Xenotransplantation: Issues and Challenges
Issue 6, April 2002
In Rome the Pontifical Academy for Life has given qualified approval to xenotransplantation. In New Zealand the Ministry of Health has declined approval for an Auckland company to carry out clinical trials involving xenotransplantation. What are the issues raised by this emerging form of biotechnology?
Xenotransplantation involves transplanting living cells, tissues or organs from one species to another. It includes animal-to-human transplants, which can take a number of forms:
- Transplantation of solid animal organs (such as hearts, kidneys, livers);
- Cell therapies, such as the transplantation of pig neural cells and pig pancreatic islet cells;
- The use of viable animal cells as part of a medical device, such as an extra-corporeal liver;
- The use of animal cells in gene therapies.
Pigs are usually the preferred donor of tissues and organs in animal-to-human xenotransplants because they are easy to breed, have the right size organs for humans and are less likely to transmit diseases than primates.
Potential Uses of Xenotransplantation
There is a worldwide shortage of human donor organs for transplantation, and people often die while waiting for a suitable donor. Xenotransplantation is seen by researchers as a means of overcoming the chronic shortage of donor organs. Overseas research into organ xenotransplants has centred on the transplantation of pig kidneys, livers, and hearts into humans and primates such as baboons and chimpanzees. Research has also been conducted into xenotransplantation as a means of treating degenerative neurological diseases; for example, by injecting fetal pig neurons into the brain of a person with Parkinson's Disease to increase the release of dopamine.
In New Zealand xenotransplantation is being investigated as a cure for diabetes. Auckland company Diatranz has been carrying out research into the use of porcine pancreatic cells as a means of treating Type 1 diabetes. The Diatranz technique involves encapsulating pig pancreatic islet cells (which produce insulin) in a coating designed to prevent their direct interaction with the patient's immune system. A small container is surgically implanted into the abdomen of the patient and some time later, pancreatic cells from a two-week old piglet are inserted into the container. These cells have the potential to begin releasing insulin as they mature.
Medical and Safety Issues
Researchers are working to overcome two major medical problems with xenotransplanation. The first of these is the rejection of the animal tissue or organ by the person's immune system. When pig organs are transplanted into primates, they are swiftly rejected as a result of the action of several forms of immune response. Scientists have genetically modified and cloned a strain of pigs to lessen the immune response pig organs trigger in recipients. The survival time of organs from these pigs in non-human primates is greater than that from unmodified pigs, but does not yet parallel that of human-to-human transplants. Research is also continuing into the development of immuno-suppressant drugs to help prevent rejection. The involvement of several major pharmaceutical companies in xenotransplantation stems from their interest in the drugs needed to support xenotransplantation.
The second major medical safety issue with xenotransplantation is the possibility of cross species infection. In particular, the potential activation of pig retroviruses in humans is a matter of fierce debate among researchers. A retrovirus is a virus which inserts itself into the DNA of its host cell, and is copied with the cell's DNA when the cell replicates. The retrovirus is thus present in every cell in the organism, although it may cause no harm to its host organism.
Pigs have sequences in their DNA which code for retroviruses known as porcine endogenous retroviruses (PERV). They are harmless in pigs but could potentially cause disease in humans. A great deal of research is being conducted to determine whether PERV infection poses a real threat to the human population through xenotransplantation. The research is not yet conclusive, but is made difficult by the fact that infection may not become obvious for many years after the animal organ has been transplanted into the recipient.
Researchers and regulatory authorities are acutely aware that HIV is a retrovirus that existed harmlessly in a species of monkey before it crossed into the human population, where it causes AIDS. Although not a retrovirus, BSE was considered to be of no significant risk to humans until it spread from cows into the human population as Creutzfeldt-Jacob Disease. The possibility of a similiar event involving PERV infection transmitted through xenotransplantation cannot at this stage be conclusively ruled out. Clinical xenotransplantation trials in humans thus raise complex safety and ethical issues.
Informed Consent and Confidentiality
While an individual may benefit from xenotransplantation, there is a possible risk to public safety through the transmission of pig retroviruses into the wider community. To protect relatives and the rest of the community, it is generally considered that xenotransplant recipients would have to agree to life-long rules which would seriously limit their freedom; for example, never travelling outside their country, not having children, identifying their sexual partners to authorities, and being monitored by authorities.
Because the risks involve not just the patient but other people as well, a new model of informed consent is needed for the recipients of xenotransplants. The traditional model of informed consent centres on the agreement of the individual patient to participate in a clinical trial or treatment. The need for other people to be monitored means that the informed consent process must include them as well as the xenotransplant recipient.
The normal requirement for patient-doctor confidentiality will also need modification for the recipients of xenotransplants, for example, in relation to the involvement of family and close contacts in the consent process. There may also be a need to require recipients of xenotransplants to declare their medical condition in particular situations, such as when they seek to enter another country. Will it be necessary for a xenotransplant recipient to have that fact recorded in his or her passport?
There are complex ethical and legal issues involved in setting up a monitoring process, and in placing obligations on the recipients of xenotransplants and those close to them. These issues need to be worked through as part of creating a regulatory infrastructure, and may ultimately require an international framework as well as regulation by individual nations.
Regulation of Xenotransplantation
The potential risk to the general public of cross-species infection is considered to be small but real. In those countries where clinical trials are proceeding, they are being carried out with the approval of a regulatory body and within a strict regulatory framework. For example, in the United Kingdom the approval of the UK Xenotransplantation Interim Regulatory Authority is required for xenotransplantation involving human subjects. In the USA, the Food and Drug Administration has a similar role.
In Canada there has been extensive public consultation carried out on xenotransplantation.  The key finding of the consultation was that the majority of informed Canadians do not want xenotransplantation to proceed at this time, preferring that organ donation issues be addressed in other ways. The consultation showed that having a strict regulatory regime in place before there is any further action on xenotransplantation is considered to be of prime importance by Canadians, even those who favour it.
In New Zealand there is no regulatory body or framework which parallels that in the UK or the USA. There has been no significant involvement of the public in the discussion about xenotransplantation, although it will be one of the many items on the agenda of the bioethics advisory body to be established in response to the recommendations of the Royal Commission on Genetic Modification.
In July 2001 a Diatranz application to carry out in New Zealand clinical trials of its treatment for diabetes was declined by the Director-General of Health on the recommendation of the Gene Technology Advisory Committee (GTAC). Approval was declined because there is insufficient knowledge of the risks of retrovirus infection, and because of deficiencies in the application. The Minister was also advised by the Health Research Council that it would not be appropriate to approve clinical trials until a regulatory infrastructure is in place and there has been public consultation on xenotransplantation.
In mid December 2001 a Supplementary Order Paper imposing temporary controls on xenotranplantation was introduced into Parliament. The proposed legislation was referred to a Parliamentary Select Committee, which reported back to Parliament on 28 March 2002.  In their report the Committee supports controls on xenotransplantation involving human subjects, with the approval of the Minister of Health being required before any clinical trial can take place. That approval will be dependent upon the application having adequately addressed health and safety risks to the public, and any ethical, cultural and spiritual issues. A proposal to exempt the Diatranz clinical trials from the legislation has been rejected in the report. The Select Committee has also supported the proposed timeframe for the legislation, which will expire on 30 June 2003 but can be extended by Order in Council to 30 June 2005.
The Select Committee's report and the proposed legislation will be debated in Parliament in late April. If passed the legislation will allow time for the bioethics advisory body to consider the ethical, cultural and spiritual aspects of xenotransplantation, for public consultation to take place, and for a regulatory framework to be established. The proposed legislation has angered diabetics, who consider that the Ministry of Health is being overly cautious. Diabetics who were involved in the clinical trials held in the mid 1990's, before they were halted by the Ministry of Health, have spoken out about the benefit they experienced from the treatment and their frustration with the current situation. Diatranz has previously carried out clinical trials in Mexico, and is now seeking to do the same in the Cook Islands.
Theological and Anthropological Issues
In New Zealand and overseas the debate about xenotransplantation has primarily focused on safety, with very little comment on the theological or anthropological issues. In 2001 the Pontifical Academy for Life convened an international working party which included specialists in all the disciplines associated with xenotransplantation. The scientific fields of expertise represented included human transplantation, xenotransplantation, immunogenetics, veterinary physiology, genetics, virology and microbiology. The working party also included specialists in moral theology, bioethics, anthropology, and international law. This multi-disciplinary approach enabled the group to consider not only the scientific aspects of xenotransplanation, but also to provide insight into deeper theological, ethical and philosophical issues.
The working group's report  identifies several theological and anthropological issues which specifically relate to xenotransplantation. A summary of their position on these issues is to be found on page 15 in this edition of The Nathaniel Report.
Some aspects of the theological approach of the writers of the Pontifical Academy's document may not sit comfortably with some schools of theological thought and spirituality in New Zealand. In a country which places a high value on the environment, conservation, and respect for all life, eco-theology and Earth-centred spirituality have been natural developments. Many New Zealanders readily identify with the thoughts expressed by the Catholic Bishops of New Zealand in one of their pastoral statements:
"Creation itself provides the primary source from which all life flows. Within creation all life forms are interconnected. Our actions, the things we use, the way we use them, and the wastes we produce need to respect the integrity of this creation. The Bible tells us in its account of the creation of the world that 'God saw that it was good'. It is also in keeping with the traditions of the Māori of Aotearoa that we need to respect the sacredness of creation, as partners in life with the earth, the oceans, the lakes, the animal world, the mountains, the fish of the sea and the birds in our forests and gardens. From such sources, balanced by the infinite hand of God we draw all life and nourishment. Without them we face death." 
Internationally the care of animals used in xenotransplantation experiments is being challenged by animal welfare groups. Major companies involved in xenotransplantation, such as Novartis subsidiary Imutran, have been accused of misleading the public in relation to the suffering caused to animals during experimentation. There are also strong objections to the capture and transport around the world of primates for use in such experiments. In 2000 a British animal welfare group and the Daily Express newspaper revealed documents from xenotransplantation experiments which they called "Diaries of Despair."  These documents revealed that the death of baboons and monkeys was occurring within days and weeks of their receiving pig organ transplants, and that the animals endured considerable suffering between transplant and death.
In New Zealand animal welfare is controlled by the Animal Welfare Act (1999). This law sets out a "Duty of Care" towards animals which covers the physical, health and behavioural needs of animals. It also provides for the partial suspension of the "Duty of Care" during research, provided strict conditions are met. Institutions doing research involving animals, whether they are companies, institutes or universities, are required to have an Animal Ethics Committee which gives approval for research, and an approved Code of Ethical Conduct. There are heavy penalties for using animals in ways which are outside the Code of Ethical Conduct. This system should provide for the ethical treatment of animals used in xenotransplantation in this country, but will not address the objections of animal welfare campaigners who are opposed to all vivisection.
Xenotransplantation challenges us at all levels of thought and action. It challenges our compassion for those with conditions which xenotransplantation may be able to address. The level of risk to the wider community remains a matter of research and debate. There are also questions about the use of animals and their welfare in relation to human benefit.
To the transplant surgeon whose patients die on waiting lists for organs, and to diabetics who must endure the daily insulin ritual, xenotransplantation offers great hope. To those who must guard the health of the community, the possibility of retrovirus transmission means that xenotransplantation poses risks. To the animal activist it is unethical and exploitative. We are all confronted with our own personal feelings about the use of animal tissue or organs in our bodies.
Our understanding of the place of human beings in creation is at the heart of our individual and collective response. But most of all, xenotransplantation, like other forms of biotechnology, raises further questions about the limits we are willing to go to in order to delay death or to improve the quality of life.
Anne Dickinson is the Director of Caritas Aotearoa New Zealand and a member of the Panel of Advisors of The Nathaniel Centre
 Health Canada, Canadian Public Health Association Public Consultation on Xenotransplantation: Final Report, January 2002
 Finance and Expenditure Select Committee Report on the Hazardous Substances and New Organisms (Genetically Modified Organisms) Amendment, Part 3, Amendments to Medicines Act 1981
 Pontifical Academy for Life, Prospects for Xenotransplantation: Scientific Aspects and Ethical Considerations, September 2001
 New Zealand Catholic Bishops' Conference A Consistent Ethic of Life: Te Kahu-o-te-Ora (1997)
 Daily Express Terrible Despair of Animals Cut up in Name of Research, 21 September 2000