack, thus allowing PERVs to resist human immune system responses. One example of a virus which is similarly protected because it is coated in several human RCAs is HIV.
Another aspect of this form of porcine transgenesis that could increase the likelihood of viral transfer into the human population is that the presence of human RCAs in transgenic pigs could allow pig viruses to adapt to human conditions. This is because some RCAs, such as CD46 and CD55, are also receptors for disease-causing human viruses. In other words they allow viruses to infect human cells. With transgenic pigs expressing these human RCAs, pig viruses might adapt to recognise the human receptor in addition to the corresponding pig receptor. "These viruses would then be preadapted for transmission to the xenograft recipient and for human-to-human transmission," says Robin Weiss. Consequently, pigs genetically-modified to express human RCAs represent an additional public health risk. (32)
We must also bear in mind the fact that the heavily immunosuppressed status of xenograft recipients would also increase the likelihood of PERVs surviving, replicating and spreading in the recipient's body. The persistence of PERVs in human bodies facilitates their adaptation to human-to-human transmission.
Summary of PERV risk:
- Zoonotic retroviruses are known to cause disease, including cancer, and can be transmitted from human-to-human.
- PERVs appear to be closely related to gibbon ape leukaemia virus and feline leukaemia virus (FeLV).
- Although harmless in their natural host, retroviruses can become pathogenic in a new host.
- Laboratory research has demonstrated the ability of retroviruses to infect human cells, and become resistant to attack from human complement.
- The immunosuppressed status of the xenograft recipient allows viruses to persist and replicate more easily, which could allow the virus to adapt, either through mutation or recombination, to human-to-human transmission and/or become pathogenic.
- Transgenesis could well aid this process further by pre-adapting PERVs to human-to-human transmission before grafting takes place.
- Should the PERV be, or become, pathogenic, then this would be a very worrying scenario.
- Furthermore, should the PERV behave like HIV or HTLV (both are also retroviruses), it could spread unnoticed for years before being detected, contaminating the general population.
- Baboon ERVs have infected baboon liver recipients. PERVs are thought to be no less likely to infect humans.
Imutran/Novartis's retrospective study of pig cell and tissue contacts
"The extent to which these outcomes can be assumed to predict the outcome of other type of exposures is limited. The risk of PERV infection among humans is likely influenced by many factors, minimally including the type of xenograft, the duration of exposure, and the extent to which the recipients' immune system has been suppressed."On August 20 1999 the journal Science published the results of a study of 160 patients from around the world who had been exposed to live pig tissue. (33) The study was conducted by the main commercial proponent of whole organ xenotransplantation, Novartis, and samples were also sent to the U.S. Centers for Disease Control and Prevention.
[Dr Louise Chapman, Centers for Disease Control, U.S. (quoted in WHO EDX, 24.8.99, Vol.4 #1 990824)]
Of the 160 patients studied, the vast majority (131) had undergone extracorporeal perfusions with pig spleens (100), the HepatAssist device containing pig liver cells (28), pig kidneys (2) or a whole pig liver (1). These extracorporeal procedures lasted only minutes to a few hours (the spleen perfusions were for one hour). The levels of exposure to live pig tissue in the case of these extracorporeal perfusions is thought to be very low compared to the implantation of whole pig organs into transplant patients, as proposed by Novartis. However, as discussed below, such short term xenotransplantation procedures do appear to lead to long term exposure to a small number of pig cells as a result of pig cells being dislodged during the perfusion procedures and entering the patients' bloodstreams.
The remaining 29 patients received either pig skin grafts (15) or porcine pancreatic islet cell transplants (14). In the case of the skin grafts, the length of exposure to the porcine tissue was 10 days, a more substantial time than in the extracorporeal perfusions, but still insignificant compared to the conditions of a whole organ xenograft. The 14 subjects who received porcine pancreatic islet cells are the least irrelevant group. However, the longest survival time (and therefore exposure time) for the porcine islet cells in any of the patients was 463 days, and the shortest was only 1 day. Only 9 of the 14 patients was administered with immunosuppressive therapy, which is thought to increase the risk of viral infection.
It is important to note that none of the patients studied were treated with whole pig organ xenografts, and none of the patients were exposed to "humanised" transgenic pig tissue. The lead author of the study claims:
In the absence of patients already treated with solid organ xenotransplantation, which would be the ideal population for this study, the above patients represent the only populations of relevance available to study. (34)
However, the degree of relevance of this retrospective study is minimal, and one must also take into account the results of important in vitro studies which have demonstrated the ability of PERVs to infect human cells.
Detection of PERV DNA
Thirty patients tested positive for PERV DNA. Twenty-three of these were investigated further and appeared to have pig cells circulating in their blood (detected through tests for the presence of pig DNA), leading the researchers to surmise that the PERV they detected was still contained within the surviving pig cells. (35) The situation regarding the remaining seven PERV DNA positive patients is quite uncertain. Second samples were obtained seven months later for four of the patients, and these tested negative for PERV DNA. However, to the best of my knowledge, no mention is made of whether these four exhibited evidence of circulating pig cells. Even if the negative results of the second test were accurate, the possibility remains that these patient were indeed infected with PERV before their own immune systems destroyed the infection. The infection status of the remaining three patients was deemed uninterpretable, and although the authors suggest that there was a very low level of PERV DNA in the sample, once again PERV infection cannot be ruled out despite negative results in the tests for virions and antibodies.
In any case, one might expect the presence of PERV DNA to coincide with pig DNA, whether the PERV was still contained within pig cells or not, given that PERV DNA will need to have emerged from pig cells. Therefore, the conclusion that PERV was still lodged within the pig cells could be open to question: this uncertainty is acknowledged by the study’s authors when they admit that "PERV infection [cannot] be excluded."
The discovery of the survival of pig cells in human patients for up to eight and a half years raises many questions. Paradis et al suggest that this lengthy exposure to pig cells without any identifiable negative effects is "encouraging," and in the company's media release to coincide with the publication of the study, Novartis conclude that "This finding demonstrates that pig tissue can survive in the human body for long periods with no ill effects." However, this judgement is equivocal and rather meaningless in terms of its implications for the microbiological safety of xenotransplantation, for one can deduce very little indeed regarding whether pig tissue will always survive in the human body without causing ill effects. In fact, the very ability of pig tissue to survive in the human body for over eight years has disturbing implications in terms of the greater opportunities it gives for PERV infection, even if it were true that the twenty-three patients in question were not productively infected by an identifiable virus. This lengthy exposure period also increases the chances of mutation or recombination of the PERV taking place, a scenario which has unfolded with closely related retroviruses leading to lethal pathogenicity in nonhuman primates. (36) Significantly, none of these patients were pharmacologically immunosuppressed, which decreases their chances of experiencing PERV infection. In addition to these concerns, it must also be borne in mind that endogenous retroviruses and other C-type retroviruses would normally be expected to have lengthy latency periods before infection took place. (37) Therefore, no evidence of infection in eight years and less may have little relevance to the potential infectivity and pathogenicity of PERVs over longer exposure times.
The one conclusion that can be confidently drawn from these findings is that detectable pig viral DNA is transferred to non-pharmacologically-immunosuppressed humans through xenotransplantation procedures which involve only short term extracorporeal treatments with porcine tissue. Therefore, the potential for infection with PERV appears to exist in what are regarded as relatively limited exposures to porcine tissue. Other exposures such as cellular implants and transgenic whole organ xenotransplants are likely to lead to much greater levels of PERV DNA transfer and contact with pig cells, involving far greater levels of immunosuppression, thereby creating a much higher risk of PERV infection taking place in the xenograft recipient.
Detection of antibodies to PERV
Two patients definitely had anti-PERV antibodies, though they had tested positive before they received xenotransplantation therapy. Two other results were ambiguous. Although such results are not uncommon, the fact remains that the presence of antibodies to PERV cannot be discounted in these two instances.
Summary of the limitations of the study:
- Most of the samples tested were from extracorporeal perfusions (131 out of 160) which lasted on the order of minutes to one hour. Data from such procedures are of little relevance to the kinds of conditions that would apply in other forms of xenotransplantation. The other patients received short-term skin grafts or cell xenografts. These procedures are not analogous to whole organ xenografts because of wide discrepancies in exposure times and number of cells xenografted.
- The overall number of patients monitored was statistically low. Therefore the study has limited relevance to the safety of any xenotransplantation procedure, whether it involves cells, tissues or organs. The more xenografts take place, the more likely it will be that virus transfer will occur.
- None of the pig tissues or cells involved were transgenic - a crucial difference.
- The tests used to try to detect PERVs are not completely reliable.
- PERVs may not necessarily show up in a blood test, and may instead be hiding in patients' brain or liver cells. (38)
- PERV DNA and antibodies to PERVs were detected in some patients. Novartis/Imutran's attempts to explain these findings away are speculative and one-sided. Other scientists interpret these results as demonstrating the potential infection risks of PERVs. Furthermore, PERVs belong to a class of retroviruses with the potential for long latency periods before symptoms become apparent.
- Generally speaking, the health of these patients' immune systems is likely to have been better than that of whole organ xenograft recipients (only 36 of the 160 were pharmacologically immunosuppressed at any point). The weaker the immune system, the more likely it is that infection will take place.
- New viruses are being discovered all the time, and relatively little is known about pig retroviruses compared to human retroviruses. The Novartis/Imutran study has nothing to say about the risks from unknown viruses, although some of the patients reported persistent rashes and fevers.
Conclusion regarding PERVs
Based on all the available evidence, we sincerely believe that Imutran/Novartis's contention that this is "a major and significant new study" that represents "an important milestone in the development of this ... technology, and addresses some of the key safety issues" is, in fact, inaccurate and misleading, and is designed to obscure the persistent and ineradicable public health dangers posed by xenotransplantation.
We urge the UKXIRA to recognise the severe limitations of this retrospective study as a guide to the safety of xenotransplantation. Instead, attention should be focussed upon the studies that have clearly demonstrated the ability of three different PERVs to infect human cells, as well as historic instances of zoonoses. Of course, biosecurity rules cannot protect the general population from PERVs. Therefore, in this respect, biosecurity recommendations are intrinsically irrelevant to the safety of xenotransplantation.
5.2 Porcine cytomegalovirus (CMV) and other herpesviruses
CMV belongs to the family of herpesviruses. CMV is common in British pig herds, and can be transmitted from mother to foetus in utero, making it impossible to eliminate it by QPF breeding conditions. (39) In his presentation to the Advisory Group on the Ethics of Xenotransplantation (AGEX) workshop on infection risk, Dr Tom Alexander said he was hopeful, but not completely confident about being able to exclude CMV by other means from source pigs. (40) At the same meeting, Dr Christopher Preston, a specialist in herpesviruses from the Medical Research Council Virology Unit in Glasgow, outlined a possible scenario where, despite the employment of QPF conditions, "a CMV infection could be maintained without our knowing about it." (41)
We do not know whether CMV has now been excluded from source animals. However, should CMV, or any other porcine herpesvirus, be present in a xenograft, then the immunosuppression of the graft recipient could result in infection in the graft, leading to graft rejection.
An example of a dangerous scenario is the ability of the monkey herpesvirus B virus to cause serious, life-threatening illness in human beings. It is thought possible that this virus could establish latency in humans which, coupled with its ability to transmit from human to human, could result in a widespread, potentially deadly disease. However, experience of this type of herpesvirus suggests that the increased hazard of the virus manifests itself in related species. Therefore, while primate herpesviruses pose a particularly dangerous threat, pigs may not harbour such a perilous equivalent herpesvirus. However, the fact remains that herpesviruses can remain inactive for long periods of time and cause severe disease in a new host. The number of strains of herpesvirus harboured by pigs is unknown. Furthermore, we suggest that the introduction of human RCA's into source animals may facilitate human infection and transmission of herpesviruses as well as retroviruses and other viruses.
The possibility of a new virus coming into being through recombination poses an unknown risk. It seems that there is only a small probability of this occurring between pig and human herpesviruses, as the viruses seem to need to be very closely related. Furthermore, when artificial recombination is attempted, the new virus is no more, and sometimes less, pathogenic than the original. Nevertheless, the element of the unknown looms large even when previous experience suggests that the new hazard will probably be small: Dr Preston explains that if such an experiment were put before a biological safety committee, "it would be regarded as somewhat risky and would require stringent containment - if indeed it were permitted at all." The risk, therefore, is considered "quite severe" in this context. (42)
In addition to the uncharted dangers posed by recombination, it is widely acknowledged that there are presently unknown pig herpesviruses in existence. (43) Naturally, the potential danger they pose to public health is simply not known. We conclude that, despite the implementation of biosecurity measures, herpesviruses could pose a possible threat of xenozoonosis to both recipient and the wider population as a consequence of xenotransplantation. (44)
5.3 Other viruses
PERVs and herpesviruses are not the only classes of virus that appear to be resistant to elimination through biosecurity measures. Robin Weiss has stated: "prevalent systemic pig viruses such as porcine parvovirus and porcine circovirus... are unlikely to be wholly excluded from closed pig herds." (45) As we have mentioned earlier, a porcine wasting syndrome-associated circovirus has recently been identified as capable of transferring from pigs to humans. Clearly, this underlines the potential danger of porcine xenografts. The AGEX had recognised the potential threat posed by circoviruses when it recommended that more information about them should be gathered. (46) However, generally speaking there appears to be very little information about porcine parvoviruses and circoviruses, although it is worth noting that the aforementioned monkey SV40 virus - which infected humans through contaminated polio vaccines and is suspected of causing cancer - is a parvovirus.
Unknown viruses present virtually insurmountable obstacles to effective biosecurity. The most optimistic characterisation of the search for unknown viruses likens it to looking for a needle in a haystack. (47) Of course, viruses that are unknown cannot be reliably eliminated from source animals. The presence of latent, non-pathogenic (for pigs) viruses in source pigs is pretty certain. Obviously, the threat that such viruses pose to humans is completely unknown, but it must be acknowledged that a potential threat does exist.
The dangerously unpredictable behaviour of viruses, including the inexplicable emergence of new viruses, was highlighted in a report by an Australian Veterinary Pathologist, Tony Ross, of the discovery of the subsequently-named Menangle virus. (48) This virus is a zoonotic paramyxovirus of pigs first seen in a large piggery near Sydney, Australia in 1997. The virus caused death and deformity in pig foetuses, although other infected pigs appeared to be healthy. Two workers at the piggery in whom antibodies to the virus were detected became ill with fever, sweats and severe headaches which combined the patients to bed for four and ten days. Lymphadenopathy, morbilliform rash and weight loss were also observed.
Dr Ross works in a laboratory which conducted tests for known zoonotic porcine diseases on pigs destined for an experimental xenotransplant programme. Some of these pigs were derived from the affected piggery before the outbreak of Menangle virus. Because Menangle virus was unknown at the time, it was not tested for. The origin of the virus appears to be unknown: a large survey of pigs throughout Australia failed to detect any antibodies to the virus.
The lesson that Dr Ross' laboratory drew from this episode? They decided to withdraw from the xenotransplant programme.
5.4 Biosecurity and ineliminable viruses: a conclusion
The Biosecurity Draft states:
A list of organisms which must be absent from the animals to minimise risk of human infection must be determined and extensive health surveillance of the animals maintained.However, the following classes of viruses are unlikely to be excluded from source animals because of their systemic nature or because they cannot be detected: PERVs, CMV and other herpesviruses, circoviruses, parvoviruses, various and numerous unknown viruses. Despite the implementation of biosecurity measures, should clinical xenotransplantation procedures take place, several viruses will inevitably be transplanted which may never have had such favourable and intimate access to human tissue before. In this respect, the ability of biosecurity systems to manage the risk of infectious disease is severely limited. Given that most new human infectious diseases originate in other species, xenotransplantation is, therefore, a uniquely efficient means of establishing such diseases. Furthermore, one must bear in mind the unpredictable and highly uncontrollable nature of viruses, as well as the huge gaps in knowledge that exist, and probably always will exist.
Therefore, we urge the UKXIRA, the UK Government and regulatory authorities around the world to acknowledge that xenotransplantation poses massive potential costs to public health which cannot be eradicated. The policy implications - based on the ethical framework underpinning the regulation of xenotransplantation - that follow from this consideration alone are twofold:
lIt is unethical to continue to impose severe and fatal costs on source animals and experimental animals in xenotransplantation research programmes.
lIt would be unethical to allow clinical trials of xenotransplantation to take place because it would place public health at risk. Ironically, any observed success of such trials in terms of the absence of identifiable xenozoonoses would lead to even greater risk to public health because of the encouragement it would give to conduct subsequent xenotransplantation therapies. The greater the aggregate and average levels of exposure to live pig tissue, the more likely it will be that the risk of xenozoonoses will be realised.
6. Animal husbandry and infection containment
The most important aim of the Biosecurity Draft is to explore whether it possible to design facilities for source animals which reflect both the welfare needs of the animals and also infection containment requirements. We should not presume that the best conceivable system is necessarily adequate for either or both criteria. For instance, the considerations outlined in the previous section cast major doubts over the adequacy of any biosecurity system in terms of microbiological cleanliness and infection containment.
6.1 Maintenance of biosecure conditions
The Biosecurity Draft goes through a number of precautionary principles and measures which are designed to reduce the risk of contamination. The housing facilities for source animals must be totally isolated from other animal facilities, and high levels of security with complex access restrictions for different kinds of staff are required. All materials, including air, water, materials and staff entering the facilities must be sterilised or decontaminated. While the implementation of these measures can minimise the risk of contamination, we note that it is not claimed that such a risk can be eliminated: once again, this demonstrates the inherent difficulties in trying to control and manage microbiological entities.
The "harvesting", transport and xenografting of material from source animals also provides opportunities for contamination. We are not confident that it is feasible to design and implement watertight systems to prevent contamination from the "suspect" areas of animals while they are being dismembered. Furthermore, we believe that sterilisation of surgical and storage equipment will not reliably destroy and prevent recolonisation by all potential pathogens, such as antimicrobial-resistant bacteria.
One initial observation we would like to make stems from the distinction made by the Biosecurity Draft between gnotobiotic conditions and QPF conditions. While gnotobiotic systems should (according to the Draft: still not 100% confident!) produce animals that are free of all exogenous infectious agents, QPF systems will inevitably fall short of this standard because the barrier conditions are less absolute. Rearing source animals in gnotobiotic conditions would be extremely cruel and perhaps practically impossible for pigs as well as primates, hence the preference for QPF conditions. We are grateful that the BSG has at least ruled out the employment of gnotobiotic systems, but we note the lower levels of biosecurity offered by QPF, which still has serious animal welfare implications. This issue draws attention to the practical difficulties of simultaneously protecting animal welfare while preventing xenozoonosis occurring.
Some breaches of the QPF barrier system may be identifiable, but the most potentially dangerous breaches may go unnoticed. Any microorganisms which cause identifiable symptoms in pigs will be relatively easy to spot and assess, and will probably (though not certainly) be known. However, it would be more difficult to detect a virus that is asymptomatic in pigs, especially if such a virus were unknown. The potential public health impact of such a microorganism would be equally unpredictable. While such an infection was undetected, the introduction of live pig tissue into patients may provide a route of infection into humans not previously possible through normal environmental exposure.
Presumably, the facilities would be managed by companies who intend to sell pig tissue to the NHS or other healthcare providers. Given the financial interest in the development and establishment of xenotransplantation, there will be an inevitable temptation for breaches of the barrier system to go unreported, especially, if breaches are only suspected or managers can rationalise such breaches as unlikely to have an impact on public health. Safety considerations tend to be compromised when they conflict with commercial interests, as we have seen in other realms such as the railway industry.
The only publicised investigation into xenotransplantation production facilities bears out these concerns. According to a report by a British Union for the Abolition of Vivisection (BUAV) investigator who worked in the transgenic pig unit housed on behalf of Imutran at Harlan UK's site at Belton, Leicestershire:
The BUAV's investigator helped to clean out the pigs during February, March and April 1999. She was told that she should shower before entering and leaving the pig unit, but as no shower was provided she and other staff entered and left 'dirty'.
Conditions at Harlan were far from ideal in other ways: rooms 1 and 2, being converted from other usage, had no drainage and so were difficult to hose down properly. In the other pens the drains blocked easily. The older piglets were kept in barred pens on sawdust, underlaid by a thick rubber mat under which dirty sawdust accumulated....
By early April 1999, the rooms were prepared for the next batch of Imutran pigs. The main entrance to the unit had not been improved with respect to minimising infectious risks: only a curtain separated the outside door from the pigs and no shower had yet been provided in the unit. (49)
Even with the best will in the world, complex systems such as that proposed for the maintenance of biosecure conditions are vulnerable to human error. Many animal technicians are poorly paid, unskilled and often very young. Once again, commercial considerations will push xenograft producers to employ the cheapest labour possible, exacerbating the risk of human error and thus contamination of the source herd.
In order to attempt to monitor the health status of source animals, the Biosecurity Draft states: "All production and source animals should be considered individually and records maintained of each animal." (p. 21) This is certainly the very least one would expect in a system designed to minimise the risk to public health. However, according to a paper presented at the joint OECD-NYAS workshop, "International Issues in Transplantation Biotechnology, Including the Use of non-Human Cells, Tissues and Organs," in March 1998:
It will be impossible to provide complete individual animal screening in a timely fashion prior to performing a xenograft transplant. (50)
Not only does this cast doubt on the practicality of monitoring source animals "adequately" (by the Draft's minimal criteria), but it alerts us to the possibility that any attempts to implement individual monitoring of animals will be prone to error and inefficacy.
We are aware that Novartis has set up an Advisory Committee to make recommendations on the breeding and maintenance of pigs. Furthermore, Tony Talbot, Director of Production of transgenic pigs for Imutran/Novartis, has claimed that the approach taken by the company to the health screening of potential source animals "obviates the need for this." (51) We fear that there will be a tendency for recommendations from Imutran/Novartis to potentially compromise public health when practical difficulties arise in the production of transgenic pigs in QPF facilities. Therefore, we would like to emphasise the need for the UKXIRA to scrutinise extremely carefully any proposals made by commercial interests in xenotransplantation that may be seen as taking short cuts in the QPF transgenic pig breeding process.
Conclusion on viable maintenance of biosecurity conditions
We would like to take this opportunity to warn the UKXIRA that not only will the biosecurity systems fail to provide source animals of sufficient microbiological cleanliness, but, either through negligence or human error, the systems will not be consistently and rigorously maintained. Inevitably, breaches of biosecurity will occur that will potentially endanger public health, and one would be naive to believe otherwise. Xenozoonosis is an accident waiting to happen.
6.2 Animal Welfare
"Within the scope of a microbiologically controlled environment attempts should be made to provide good welfare standards for the animals." (52)This statement encapsulates the attitude to animal welfare exhibited in the Biosecurity Draft. However, it is imperative that the inevitable welfare implications for pigs of QPF housing conditions are assessed in themselves to see if they are ethically acceptable, rather than it being presumed that animals should have to endure whatever harms are necessary to facilitate a "microbiologically controlled environment." We shall comment in more detail on the presumptions of the UKXIRA in the conclusion of this section. In the meantime, it is necessary to describe the harms being suffered by source animals in the process of the production of material for xenotransplantation.
Pigs
As the Biosecurity Draft acknowledges, pigs are intelligent, sociable and inquisitive animals. They are widely regarded as being of similar intelligence to dogs. (It may therefore be helpful if one considered whether one would think it ethically acceptable to subject a dog to the treatment currently endured by source pigs. The fact that pigs are killed for food, and dogs are not, does not point to relevant differences in the moral worth of dogs and pigs, but rather the inconsistencies which are so prevalent in our society's treatment of nonhuman animals.) In arguing for a right to consideration for animals, the Kennedy Report states: " ...all animals, human and non-human share certain interests, such as in avoiding suffering and leading a life." (53) Leaving aside the actual suffering endured by individual pigs for one moment, the interest that pigs have in leading a life forces us to acknowledge the quite devastating and ultimate harm that a pig suffers when it is killed.
Therefore, the deliberate and systematic destruction of pigs inherent to the xenotransplantation programme is a grave moral cost that is often overlooked in ethical deliberations about xenotransplantation. Even from my own human perspective, I must admit that the continuing mass killing of pigs in our society, and the development of xenotransplantation, are based not upon a fair assessment of the moral worth of pigs, but upon a brutal and misguided pursuit of self-interest by certain industries and companies which is sustained by a violent disregard for the interests of pigs because they happen to belong to a different species. But whether one agrees wholeheartedly or not with this moral position, the killing of pigs must be acknowledged as a serious cost that must be taken into consideration.
The acquiescence to the infliction of suffering on other animals such as pigs is facilitated by a pervasive attitude (especially in parts of our society with an interest in their exploitation) that presumes that because they are not human, therefore, they are utterly different to humans in terms of their intelligence and capacity for suffering. Thankfully, Darwin's insights of emotional and psychological continuities between species are slowly filtering through our society. In a similar vein, Donald Broom, Professor of Animal Welfare at Cambridge University, has written: "It would be surprising if animals such as our domestic animals, all of which have an elaborate social organisation, did not have feelings similar to many of those of man [sic]." (54)
A fairer view of animals, especially highly intelligent mammals such as pigs, must acknowledge that the complexity of their experience of the world and their capacity for both psychological and physical suffering are closer to ours than many of us care to admit. Not only does this cast doubts over the propriety of the whole concept of xenotransplantation, but, in this context, I think we have to accept that the levels of psychological suffering that will result from incarcerating pigs in QPF conditions will be very intense indeed.
QPF conditions
The requirement to maintain pigs at a QPF status will undoubtedly lead to suffering, manifesting itself in behavioural and physiological abnormalities. In particular, the intrinsic limits to the level of environmental complexity achievable within biosecurity requirements will result in harms to the animals. When given the opportunity under natural conditions, pigs will spend some 75% of their daylight hours in rooting, foraging and exploratory activities. However, QPF pigs will be denied the opportunity to satisfy their desire for exploratory behaviour sufficiently, leading to behaviours indicative of psychological suffering such as stereotypical behaviour and aggression. This denial is cruel and therefore, in itself, provides sufficient reason to conclude that raising pigs in QPF conditions - and therefore xenotransplantation - is intrinsically wrong.
The Home Office's "Code of Practice for the Housing and Care of Pigs Intended for Use as Xenotransplantation Source Animals" (hereafter referred to as "the Code of Practice") suggests that straw or other bedding materials may ameliorate the psychological damage caused by the absence of suitable foraging substrate in QPF conditions (para 3.30). Such measures will fail to provide adequate environmental enrichment and, in any case, Imutran/Novartis have ruled out the use of straw in QPF facilities because of the risk of contamination. (55) The use of other materials to provide a soft surface will fail to provide adequate foraging substrate and the provision of other enrichment strategies could never come close to creating an environment that does not cause deprivation to pigs.
Our opposition to the raising of pigs in QPF conditions has been reflected in the RSPCA's attitudes, stated in a letter to my former colleague Alistair Currie from Maggy Jennings: (56)
The RSPCA has always expressed extremely serious concern at the welfare implications of keeping pigs in SPF/QPF conditions. We believe that this seriously curtails one of the Five Freedoms widely recognised as important farm animals.
Jennings goes on to quote from the RSPCA's submission to the AGEX:
The RSPCA is seriously concerned that the recommendation relating to the maintenance of animals in biosecure conditions will result in environmentally sterile and barren accommodation.
Other housing issues
The BUAV investigation at Harlan UK uncovered further welfare problems. Several rooms of transgenic pigs were overcrowded relative to the specifications in the "Code of Practice for the Housing and Care of Animals used in Scientific Procedures." Due, we suspect, to the overcrowding and insufficient environmental enrichment, the pigs fought on occasions causing scars to each other. Although Imutran/Novartis's promotional literature attempts to play down such behaviour by claiming that pigs "rarely inflict more than superficial scratches and grazes on each other," (57) in this instance at least they must have thought the fighting to be serious because they ordered anti-fighting spray to be used.
At Harlan, the investigator observed tiny piglets housed in weaner units that were said to contain "only a small amount of sawdust in the resting area, insufficient to provide any comfort." The report continues:
Towards the end of April two piglets, only six weeks old, were killed apparently because they had become lame. The open floors of the weaner units did not sufficiently support the trotters of small piglets, especially in the absence of bedding materials. The open floors may have caused or exacerbated lameness and hence these animals' deaths.
In February and in April 1999, the BUAV understands that more than a dozen piglets were culled. In some cases we believe this was because the pigs were found not to be transgenic; in other it was due to illness (including lameness).
It is quite clear that suffering and death are endemic features of the rearing of animals for xenotransplantation purposes, caused not only by the requirements of biosecurity, but also because of the cultures and attitudes which inevitably exist in establishments in the business of exploiting and destroying animals. Several investigations into numerous animal research and breeding establishments have repeatedly and consistently uncovered the routine flouting of regulations designed to give animals a minimum of welfare protection, not to mention instances of downright sadism. (58)
Surgical derivation and early weaning
The Code of Practice states:
The requirement for QPF xenotransplantation source animals will almost inevitably need at least one, if not both, of these procedures to provide an animal of suitable health quality for use in humans.Although, puzzlingly, the Biosecurity Draft reckons that these are not "essential safety steps," we think that we can presume that the Home Office is correct and that these procedures will almost certainly be deemed essential at some point. Both Drafts admit that such procedures will have "adverse welfare consequences." These will manifest themselves in the killing of the sow, maternal deprivation for piglets, and deprivation resulting from isolated rearing.
[para. 4.2]
We note that early weaning would involve the removal of piglets from the sow at 5-7 days (with surgical derivation, separation is immediate). Piglets naturally suckle from their mothers for 9-20 weeks and early maternal separation causes considerable distress. The Code of Practice tells us:
Physiological disorders and some abnormal behaviours in the piglets have been reported following early weaning, such as belly nosing and increased vocalisation, some persisting for several weeks. [para. 4.5.7]
Early weaning even threatens to break the rather weak regulations contained in schedule 3 of the Welfare of Livestock Regulations 1994, which stipulate that weaning before 21 days of age should not take place for animal welfare reasons.
Both surgical derivation and early weaning are particularly cruel aspects of the xenotransplantation programme. Therefore, we conclude, it would be deeply unethical to deliberately subject animals to such treatment.
Animal welfare conclusions and the overall ethical acceptability of xenotransplantation
QPF conditions and the use of surgical derivation and early weaning techniques are not only cruel and therefore wrong in themselves, but they appear to breach, in both letter and spirit, existing Welfare of Livestock Regulations (1994) which are designed to implement Conventions and Directives such as Directive 91/630/EEC. In addition to the weaning regulations mentioned above, section 20 of the Regulations states that pigs must have access to straw or other materials to satisfy behavioural needs. This will not be achieved in QPF conditions.
In sum, we must express in the strongest terms possible our deep and unequivocal opposition to the housing conditions and other procedures which are said to be necessary to minimise the risk of xenozoonosis to public health. Furthermore, we confidently predict that the reality of animal care will be even worse than the proposed guidelines suggest. The deterioration in animal welfare standards envisaged in the standards of housing and care for the pigs is a regressive and morally repugnant prospect that should have no place in a modern, enlightened society. It is quite clear that the (inadequate) biosecurity measures severely compromise decent animal welfare standards, and for that reason alone one must conclude that xenotransplantation is ethically unacceptable.
In every situation where the welfare of animals may be at odds with biosecurity requirements (e.g. lacking of foraging substrate and circumstances calling for surgical intervention or early weaning), it is the welfare of animals that stands to be compromised further. In drawing up the Biosecurity Draft and the Code of Practice, the UKXIRA and the Home Office have systematically sacrificed the wellbeing of animals for the sake of the development of xenotransplantation.
This is unjustifiable, not only because it is fundamentally abusive and unethical, but - and more importantly perhaps from a contemporary policy-making perspective - it even fails to apply the ethical decision-making framework laid down by the Kennedy Report to guide the formulation of xenotransplantation policy. To reiterate that ethical framework: the acceptability of xenotransplantation is to be determined by balancing the benefit to humans against the harm both to the pig and to humans. Only when this assessment has taken place and continues to be reappraised, and consistently and clearly demonstrates that the benefits of xenotransplantation will in all probability outweigh the costs, should it be presumed that, according to the Kennedy principles, xenotransplantation can continue to proceed.
The drawing up of the Biosecurity Draft should have been conducted in an objective, neutral spirit, exploring the feasibility and effectiveness of biosecurity measures and the level of suffering that would be endured by pigs, in order to try to determine whether the potential costs to public health and the costs to animals fall below a certain threshold.
The Kennedy Report, although far from being ethical in our opinion, at least began to reflect deep public concern over the institutionalised abuse and destruction of animals by acknowledging their right to consideration in situations where their interests are put in jeopardy. Most significantly, it suggested that animals should only be harmed and killed if the concomitant human benefit would be greater (taking into account the fact that there is only a possibility rather than a definite expectation of such benefits being realised).
The approach since adopted by the UKXIRA has regressed from this basic moral position. It is now proposed that animals should suffer however much is required in order to facilitate the development of xenotransplantation. Rather than the interests of animals being considered fairly, they will by systematically overridden for the sake of this technology.
We hope that, upon reflection, the UKXIRA will realise - and behave in a manner which exhibits the realisation - that xenotransplantation is not automatically ethically acceptable, and it most certainly is not inevitable. The UKXIRA must rediscover its ethical basis in the Kennedy Report. When the UKXIRA approaches the issue of xenotransplantation from this perspective, then we sincerely believe that they will be compelled to agree that the suffering of animals and the ineliminable threat to public health weigh heavier than the rather speculative benefits offered by xenotransplantation.
7. Summary of main conclusions and recommendations
Newly-emerging viruses pose one of the greatest threats to human wellbeing. Xenotransplantation provides a unique direct route of entry for animal viruses into the human population.
Viruses are difficult to predict, control and treat. There are vast gaps in scientific knowledge about viruses, and there will be for the foreseeable future. Indeed, viral phenomena may always lie beyond the effective grasp of technology. We should be cautious and humble in our approach to viruses: we should expect the unexpected.
Several viruses, such as PERVs, other systemic viruses and unknown viruses cannot be excluded through biosecurity measures. PERVs have been shown to be capable of infecting human cells. A commercially-sponsored retrospective study of recipients of live pig tissue has detected the presence of PERV DNA in some recipients, demonstrating the opportunity that exists for human infection by PERVs. Lack of evidence for such infection in this study fails to provide reassurance because of the fundamental limitations of the study.
Raising pigs in QPF facilities, apart from being ineffective at excluding endogenous, systemic and unknown viruses, will not reliably exclude other pathogens from the herd due to practical limitations and the inevitable occurrence of negligence and human error.
Therefore, taking the above considerations into the account, we conclude that the proposed biosecurity measures will fail to provide source animals of sufficient microbiological cleanliness. Furthermore, we believe that no biosecurity system can achieve this goal. Therefore, we recommend that the inherent risk to public health posed by xenotransplantation renders the technology unethical, at least in terms of a cost/benefit assessment of the technology.
The source animals – pigs – are highly intelligent, sociable and inquisitive animals. Biosecurity conditions will cause deep suffering to these animals, for example, the lack of environmental complexity and rooting and foraging material will cause emotional and psychological harms. Surgical derivation and early weaning will intensify animal suffering. Last but not least, the killing of animals represents the ultimate, irrevocable harm.
We believe that the deliberate exploitation, incarceration, deprivation and destruction of animals inherent to the xenotransplantation programme is wicked, and that any benefits that may accrue cannot justify such violence. However, even according to the cost/benefit assessment, when we consider these current, definite harms to animals, the potentially devastating effects of the introduction of new viral pathogens into the human population, and the rather speculative benefits offered by xenotransplantation, we believe that the harms of xenotransplantation will always massively outweigh the benefits. Therefore, as a matter of urgency, the development of xenotransplantaton should be halted, and any animals caught up in the programme should be rehomed safely in sanctuaries or other suitable accommodation.
Footnotes
1. From covering letter issued with Biosecurity Draft by the UKXIRA Secretariat in September 1999.
2. Clare Thompson, "Dead Reckoning", Sunday Times magazine, 26.6.97: 17.
3. Department of Health: The Advisory Group on the Ethics of Xenotransplantation [AGEX]. Animal tissue into humans. London: Her Majesty's Stationery Office, 1997: 34.
4. Nuffield Council on Bioethics. Animal-to-Human Transplants: the ethics of xenotransplantation. London: Nuffield Council on Bioethics, 1996: 68.
5. Thompson: 19.
6. AGEX: 34. Dr Ray Greek, "Risks and Alternatives in the United States", in Animal-to Human Organ transplants: A Medical and Legal Perspective, Fourth International Scientific Congress Vancouver, July 1997. Doctor and Lawyers for Responsible Medicine (DLRM): 12.
7. E. Hooper, The River: a journey back to the source of HIV and AIDS, Allen Lane, 1999.
8. Steve Sternberg, "Origins of an outbreak", USA TODAY, 2.7.98: 8.
9. Thompson: 17.
10. Michael Day, "Pigs caused Great War flu deaths", New Scientist, 29th March 1997: 20.
11. Robin A. Weiss, "Transgenic pigs and virus adaptation". Nature 391: 328.
12. L. Chapman, World Health Organisation electronic discussion on international xenotransplantation policy considerations (copies of discussion found at: ) (WHO EDX), Vol. 4 #1 990824, posted 25 August 1999.
13. Thompson: 17.
14. Jonathan S. Allan, "Xenotransplantation at a crossroads: Prevention versus progress", Nature Medicine 2, 1, January 1996: 18.
15. In particular, we refer to paragraph (a) of the terms of reference: "... [T]o advise: on safety, efficacy and considerations of animal welfare and any other pre-conditions for xenotransplantation for human use, and whether these have been met;...". The core ethical conclusion of the Kennedy Report was: "We conclude that the use of the pig for xenotransplantation may be ethically acceptable. We conclude further, however, that the acceptability lies in balancing the benefit to humans against the harm both to the pig and to humans."
16. According to a report at www.healthscout.com October 26 1999, "U.K. Animal Organ Patients May Face Child Ban - Proposals meant to prevent animal viruses from crossing to humans", by Nicolle Charbonneau, David Cook says that xenotransplants are inevitable. This seems to be a rather prejudicial statement.
17. Crick SJ et al, "Anatomy of the pig heart: comparisons with normal human cardiac structure", J Anat 1998 Jul; 193 (Pt 1): 105-19.
18. Langley G & D'Silva J, Animal organs in humans (BUAV & CIWF: 1998): 33-38.
19. L. Chapman, (WHO EDX), Vol. 4 #1 990824, posted 25 August 1999.
20. Takeuchi Y et al, "Host range and interference studies of three classes of pig endogenous retrovirus", J Virol 1998 Dec; 72 (12): 9986-91. Martin U et al, "Expression of pig endogenous retrovirus by primary porcine endothelial cells and infection of human cells", Lancet 1998, 352: 692-94.
21. Stoye J, "No clear answers on safety of pigs as tissue donor source", Lancet 1998, 352: 666-667.
22. Patience C et al, "Infection of human cells by an endogenous retrovirus of pigs". Nature Medicine, 1997, 3: 282-286.
23. Martin U et al, 1998.
24. Stoye J & Coffin J, "The dangers of xenotransplantation", Nature Medicine, 1 (No. 11), 1995: 1100. Proviruses are retroviral elements.
25. Allan J, "Silk purse or sow's ear", Nature Medicine, 1997, 3: 275.
26. Ibid.: 276.
27. Stoye J, "Proviruses pose potential problems", Nature 1997, 386: 126.
28. Denner J, "Imuunosuppression by retroviruses: implications for xenotransplantation", Annals of the New York Academy of Sciences, 1998, Dec 30, 862: 75-86.
29. Allan J S et al, "Amplification of simian retroviral sequences from human recipients of baboon liver transplants", AIDS Res. Hum. Retroviruses 1998, 14: 821-824.
30. Allan J, "Silk purse or sow's ear", Nature Medicine, 1997, 3: 276.
31. UKXIRA, Report of the Workshop on Porcine Endogenous Retroviruses, (6th August 1998, London, UK): 34.
32. Robin A. Weiss, "Transgenic pigs and virus adaptation". Nature 391: 328.
33. Paradis K et al, "Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue", Science, 20 August 1999, 285: 1236-1241.
34. Paradis K, WHO EDX September 14 1999, Volume 4: Number 6 990914.
35. Anon., "No PERVersion," The Economist, 21 August 1999: 75.
36. Allan J, "Silk purse or sow's ear", Nature Medicine, 1997, 3: 276.
37. For example, Dr David White, co-founder of Imutran and leading xenotransplantation researcher, has said: "If you have a pig transplant, you may die of leukaemia in 20 years' time." In Clare Thompson, "Dead Reckoning", Sunday Times magazine, 26.6.97: 22.
38. According to Peter Collignon, a microbiologist in the Infectious Diseases Unit at Canberra Hospital, Australia. (Quoted in Press Release from Campaign for Responsible Transplantation (CRT), "Coalition Exposes Flaws in Pig Transplant Study," August 23 1999.)
39. AGEX: 34-5.
40. AGEX: 204-5. At the time of publication of the AGEX report, Dr Alexander was Deputy Head of the Department of Clinical Veterinary Medicine at the University of Cambridge, and an adviser to Imutran. He claimed to be a messenger from Imutran in his workshop presentation. (213)
41. Reported AGEX: 225.
42. ibid.: 223-225.
43. ibid.: 35.
44. We would welcome feedback on the situation with herpesviruses as relatively little attention appears to have been devoted to these pathogens compared to PERVs.
45. R. Weiss, "Xenografts and Retroviruses," Science, 285 (20.8.99): 1221-1222.
46. AGEX: 73.
47. Comment from moderator on ProMED electronic discussion on xenotransplantation risks in response to posting by Dr Raymond G. Whitham ( ), 23 August 1999.
48. T. Ross, "Xenotransplants & Porcine Menangle Virus," (WHO EDX), Vol. 4 #2 990829), posted 29 August 1999.
49. BUAV, "Genetically Engineered Pigs at Harlan UK," published July 1999.
50. Swindle MM, "Defining appropriate health status and management programs for specific-pathogen-free swine fro xenotransplantation,"Annals of the New York Academy of Sciences, 1998, Dec 30, 862: 111-120.
51. (WHO EDX), Vol. 3 #6 990730, posted 30 July 1999.
52. Biosecurity Draft: 13.
53. AGEX: 62.
54. Quoted in Langley G & D'Silva J, Animal organs in humans (BUAV & CIWF: 1998): 57.
55. "Xenotransplantation: Animal Welfare", 1999, Imutran/Novartis promotional leaflet.
56. Dated 9 September 1998, Ref: MJ/ijb
57. "Xenotransplantation: Animal Welfare", 1999, Imutran/Novartis promotional leaflet.
58. Apart from Harlan UK, Huntingdon Life Sciences (HLS) has been subjected to two investigations in the last eleven years, the second one resulting in a threat by the Home Office to revoke its Certificate of Designation and the conviction of two HLS employees for cruelty to animals (HLS is one of the establishments to have been utilised in xenotransplantation breeding and research.) Other establishments to have been investigated include the Charing Cross and Westminster Medical School and the Institute of Neurology.
6. Alternatives to xenotransplantation
"Organs should be donated by humans, not stolen from animals."Companies trying to develop pig organs for human transplant, such as Cambridge-based Imutran Ltd. , have claimed that pig organs are the only way to meet the growing demand for organ transplants. Indeed, the lengthy waiting list for organs is cited as the reason for developing xenotransplantation in the first place. However, a closer examination of alternative approaches to xenotransplantation reveals that there is huge scope for improving the supply of human organs.
Strategies to improve the supply of human organs include:
Increasing the numbers of people carrying donor cards. Opinion polls consistently demonstrate that about three-quarters of the British public are willing to donate their organs in the event of their death. However, only a fifth of the population actually carry organ donor cards. (Call Freephone 0800 555 777 for copies of NHS Organ Donor Register leaflet and donor dard.)
Improving the management of the organ retrieval system. A well-funded decentralised network of transplant co-ordinators in Spain has resulted in an 'impressive' increase in Spain's transplant rates, which almost doubled over a six year period (1989-1995). The improvement is that much more impressive because it occurred despite a decrease in the number of road traffic deaths.[1]
Clarifying the currently muddled legal situation regarding organ donation, which is currently governed by the outdated Human Tissue Act 1961.
Reassessing the criteria for suitable organ donation. At present cadaveric human organs are harvested only from "heart beating" donors in intensive care facilities, but recent evidence shows that usable organs can be obtained from "non-heart beating" donors, and preliminary results suggest similar medium term success rates to "heart-beating" organs.Translated into national policy, this finding could dramatically increase the supply of organs. [2]
Changing the law. A review of the laws governing consent will increase the supply of organs. Options such as required request (legally obliging doctors to request organs) and presumed consent (the assumption of willingness to donate organs unless otherwise directed), among others, have been employed in other countries with considerable success.[3] In Belgium the introduction of a presumed consent system doubled the number of donors and transplants. A Manual of Kidney Transplantation (1994) estimates demand for kidneys, the organ for which the waiting list is the greatest, at 50 per million population (pmp) and states "it can be estimated that for most developed countries there exist up to 50 cadaver donors (or 100 cadaver kidneys) pmp per year if all potential donors are identified, managed appropriately and if consent is granted."[4]
Live Donation. The organ for which the shortfall is the greatest is the kidney, but this organ can, of course, be obtained from living donors. 20 year follow-up of living donors shows no evidence of statistically significant increase in prevalence of renal disease and recipients have better long term survival than those receiving cadaveric transplants.[5] In this country under 10% of organs are obtained from this source, but in theory it could answer the entire demand for kidneys.
Extrapolating from a U.S. Government study, every year up to 31,000 deceased people in the UK could contribute to the supply of organs,[6] easily coping with the current waiting list of between six and seven thousand patients. What particularly worries Uncaged Campaigns is that hype about the prospects for pig organ transplants may further discourage the public from carrying donor cards and registering as donors. That would be a tragedy for patients waiting for organs as human organs will always be a far better option than an organ from another animal. This concern has also been expressed by bioethics reports such as the British Kennedy Report, and a Dutch Committee:
"The [Health Council of the Netherlands] Committee [on Xenotransplantation], however, believes that... by far the best way of resolving the shortage in organs for transplantation is to increase the supply of human donor organs."Prevention
Xenotransplantation, Health Council of the Netherlands: Committee on Xenotransplantation, 1998
The best way to tackle ill health is to prevent it in the first place. Lifestyle and environmental factors contribute to many instances of organ failure. Greater investment in the prevention of illnesses which may lead to organ failure will, in the long term, reduce the demand for organs. A seriously increased commitment to the reduction of smoking and alcohol consumption along with general improvement in diet could lead to a significant reduction in pulmonary and cardiac disease, hepatic failure and diabetes, which is a significant factor in the prevalence of renal failure.
Conclusion
The imbalance between supply of and demand for human organs can be reduced significantly, or possibly even eliminated by changes in policy, rendering the argument in favour of xenotransplantation ineffective. Although many of these changes are not without their own ethical implications they carry neither the dangers nor the cruelty intrinsic to xenotransplantation. Furthermore, the potential negative impact on human organ donation of any public perception of successful xenotransplantation could significantly affect allotransplantation, which must remain the treatment of choice.
Notes and references
[1] Animal Tissue into Humans, Advisory Group on the Ethics of Xenotransplantation (AGEX), Department of Health, 1997, pp. 92-93.
[2] Nicholson M (1996) Kidney Transplantation from asystolic donors British Journal of Hospital Medicine vol 55 p51-52.
[3] Allen & Chapman, A Manual of Renal Transplantation (1994), p.22
[4] The Times 21/1/97
[5] Najarian et al (1992) The Lancet vol 340 88 p23-25
[6] From a report by the U.S. General Accounting Office (April 1998) on the state of organ procurement in the U.S.. The study suggests that were up to 147,000 (6% of deaths) potential donors in the U.S. in 1994, after adjusting for age and cause of death. The UKís population is approximately 20% of the U.S. population, hence the UK figure of 31,000.
7. Xenotransplantation Links
- Xenotransplantation news archive
- Xeno action page
- Interim response to Emerging Biotechnologies and the Animals (Scientific Procedures) Act 1986
- The website of Campaign for Responsible Transplantation (US site)
- Send an email Postcard to the Department of Health registering your opposition to xenotransplantation
- Diaries of Despair website
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