2005 Xenotransplantation 19-5-05

19 May 2005

Bioethics Council
PO Box 10 362
WELLINGTON

Submission on Xenotransplantation

Considerations

For the purposes of this submission, PSRG regards xenotransplantation as the transplantation or implantation of live cells, tissues or organs across species barriers, e.g. from animals to humans or vice versa, by artificial means.

PSRG will use ‘xenotransplantation’ as a single description for xenotransplantation and any related technologies, unless otherwise stated.

While the procedure does not per se involve genetic engineering, it has many points in common with the biosafety issues related to genetically engineered organisms. Further, it does not exclude genetic manipulation(s) of the transplanted cells or tissues whether from human or non-human origin.

PSRG’s position on xenotransplantation resembles that for genetic engineering technology: xenotransplanted cells, their hosts and the products of these cells should be kept strictly isolated from the common biological environment, including the human environment. Only fully confined experimentation is acceptable.

We also state that the ethics of xenotransplantation cannot be debated without consideration of the science and its consequences.

PSRG maintains that xenotransplantation poses massive potential costs to public health that, with the current application of funding cuts worldwide, puts public health at substantial risk. Society’s record in managing the consequences of modern science and technology - increasingly lethal military weapons, environmental pollution, rainforest destruction, AIDS, etc. – is inadequate and costly. PSRG asks whether humankind has the medical and scientific knowledge, the wisdom and moral maturity to put aside vested interest in order to deal with the consequences of xenotransplantation and related genetic technologies. We believe its record shows that it does not.

PSRG upholds that all organisms have complex inter-relationships about which we have little knowledge, and the timescale for important biological phenomena can be much longer than ordinary ‘human’ time. With xenotransplantation, medical science can be claimed to be using short-term solutions and not recognizing or acknowledging the long-term consequences.

Clinical xenotransplantation breaches species barriers that have evolved over billions of years. It creates real possibilities of new diseases entering the human population. The ethical issue of individual benefit versus societal risk demands a different approach from that usually taken in the evaluation of new medical technologies.

PSRG proposes the establishment of a moratorium on the introduction of xenotransplanted-related material into the common biological environment for the foreseeable future.

This submission gives attention to three areas of concern: public health, the societal consequences of adopting xenotransplantation, and the evaluation and monitoring of xenotransplantation research and funding.

Public health and associated issues

1. PSRG acknowledges that there is an on-going, critical shortage of donated human organs worldwide. It is claimed that xenotransplantation could provide unlimited numbers of organs for transplantation and that, with the advances in immunology and in the knowledge of the biology of organ and tissue rejection, xenotransplantation is a technology that offers potential treatment for a wide range of conditions and disorders that involve tissue destruction and organ failure.

1.1. Emotive arguments for adopting xenotransplantation are misleading. For example, the number of whole organ, tissue and/or cell transplants required is likely to be too great for health systems, under the current funding crises, to accommodate in terms of personnel and financially. There is the certain potential for xenotransplantation procedures to benefit only those who can afford to pay, and for profits to only benefit the wealthy investor. (See also comments on research funding.)

1.2. PSRG maintains that xenotransplantation research and implementation pose proven risks for the transmission of pathogens from animal donors to human recipients with the potential to result in pandemics, and/or the experience and/or establishing of disorders in humankind that may not have been previously known. There are essentially little or no data that can specifically be used to accurately assess the level of such risks. The range of uncertainty is huge. We can draw on the following examples to illustrate this:

(a) The 1918 influenza epidemic, estimated to have killed 20 to 50 million people world wide, is believed to have been a mutation of a pig influenza virus spread from pigs by US troops during World War I. (M Day, Pigs caused Great War flu deaths, New Scientist, 29 March 1997: 20.)
(b) Test results on the tissue of a baboon liver recipient located infection with a herpes virus from the donor animal thought incapable of infecting humans. (C Norton & C Arthur, Transplant of baboon liver gave man virus, The Independent, 1 October 1999, p.13.)
(c) In Malaysia, the previously unidentified Hendra-like Nipah virus passed from pigs to humans and killed over a hundred of the two hundred and fifty or so people it infected. Rats fed pig carcasses and leftover feed are now thought to be capable of carrying the Nipah virus; dogs and cats are confirmed carriers. (The Sun, 5 May 1999, Kuala Lumpur (Malaysia.)

(d) The recent H5N1 ‘chicken’ flu epidemic in Asia is claimed to have now progressed to pass from human to human. As at 6 April 2005, there were 50 human victims. The WHO and US Centers for Disease Control and Prevention claim that this avian flu may be the single biggest health threat the world is current facing. (Reuters, Hanoi, 6 April 2005; AnimalNet 6 April 2005; Reuters, 5 April 2005, Washington; http://archives.foodsafetynetwork.ca/animalnet-archives.htm.)
(e) The Ebola and Marburg viruses are closely related. The Ebola virus is one of two members of a family of RNA viruses (Filoviridae), of which there are four identified subtypes; three of the four have caused disease in humans. The Ebola virus is zoonotic (animal-borne) and is normally maintained in an animal host. Outbreaks of Ebola and Marburg virus in Africa were thought to originate from bats, but an outbreak of Marburg virus in a German laboratory in 1967 came from the blood and tissue of Ugandan African Green Monkeys. In 1995, an Ebola epidemic in Kikwit killed 220 people and in 1999 an epidemic in Eastern Democratic Republic of Congo (DRC) claimed 46 lives. A WHO report (1 April 2005) claimed that an outbreak, caused by the Marburg virus, killed 127 of the 132 Angolans infected; this being confirmed by blood samples from victims and tested by the National Institute of Virology in South Africa. (The Sun, 7 May 1999, Geneva; Guardian Newspapers Limited 2005 http://www.guardian.co.uk/print/0,3858,5158523-111492,00.html; C Thompson, Dead Reckoning, Sunday Times magazine, 26 June 1997: 17; The Department of Health: The Advisory Group on the Ethics of Xenotransplantation [AGEX], Animal tissue into humans. London: Her Majesty's Stationery Office, 1997: 34; The Sun, 1 May 1999, Kinshasa (Democratic Republic of Congo.)
(f) It is widely claimed that HIV (a retrovirus) infection in humans, and thus AIDS, is a result of the transmission of a simian immunodeficiency virus (SIV) from primates to human beings. (Nuffield Council on Bioethics. Animal-to-Human Transplants: the ethics of xenotransplantation. London: Nuffield Council on Bioethics, 1996: 68; E Hooper, The River: a journey back to the source of HIV and AIDS, Allen Lane, 1999.)
(g) Sin Nombre is a little-known fatal Hantavirus usually carried by rodents. In the 1990s, it is known to have broken out among humans twice in the southwest of the USA. (S Sternberg, Origins of an outbreak, USA TODAY, 2.7.98: 8.)
(h) Recently, the infectious agents porcine hepatitis E virus and the wasting syndrome-associated circovirus, have been shown to transfer between pigs and humans. (R A Weiss, Transgenic pigs and virus adaptation. Nature 391: 328; L Chapman, WHO electronic discussion on international xenotransplantation policy considerations, discussion at http://www.oecd/dsti/sti/s_t/biotech/ xenosite/country.htm>) (WHO EDX), Vol. 4 #1 990824, posted 25 August 1999.)
(i) Contaminated polio vaccine was administered to millions worldwide between 1955 and 1963. It was grown on minced kidney tissue from rhesus monkeys and the original research revealed around 26 Simian contaminants. Medically induced zoonosis occurred when the monkey parvovirus, SV40, went undetected in the vaccine. By 1996, improved DNA detection techniques found evidence of the SV40 virus in human tumours, including rare brain, bone and lung-related cancers called mesotheliomas. Other researchers found SV40 in tumours of children and adults born after the contaminated polio vaccine was taken off the market (1963). SV40 fragments were found in 42 percent of 154 non-Hodgkin lymphomas in one study and 43 percent in 68 cases in another. Italian researchers found SV40 in 45 percent of seminal fluid samples and 23 percent of blood samples taken from healthy donors, meaning that SV40 could have been spreading through sexual activity, from mother to child, or by other means, explaining how those who had not received the contaminated vaccine were being infected. Scientists are now asking if other undetected monkey viruses have been transmitted in vaccine batches. (Dr R 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; http://www.theatlantic.com/issues/2000/02/002bookchin.htm.)

We also note the recent withdrawal for health reasons of a dietary supplement from the New Zealand market because it contained digestive enzymes extracted from the pancreas of pigs.

1.2.1. Some viruses can be transmitted simply by a cough or sneeze, thus a virus from a donor animal residing in a xenotransplant recipient may become airborne, infecting unpredictable numbers of people, and causing a potential viral epidemic or pandemic.

1.2.2. Risk levels for such infection/s to the recipient and the likelihood that such infection/s will spread to others pose unknown and unacceptable risks to human health.

1.3. Harvesting and transportation of material from donor animals provide opportunities for contamination, and the risks associated with xenotransplantation are potentially greater than those of allotransplantation. For example:

(a) An organism can become a pathogen in the immuno-compromised human host, and the level of immune suppression and/or rejection may be greater in xenotransplant recipients and may thus enhance the activation of latent pathogens.
(b) Transmitted organisms may not be known human pathogens and/or may include xenotropic organisms.
(c) Organisms that are not pathogens in the native host may cause disease in other species.
(d) Microbiologic assays may not exist for some organisms derived from non-human species.
(e) Novel, animal-derived, organisms may cause novel and thus unrecognized clinical syndromes.
(f) Genetic engineering of a donor animal or the treatment of the recipient with, for example, tolerance induction or antibody removal, are xenotransplantation strategies, which may alter the susceptibility of a host to organisms.

1.3.1. On whole organ transplants we quote from A Layperson's Guide to the Problems With Animal-to-Human Organ Transplants (Alix Fano, M A, Murry J Cohen, M D, Marjorie Cramer, M D, FACS, Ray Greek, M D, Stephen R Kaufman, M D):

(a) “There have been some 55 animal-to-human whole organ transplants attempted since 1906. All have proven unsuccessful, resulting in the suffering and death of all patients and donor animals. The thousands of cross-species experiments (between goats, rats and chickens, rats and hamsters, cats and dogs, pigs and primates) performed since 1906, and continuing today, have not provided reliable information about what would happen to human xenograft recipients.”
(b) “Baboon viruses flourish on human tissue cultures, before killing the cultures. There are over 20 known, potentially lethal viruses that can be transmitted from nonhuman primates to humans, including Ebola, Marburg, hepatitis A and B, herpes B, SV40, and SIV. Numerous scientists have urged US public health agencies to exclude primates as donors for xenotransplantation.”
(c) “Pig retroviruses have infected human kidney cells in vitro; and virologists believe that many pig viruses have not been adequately studied. Viruses that are harmless to their animal hosts, can be deadly when transmitted to humans… Macaque herpes is harmless to Macaque monkeys, but lethal to humans.”
(d) “Leptospirosis (which produces liver and kidney damage), and erysipelas (a skin infection), are among the approximately 25 known diseases that can be acquired from pigs, all of which could easily affect immunosuppressed humans.” There may be unknown ‘pig diseases’ undiscovered.

1.4. All transplanted organs are liable to rejection and xenotransplants are reported to bring extremely strong responses such as hyperacute rejection, a reaction that destroys the new organ within minutes. Pigs are being genetically engineered to carry human genes on the premise that introducing human genes into pigs may avert this hyperacute response. However, a pig organ will still face other rejection processes which scientists believe will be stronger than those faced by human organs.

1.4.1. Transplantation currently requires immunosuppressive drugs to be taken life-long, with consequent toxic effects.

1.5. Animals and humans carry viral-like DNA sequences within their genes and it is possible that the close juxtaposition of tissue from different taxa brought about by xenotransplantation could eventually result in the evolution of new viruses capable of infecting either the host or donor species.

1.5.1. Some 30 new ‘human’ diseases have been discovered in the last two decades, most of them transmitted from nonhumans to humans. Pigs are proposed as the most promising donors, but are acknowledged as carrying infectious agents potentially dangerous to human health. Evolutionarily closer, non-human primates are claimed to pose greater risks of infection. Science has not yet found the functions of all human genes and has identified only a tiny fraction of pigs’ DNA.

1.5.2. Jon Allan, a virologist and advisor to the FDA, speaking about the potential of virus transfer in xenotransplantation, said 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." (J S Allan, Xenotransplantation at a crossroads: Prevention versus progress, Nature Medicine 2, 1, January 1996: 18.)

1.5.3. With current and foreseeable scientific uncertainty about this technology, it is impossible to provide donor transplant material that is pathogen-free. Even pigs obtained from remote islands (reference Professor Bob Elliott’s experiments with diabetic recipients) have been found to have infectious agents. Some viruses carried by pigs are claimed to be impossible to eradicate. The June 1996 report of the Institute of Medicine acknowledged that, “it is not possible to have completely pathogen-free animals, even those derived by Cesarean section, because some potentially infectious agents are passed in the genome and others may be passed transplacentally.” British virologists claim there are an estimated 50 PERV (pig endogenous retroviruses) in the pig genome.

1.6. Xenotransplantation bypasses the normal human body defence barriers that protect it from pathogenic microorganisms: the skin, mucus linings and the acidic environment of the gastro-intestinal tract. It can directly and efficiently introduce potentially infectious agents to human tissue.

1.6.1. Xenotransplantation potentially enhances the occurrence of zoonosis.

1.6.2. The administration of immuno-suppressant drugs to xenotransplant recipients, patients who are already ill, will potentially increase the range of symptoms they experience and/or are susceptible to. It is claimed that it will be difficult to identify a particular symptom as being the result of a xenozoonosis, further compounding the inherent complications of detection.

1.6.3. Viruses are difficult to treat with the current range of drugs available. Some can mutate rapidly to resist the immune system and infect humans more readily.

1.6.4. Currently, science and medicine are unable to identify even known viruses readily and viral infections are 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. Detection and treatment of previously unknown viruses would exacerbate the above difficulties.

1.7. Xenotransplantation research and implementation may also pose risks to the animal donors. This area of risk has not been adequately researched, if at all.

1.7.1. Xenotransplantation research involves the potential for ongoing suffering for animals, for animals to be bred solely for destruction, for animals to be raised in confined, artificial conditions and for animals to be subjected to allied genetic manipulation. (See Diaries of Despair; Daily Express 21 September 2000, This email address is being protected from spambots. You need JavaScript enabled to view it.; and Lethal Medicine, a video produced by The Nature of Wellness, available from NZAVS, PO Box 9387, Christchurch, www.nzavs.org.nz.) The treatment of most ‘laboratory’ animals in seeking cures for human conditions is totally unacceptable and unnecessary.

1.7.2. Most animal experimentation is investment-driven and unproductive in terms of human benefit. Humans are biochemically different from other animals. A cat would die if given aspirin, a sheep can take very large quantities of arsenic with little effect, and a guinea pig is not worried by strychnine. Laboratory animals deliberately infected with HIV do not develop AIDS.

1.7.4. Breeding genetically engineered donor animals for xenotransplantation procedures would create biosecurity risks for the environment, including soil and groundwater contamination.

1.7.5. It would be difficult to provide a pathogen-free ‘natural’ environment to raise animal donors, especially in the high numbers that would be required.

1.7.6. It is imperative that the breeding, welfare and housing conditions of donor animals are stringently researched and assessed, and regulated and legislated for. The destruction of donor animals inherent to xenotransplantation is often given insufficient attention. This self-interest is often sustained by a disregard for the interests of donor animals. Their capacity for psychological and physical suffering is now universally acknowledged by competent experts.

1.8. There are physiological and anatomical differences between humans and donor animals that pose possibly insurmountable difficulties: differences in lifespan, heart rate, blood pressure, metabolism, immunology, and regulatory hormones.

1.8.1. The claim that pigs are suitable donors because of the appropriate size of their organs is incorrect. A study (Crick SJ et al, Anatomy of the pig heart: comparisons with normal human cardiac structure, J. Anat. 1998 July; 193 (Pt 1): 105-19) identified eight major anatomical differences between human hearts and pig hearts, and the report Animal organs into humans highlights a number of discrepancies between pig kidneys and human kidneys (Langley G and D'Silva J, Animal organs in humans (BUAV & CIWF: 1998): 33-38).

PSRG does not advocate nor support the free therapeutic use of transplantation of animal components to human recipients in the state of current and foreseeable scientific uncertainty.

PSRG urges that funds proposed for xenotransplantation research and methods of raising donor animals be more profitably used for:

(a) Research to find conventional methods of treatment, and to improve the efficiency and availability of existing medical technologies, including allotransplantation.
(b) Public education on sound nutrition, and good health and fitness practices.
(c) On rewarding industry for providing improved standards of food product composition, including ingredients free of genetically engineered organisms, pesticides, the products of irradiation and nanotechnology, and other contaminants and/or adverse health indicators.
(d) Researching and establishing more effective detection, monitoring and treatment of disease in the early stages.
(e) To improve health care services to benefit the public;
(f) To improve the quality of palliative care.

With the expansion of genetic engineering biotechnology research, conventional research has been grossly under-funded. Patents associated with this development have also restricted or inhibited much valuable research. PSRG believes the adoption of xenotransplantation will add to this dilemma to the detriment of society.

(2) Societal implications

2. PSRG maintains that the risks from xenotransplantation are also societal, and not merely risks for the individual. The ethical issues demand a different approach from that usually undertaken in evaluating new medical technologies. Society needs to evaluate and define the scientific, medical, ethical and spiritual concerns, and the potential risks and unproven benefits of clinical xenotransplantation. These areas should not be treated as unrelated, separate areas for consideration, but also be evaluated in the areas where they overlap.

2.1. The legal and ethical problems associated with recipient surveillance will be exacerbated by the transient nature of populations - Canada proposed monitoring a section of the population ingesting genetically engineered foods and found it extremely difficult to maintain contact with participants - and by the fact that it may need to extend throughout a recipient’s lifetime. This would pose enormous difficulties for such aspects as patient confidentiality and for maintaining the momentum of the surveillance. A successful treatment could even reduce a recipient’s incentive to comply.

2.2. Surveillance and monitoring may have to be extended to and beyond a recipient’s immediate family and/or close associates, to offspring, and to subsequent generations.

2.3 It is possible that recipients and close associates may have to be quarantined, with the costs and difficulties associated with maintaining consistent standards and strict regulation over a potentially long period of time. This could infringe on basic human rights to freedom.

2.4. Legislation may be needed to require recipients to agree to contraception for life or sterilization in extreme cases, and this could be difficult or impossible to enforce in practice. This could also infringe basic human rights.

2.5. Questions of consent and enforcement become difficult if recipients are required to have their current and future sexual partners registered and monitored by health authorities. Imposing restrictions on contacts and partners, especially on future partners, could be extremely problematic. This could also infringe basic human rights.

2.6. Compliance conditions are vulnerable to human error. Recipients may withdraw from post-operative surveillance schemes at any time. Expecting recipients’ contacts to comply with surveillance requirements will be difficult, and changes in recipients’ future relationships will complicate matters further.

2.7. The risks faced and our capacity to deal with these unknown factors are not satisfactorily known. The monitoring of patients and others would be costly in terms of funding from national and private health care systems, and insurance companies, for the period required. Comprehensive legislation would be essential.

<>2.8. The potential for recipients to give rational consideration to potential compliance demands when in states of ill health is debatable. Relying on individual voluntary consent to compliance removes the right of society as a whole to defend itself. Lack of confidence in voluntary consent suggests that xenotransplantation raises public interest justification for the introduction of legislation to ensure compliance with surveillance requirements.

2.9. Consideration needs also to be given to the following:

(a) Establishing and enforcing standards and protocols.
(b) Maintaining standards and uniformity of care by hospitals, research centres and institutions.
(c) The quality of care provided.
(d) The rigorous standards needed for quarantine facilities.
(e) The management of risk and monitoring.
(f) The evaluation of the effectiveness of the procedure.
(g) Patient-physician interactions, consent and confidentiality.

2.10 Polls have shown that xenotransplantation does not have the approval of the majority of the public. In a recent European poll 36 percent and a British poll 21 percent of people found xenotransplantation acceptable.

2.11. Pharmaceutical and biotechnology companies are carrying out xenotransplantation research with profit in mind. For example, the main UK researcher is Novartis, a multinational drug and biotechnology company that manufactures the anti-rejection drug Cyclosporin. Estimated potential markets suggest billions in profits.

Should the current scientific uncertainty about this technology be overridden and should a procedure/s be claimed justifiable, PSRG maintains that because of the risk of transmission to the greater public of
pathogenic organisms a recipient of xenotransplantation would need to be required:
(a) to agree to their status being monitored,
(b) to agree to the risks attendant to a transplant procedure,
(c) to be contractually bound to carry out future obligations, including possible quarantine,
(d) to agree to any necessary modification of the guarantees of confidentiality and to surrender any right to withdraw from the study,
(e) to agree to the possibility of their being named publicly in the greater interest of the public in general, and
(f) even to the possibility of their being required to not reproduce or be sterilized.

PSRG maintains that the following safe practices should given consideration:

(a) The risk to the public of the approval of xenotransplantation requires an independent public mechanism for deciding its acceptability or not on a case-by-case basis.
(b) That the approval of one application should not provide the basis of proof of safety and/or acceptability for the automatic approval of subsequent applications.
(c) Xenotransplantation and allied technologies do not pose a one-time risk to the recipient, or to the public: there are on-going risks that must be continually reassessed and regulated for.

<>(d) Individual informed consent standards for medical interventions need to be modified and continually reassessed. The risks associated with xenotransplantation involve third parties, and require patients and close contacts of the patient to be monitored, possibly or probably for the span of a lifetime and even into succeeding generations. Consideration must be given to the possibility that it may also be necessary to bar a recipient from procreating.
(e) There is a proven possibility that a new infectious agent with altered pathogenicity will arise within the recipient, and consequently threaten the population in general. It may also represent a danger to the donor animal population.
(f) That any xenotransplantation infection surveillance programme would raise practical difficulties in implementation, posing unacceptable risks for transmitting pathogens and risk transgressing basic human rights. Latent infection and unknown viruses pose difficulties for detection, control and treatment. Compliance to voluntary surveillance requirements by recipients and contacts could be unreliable and inadequate as a safeguard to public health. The cost could be prohibitive and not an effective allocation of scarce healthcare resources.

PSRG urges:

(a) That comprehensive regulation and legislation for New Zealand be established, together with the New Zealand government working towards comprehensive international regulation and legislation.
(b) The continuous, ongoing monitoring and updating of current and proposed xenotransplantation technology and associated technologies in New Zealand; and that New Zealand support and encourage this worldwide.
(c) That comprehensive monitoring and surveillance be carried out of recipients, their families and/or close associates, of offspring and subsequent generations and that this be standard practice worldwide should the tools and guarantees of safety appear to be provided and xenotransplantation be given approval.

(3) Evaluation and monitoring of xenotransplantation research and funding

3. The public response to the research carried out by Imutran on animal subjects was – justifiably - one of horror. Papers were revealed that recounted (a) horrific animal suffering over a number of years and (b) that the researchers exaggerated the success of the work that was aimed at adapting animal donor organs for human transplant. (See Diaries of Despair; Daily Express 21 September 2000, This email address is being protected from spambots. You need JavaScript enabled to view it..)

3.1. Public disclosure simply caused Imutran to transfer its research overseas. The promises of this company have to date not given society any breakthroughs. It is, regrettably, common practice by proponents to overstate the potential and obviate the risks.

3.2. Society cannot justify spending huge sums of money on research – often supplemented or maintained by the public purse - that may result in few or no benefits to humankind. The money used by Imutran could have been applied to conventional medical research without the animal suffering and with equal or more potential for benefiting humankind.

3.3. Science has not yet mastered in its entirety human-to-human transplantations. Animal-to-human transplantations would raise many other known and potential risks.

3.4. At this stage of scientific and medical knowledge and uncertainty, we cannot justify using animal-to-human transplantations for the claimed benefit of a few when we are potentially risking the whole of society. Science has not adequately shown that transmitted viruses and genetic traits – bad as well as good, foreseen and unforeseen – will not be transferred to the recipient and to future generations. The consequences are simply not known.

3.5. It is not sufficiently known if humans who have received animal cells, tissue or organs to date have been monitored, how thoroughly they may or may not have been monitored, or for how long they have been monitored. Xenotransplantation is being practised in a regulatory vacuum.

3.6. One difficulty in providing legislation and regulation in New Zealand is that experimentation can simply be transferred overseas (as did Professor Elliot and Imutran). New Zealand should consider legislating against the recipients, products and/or effects of such research not being given admission to the country, and/or being monitored while in the country.

PSRG maintains that it is essential that New Zealand has its own stringent regulation and legislation for monitoring and evaluating xenotransplantation research and clinical trials, of both animal donor and human participants, and that government become front-runners for establishing thorough, international legislation that is constantly in the light of developments in xenotransplantation and allied technologies.

We maintain that, before any consideration is given to such applications of xenotransplantation being approved, there should be in place:

(a) sound scientific proof, confirmed by independent sources, of efficacy, and
(b) a strategy for balancing the ethical, medical, scientific and societal demands of xenotransplantation prior to human clinical trials. These critical scientific and ethical issues raise the need for stringent, transparent legislation and regulations to be developed nationally and internationally.

PSRG maintains that it is imperative that efforts be coordinated internationally. The Asilomar proposals, which set standards for recombinant DNA research, could be used as a base reference. (Berg et al, Summary statement of the Asilomar conference on recombinant DNA molecules, Proceedings of the National Academy of Sciences of the USA 72, 1981-1984 [1975]; Berg et al, Asilomar conference on recombinant DNA molecules, Science 188, 991-994 [1975]).

PSRG advocates an on-going process of education in which public discussion and iterative evaluations are used to define the ethical concerns, the potential risks and possible benefits of clinical xenotransplantation at the societal level, for the purposes of oversight and on a case-by-case basis; and that this should be organized and controlled by independent sources unimpeded by vested interest.

PSRG maintains that any decisions, regulations and legislation, in respect of xenotransplantation, should involve a broad range of public participants comprising individuals who represent a wide range of philosophical backgrounds and disciplines without affiliations to political parties or industries with vested interests: for example, physicians, scientists and others involved in the science of xenotransplantation, epidemiology, ethical aspects of the problem, animal welfare and rights; experts in the law and economics of the technical aspects of the problem; transplant recipients and family or close associates; ethicists; interested non-government organizations, and the general public.

PSRG maintains that if clinical xenotransplantation procedures are approved and become commonplace, viruses will inevitably be transmitted to human tissue given that most new human infectious diseases originate in other species. Xenotransplantation is a uniquely efficient means of establishing such diseases. The ability of biosecurity systems to manage the risk of infectious disease is severely limited.

PSRG considers that the following risks must be taken into account:

(a) The transfer of infections by xenogeneic tissues or organs (xenosis or xenozoonosis). This poses unique epidemiological risks because pathogens, particularly viruses, transmit efficiently. There is an undeniable possibility that a xenotransplantation procedure could introduce a novel infectious organism into the human population that could then cause a pandemic of catastrophic proportions.
(b) Transferred viruses are a major source of concern with cross-species transplantation. For example, molecular data suggest that there exists a family of porcine endogenous retroviruses (PERV) that may infect human recipients and then remain latent for many years; some appear to be infective for human cells in vitro. (Patience et al, Infection of human cells by an endogenous retrovirus of pigs, Nature Med. 3, 282-286 (1997). This effect must be monitored and mitigated, especially the possible transmission of new forms of these viruses
(c) It is possible that a new disease entity may develop and such pathogens might spread undetected with very real risks to the general population. Zoonotic retroviruses are known to cause disease, including cancer, and can be transmitted from human to human. They are harmless in their natural host, but can become pathogenic in a new host. Transgenesis could aid this process further by pre-adapting PERVs to human-to-human transmission prior to xenotransplantation procedures taking place. If a PERV behaves like HIV or HTLV (both retroviruses), it could spread unnoticed for years before being detected. Baboon ERVs have infected baboon liver recipients.
(d) Using animal donor species raises concerns about the economics and practicalities of quarantine requirements, the impossibility of obtaining pathogen-free donor animals, and the ethics of raising animals solely as transplant donors and under what physical conditions.
(e) There is a very real risk that organisms carried by transplanted material may not be known human pathogens. Novel, animal-derived organisms may cause novel and thus unrecognised clinical syndromes in humans. Genetic engineering of the donor animal may alter the host’s susceptibility to organisms.
(f) Cellular grafts can serve as a ‘culture plate’ for organisms to spread to the human host. Cell migration may then carry cell-associated infection anywhere in the new host’s body. Prescribing immuno-suppressant drugs lessens the host’s response to infection, thus allowing infection to advance. (Fishman, J A, Miniature swine as organ donors for man: Strategies for prevention of xenotransplant-associated infections. Xenotransplantation 1, 47-57 [1994]; Fishman and Xenosis, Xenotransplantation: addressing the infectious risks posed by an emerging technology, Kidney International - Supplement 58, S41-S45 [1997]; Chapman et al. Xenotransplantation and xenogeneic infections. N.E.M. 333, 1498-501 [1995]).
(g) Organs transplanted human to human are liable to rejection; the body’s own defence mechanism attempts to destroy the ‘foreign’ organ. Xenotransplantation would not be different, and may even raise unpredictable pleiotropic effects.
(h) A xenozoonotic infection may remain latent and emerge after many years of evolutionary selection in the host. This exacerbates the long-term risks of xenozoonosis and underlines the need for consistent life-long monitoring. A xenozoonotic outbreak many years on may require detention and quarantine for testing and could threaten basic human rights to freedom of choice.

PSRG urges that:

(a) Attention be given to distinguishing different xenotransplantation procedures with their associated different risks before preparing guidelines on the use of clinical xenotransplantation procedures.
(b) Any decision on undertaking or not undertaking clinical xenotransplantation be based on a wide-ranging debate on whether society wishes to embark on such work, rather than on the wishes of vested interest.
(c) There be an iterative process of analysis and deliberation involving public, public officials, scientists and physicians, and interested and affected parties for xenotransplantation (see also previous list).
(d) The larger public interest – ethical, societal and spiritual considerations - be adequately aired and developed prior to any commitment to proceed being arrived at, and prior to developing a regulatory and legal framework driven by technical and scientific considerations; and that that regulatory and legal framework be transparent, thorough and international.
(a) The fundamental aim of any considerations should be to develop a public consensus about the risks posed by present research and any clinical trials, whether research and/or clinical trials in xenotransplantation should be discarded, accepted or expanded, and if the latter two under what conditions. Efforts should be coordinated nationally and internationally.
(e) The impact of commercial interests be regulated and legislated for urgently. The history of medical innovation and enthusiasm has proven that vested interest often minimises risk(s) and exaggerates benefits. It is incumbent upon New Zealand to provide public protection, and independent analysis of current, proposed and future xenotransplantation research, experimentation and clinical trials.
(f) If a decision is made to approve clinical xenotransplantation trials, then only a limited series of experiments should proceed with a clearly defined and limited number of human recipients, and only to the point where risk(s) reaches a pre-defined level. A non-aligned committee should serve to define the pre-defined criteria and the stages at which evaluations of the process(es), risk(s) and results are made. Such an approach should be used to aid in defining and refining regulatory, institutional and legal mechanisms for the evaluation of these technologies.
(g) A central database of information on xenotransplantation clinical trials should be maintained.
(h) An initial surveillance phase should last for as long as there is any risk of infectious transmission, or until such risk is satisfactorily proven to be no longer a risk.
(i) A list of organisms to be absent from donor animals to minimise the risks for human infection should be determined, and that extensive surveillance and testing of the donor animals be maintained.

PSRG will not present this submission in person.

Signed by the Trustees of Physicians and Scientists for Responsible Genetics

Paul G Butler, BSc, MB, ChB, Dip. Obst. (Auckland), FRNZCGP
General Practitioner, Trustee PSRG, AUCKLAND

John R Clearwater, BSc, MSc, PhD
Principal Scientist, Clearwater Research and Consulting, Trustee PSRG, AUCKLAND

Bernard J Conlon, MB, BCh, BAO, DCH, DRCOG, DGM, MRCGP (UK), FRNZCGP
General Practitioner, Trustee PSRG, MURUPARA

Michael E Godfrey, MBBS, FACAM, FACNEM
Director, Bay of Plenty Environmental Health Clinic, Trustee PSRG, TAURANGA

Neil Macgregor, BSc, MSc, PhD
Soil Microbiologist, Institute of Natural Resources, Massey University,
Trustee PSRG, PALMERSTON NORTH

Peter R Wills, BSc, PhD
Associate Professor, University of Auckland, Trustee PSRG, AUCKLAND

Robert G Anderson, BSc, PhD
Lecturer retired, Trustee PSRG, TAURANGA

Jean Anderson
Businesswoman retired, Trustee PSRG, TAURANGA.

Signed on behalf of PSRG
Jean Anderson
Secretary

Submission ends.

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