Doc. 8166 revised

15 October 1998

Xenotransplantation

Report

Committee on Science and Technology

Rapporteur: Mr Gian-Reto Plattner, Switzerland, Socialist Group

Summary

Advances in transplantation technology have resulted in successful human-to-human transplants (allotransplantation) and could be at the brink of allowing clinical transplants of animal cells, tissues or organs into humans (xenotransplantation). This might be a relief for the many waiting transplant patients, but it raises a host of scientific, medical, legal, social, ethical and public health questions. One of the most serious risks is the transfer of animal diseases and retroviruses to humans which might in the worst case cause major pandemics.

This report argues that these questions must be debated and find satisfactory answers before proceeding with clinical xenotransplantation trials. To achieve this it suggests the introduction of a legally binding moratorium on clinical xenotransplantations until the outstanding questions have been answered.

I.       Draft recommendation

1.       The advancement of transplantation technology has allowed considerable success in human-to-human organ transplants (allotransplantation) and is promising a radical breakthrough for the transplantation of animal cells, tissues, and organs into humans (xenotransplantation).

2.       Whereas rejection problems and the transfer of diseases can be satisfactorily controlled in allotransplantation, these risks remain today uncontrollable for xenotransplantations.

3.       The transmission of animal retroviruses and prions into humans through xenotransplants may cause diseases, which if transmitted to other humans, may cause major pandemics.

4.       The public health risks must therefore be evaluated against the estimated benefits of xenotransplantations and methods must be found to eliminate any risk to public health.

5.       There are considerable scientific, medical, ethical, social and legal problems that should be answered before clinical xenotransplantations proceed.

6.       The Assembly, noting Recommendation No. (97) 15 of the Committee of Ministers to member states on xenotransplantation, recommends that the Committee of Ministers:

i.       work for the rapid introduction in all member states of a legally binding moratorium on all clinical xenotransplantations;

ii.       take steps to make this moratorium a world-wide legal agreement;

iii.       ask its Public Health and Bioethics Committees to work out, in co-operation with the World Health Organisation, a strategy for balancing the ethical, medical, scientific, legal, social and public health aspects of xenotransplantations, before the scientific and medical establishment is permitted to proceed with clinical trials on humans.

II. Explanatory memorandum by Mr Gian-Reto Plattner

Table of contents

Paragraphs

Introduction       1-3

Animal to human transplants       4-7

Risks of disease transmission       8-11

Should there be moratorium on xenotransplantation?       12-17

Conclusions       18-22

Introduction

1.       The transplantation of organs and tissues from one human to another (allotransplantation) has proved to be extremely successful and of considerable benefit especially with kidneys, hearts, bone marrow and livers. A major obstacle to such transplantation is the increasing gap between organ demand and offer. In the U.S.A. alone, some 50, 000 patients are awaiting transplants because there are less than 5000 human donors annually. Approximately 3000 people die each year because donor organs are not available to them.

2.       This situation has led to a strong interest in using animal organs, tissues and cells for transplantation into humans (xenotransplantation) since the development of artificial organs is believed to be decades away. There are also substantial financial and commercial interests to be taken into account, since the market for xenotransplantations may be worth six million ECUs by the year 2010.

3.       Your Rapporteur has taken the initiative of suggesting and preparing for a Pan-European Parliamentary debate on this issue given the many questions of a scientific, public health, ethical, social and legal nature that xenotransplantation raises.

Animal to human transplants

4.       Transplanted organs and tissues are perceived by the immune system of the recipient as a huge infection and are therefore immediately destroyed or rejected. This problem has been overcome in allotransplantation by using powerful drugs to suppress the immune system reaction until the organ or tissue has begun to function properly. However, with the immune system out of action, the patient is unable to fight off any other infection.

5.       The grafting of animal tissue or organs into humans enhances such rejection problems because of the greater immunologic disparity between donor and recipient. Non-human primates such as baboons or chimpanzee have therefore been used in xenotransplantation experiments because of their close resemblance to humans. Pig heart valves are routinely used in cardiac surgery, which has led to increased interest in pigs as donor animals, although the immunologic disparity is even greater. A strategy followed for heart transplants is to introduce human genes into the pig, thus genetically customising the organs to resemble the original, which should avoid or strongly reduce rejection. Another reason for choosing pigs lies in the fact that in contrast to primates their internal organs are of a size similar to those of humans and they are easier to breed than primates.

6.       Xenotransplantations can also be used as "bridges" until a human organ can be found for a permanent transplant.

7.       The use of animal cells and tissues offers potential benefits to a larger number of patients than those considered for organ transplantation. The transplant of pancreatic islet cells could cure diabetes, and implants of neuronal tissue could treat Parkinson's and Huntington's disease, multiple sclerosis and the effects of strokes.

Risks of disease transmission

8.       Animals carry viruses that are not found in humans and for which we have no defence system. Transferred animal cells, tissue or organs into humans can carry with them such viruses or prions. These may develop in humans and cause diseases, which in the worst case might be transmitted to other humans and could cause major pandemics. Cell to cell contacts might favour recombination with human viruses, a mechanism known to generate pandemic viruses. Infections with long incubation periods are particularly dangerous because they may not be detected until after they have been transmitted to other individuals.

9.       It should be recalled that Ebola and Marburg monkey viruses have caused large outbreaks of diseases in humans, and that there is compelling evidence, that "HIV" originated from monkey retroviruses. An important body of evidence also suggests that transmissible spongiform encephalopathies (TSEs) such as mad cow disease can spread from animals to humans, where it is known as Creutzfeldt-Jakob disease.

10.       A retrovirus present in an animal, that is transmitted to a human, can also mutate in the new environment and in turn infect the animal species it originated from.

11.       A strategy to reduce such risks of disease transmission is to keep uninfected herds of transplant animals. This is however difficult. In addition, all viruses or other transmittable diseases may not be known or be possible to identify and eliminate. The recent discovery, that pigs harbour endogenous retroviruses, that can infect human cells in vitro, has discredited those who believed in disease-free animals to overcome viral risks. According to the magazine Nature, ten renal diabetic patients in Sweden, who received foetal pig islets, have antibodies reactive to swine influenza and five or them have porcine porcovirus.

Should there be moratorium on xenotransplantation?

12.       The question of public health risks is at the centre of this debate. An individual seeing the possibility of prolonging his/her life might be willing to accept the risk of being contaminated. But if there is a risk that the disease can be transmitted to others, the public must also consent or reject such transplantation. The problem of how to control patients, who have undergone xenotransplantation, and health personnel involved must be solved to achieve absolute certainty that there is no public health danger involved. This might result in partial or total quarantine of persons involved.

13.       The Committee of Ministers of the Council of Europe has in its Recommendation No. (97) 15 addressed the problem of registration and regulation of the following aspects of xenotransplantations:

"i.       Basic research and clinical trials.

ii.       The source and care of animals for use in xenotransplantation.

iii.       Xenotransplantation programmes.

iv.       Long term follow-up and review of xenograft recipients and the xenograft source animals."

14.       The requirement of informed consent, as established in the Convention on Human Rights and Biomedicine, is another issue that will need further consideration. In Chapter II, Article 5 of this Convention it is written that " This person shall beforehand be given appropriate information as to the purpose and nature of the intervention as well as on its consequences and risks". These latter are at present not sufficiently well known.

15.       Xenotransplantation may have effects on the human gene pool. Problems that this may cause in a long-term perspective must be assessed carefully. The development of transgenic animals, from which organs or tissues can be taken, must also be analysed from the point of view of any risk for genetic alterations in the genetic code of animals caused by spill over.

16.       The problem of controlling this process must be addressed at an international level. The acceptance of xenotransplants in one country will present a risk for the spread of disease to other countries. A horror scenario is the creation of "xeno-havens" run by unscrupulous surgeons, allowing animal viruses to escape into the human population. Your Rapporteur welcomes the work of the World Health Organisation in this area believing that a formal and binding international agreement in this field is needed.

17.       The legal and economic problems of ownership of transgenic animals and their patentability as well as animal welfare issues would also deserve careful consideration.

Conclusions

18.       For all of these reasons, your Rapporteur considers that the risks involved in allowing xenotransplantations in clinics is currently too high to be acceptable. Much more research is needed before we will have satisfactorily answered all the unanswered questions.

19.       There are also important ethical as well as legal and social aspects that need to be analysed and debated.

20.       The UK introduced a moratorium on clinical trials in 1997 and has set up a xenotransplantation Interim Regulatory Authority to oversee the field. Switzerland has set up a national commission on xenotransplantation, and similar initiatives are taken in many other countries. The U.S.A. is working on regulations regarding xenotransplantations.

21.       Given the many uncertainties involved and the lack of a public debate on xenotransplantation, it would be an irresponsible act to allow clinical trials to proceed. The world needs a moratorium on clinical trials, until all of the existing information in this field has been thoroughly analysed. Much more research is needed to fully understand the possibilities and risks of xenotransplantations.

22.       A public debate is necessary to clarify the public health, legal, social, ethical and other issues involved. The Assembly should therefore ask the Council of Europe's Public Health and Bioethics Committees, in co-operation with the World Health Organisation and other competent bodies, to work out a strategy for balancing the ethical, medical, scientific, legal, social, and public health aspects of xenotransplantations, before the scientific and medical establishments proceed with human clinical trials.

Reporting committee: Committee on Science and Technology.

Budgetary implications for the Assembly: None.

Reference to committee: Doc. 8050 and Reference No. 2274 of 24 April 1998.

Draft recommendation adopted by the committee on 23 June 1998 with two abstentions.

Members of the committee: MM. Melnikov (Chairman), Birraux (Vice-Chairman), Mrs Terborg (Vice-Chairperson), Mr Tiuri (Vice-Chairman), MM. About, Ataç, Bauer, Beaufays, Brunhart, Cherep, Cherribi, Chornovil, Cioni (Alternate: Speroni), Cunliffe, Mrs Faldet, MM. Fernandez Aguilar, Frey, Ivanov, Janecek, Johansson (Alternate: Mrs Johansson), MM. Kitov, Kittis, Kurucsai, Lambergs, Langthaler, Leers (Alternate: Dees), Lekberg, Lengagne (Alternate: Mattei), Lenzer, Liiv, Lorenzi, Maass, Melcak, Molnar (Alternate: Hegyi), Mozgan, Naysmith (Alternate: Earl of Dundee), Lord Newall, MM. Niculescu (Alternate: Glavan), Niza, Olrich, Onaindia, Pawlak, Plattner, Prokes, Prusi, Raskinis, Rokos, Roseta, Ryabov, Skaarup, Steolea, Theis, Turini, Upton, Uroic, Vella, Weyts, Wittbrodt (Alternate: Luczak), Yürür, Zhebrovsky, Mrs Zissi.

N.B. The names of those members present at the meeting are printed in italics.

Secretaries of the committee: Mr Lervik, Mr Torcătoriu