Network for European CNS Transplantation and Restoration (NECTAR)

Network for European CNS Transplantation and Restoration (NECTAR), Ethical Guidelines for the Use of Human Embryonic or Fetal Tissue for Experimental and Clinical Neurotransplantation and Research (1994).

ABSTRACT
Recently a Network of European CNS Transplantation And Regeneration (NECTAR) has been founded, aimed at a concerted effort to develop efficient, reliable, safe and ethically acceptable transplantation therapies for neurodegenerative diseases, in particular Parkinson's and Huntington's disease. Due to the use of human fetal brain tissue in such studies, usually obtained from elective abortions, ethical concerns have been focused on the relation-ship between abortion and transplantation activities. There is no uniform code on the retrieval and use of human embryonal or fetal material for experimental and clinical research or application in Europe. NECTAR has therefore presently formulated self-restraining ethical guidelines for its European member groups.
These guidelines consist of a series of restrictions intended to prevent the use of grafts to encourage induced abortions and to maintain high standards of respect for life and human dignity. In order to support applications for human embryonal or fetal neuro-transplantation studies of NECTAR member groups to local or national medico-ethical committees and to stimulate the gaol of reaching an European legislation on this issue, the guidelines are presently justified in extensive explanatory notes. Only in this public manner the lines of thought behind these NECTAR guidelines can be addressed critically by those working in the fields of biomedical ethics and legislation as well by politicians and the general public.

INTRODUCTION
Parkinson's disease is a common and severe neurodegenerative disorder which is due to a progressive loss of dopamine neurons in the nigro-striatal system of the brain. Current medical therapy, which is based on drugs increasing dopamine in the affected areas (e.g. L-dopa), is effective in the early stages of the disease, but after 4-10 years, as the disease progresses, the efficacy of the drug treatment is limited by severe side-effects in the majority of cases [34]. During the past decade techniques for dopamine replacement by intracerebral cell transplants into the striatum have been worked out in animal models of Parkinson's disease, first in rodents and later in primates. On the basis of these results, which showed that trans-planting a preparation containing fetal mesencephalic dopaminergic neurons induced long-term recovery of motor deficits, clinical trials in patients were initiated in several research centres in Europe, Central and North America and China [19,26,31,38,39,40,42,49,64,68]. The prospect of therapeutically effective dopaminergic cell trans-plantation in Parkinson's disease and consequently in other neuro-degenerative disorders [22,55] has recently led to the formation of a joint trans-national network to coordinate clinical trials and methodological developments in Europe. At the inaugural meeting of this Network of European CNS Transplantation And Restoration (NECTAR) in Le Vésinet (near Paris, France) on 10-11 May 1991, representatives of 13 groups from 11 European countries aimed for a concerted effort to develop efficient, reliable, safe and ethically acceptable transplantation therapies for neurodegenerative diseases, in particular Parkinson's disease. More recently also Huntington's disease has become a focus of interest [29,53].
An important aspect in neural transplantation in humans is the fact that it touches upon relatively new ethical questions in bio-medical research concerning the retrieval and use of human embryonal and fetal material and emphasizes the questions involved [2,44]. So far, the donor tissue for the most promising treatment schedules became available through legally induced abortions. In principle, the possible use of embryonal and fetal organs or tissue would be analogous to the use of organs and tissue from deceased persons [20,24,41], for which legislation normally exists. However, since the decision on therapeutic abortion might be influenced by the donation of tissue for a given therapy [24] and conception might even be effectuated with the sole purpose of obtaining organs or tissue from embryonal or fetal origin, additional regulation is called for. If, moreover, transplantation were to become a standard therapy for certain common diseases, this could create a great demand for human fetuses or embryos, with the chance that they would then be debased to organ or tissue sources. Therefore, the ethical and legal regula-tions for the use and transplantation of embryonic and fetal organs or tissue cannot be completely separated from those concerning induced abortions [16,27,46,54].
In most European countries political and legal debates have resulted in legislation on elective abortions, ranging from strictly pro-life to a qualified pro-choice [7,18,70]. Still, the issue is problematic in all countries, since there is no unanimity among the population about the moral judgement. It is not surprising, there-fore, that critical questions have been asked and strong protests raised about the use of human embryonal organs and tissue, obtained through artificial abortion, for experimental work including neurotrans-plantation. Some pro-life critics have denounced the use of embryos or fetuses of still occurring elective abortions as com-plicity after a murder sanctioned by law [8,11]. Other critics have said that the ethical questions are too often approached only from a scientific and technological perspective with the rationale that scientific research is tremendously important and beneficial to mankind, because in the end it may cure or prevent illnesses in numerous human beings. Consequently, they said, norms have been established that impede research as little as possible [36]. Such statements are belied by the growing body of publications on the ethical aspects of using embryonal and fetal organs and tissue, especially those showing complete openness on the part of the scien-tific community [28,47,62]. A full ethical judgement however, general-ly lags behind scientific developments: indeed, ethical issues are often raised through scientific achievements. Therefore, ethical issues on the use of human embryos or fetuses will remain continuous-ly open and under discussion.
Currently, there is no European country with complete legislation on the use of human embryos and fetuses for scientific, diagnostic, therapeutic, industrial and commercial purposes (Spain being the exception) [63,70]. But in Europe (as elsewhere in the world [65,71]) guidelines have been published or proposed by many national health or ethical committees [13,15,16,27,51,52] as well as the Parliamentary Assembly of the Council of Europe [57,58]. These guidelines expressed considerably different views [66]. One of the aims of NECTAR, there-fore, was to formulate self-imposed ethical guidelines for the use of human embryonic and fetal tissue for scientific and therapeutical purposes, including their rationale. It would then ensure a uniform code of conduct for the European member groups and would guide and support any application for human embryonal or fetal neurotrans-plan-tation studies in local or national medico-ethical committees. In addition it could serve as a source for those involved in the future determination of national or European legislation on this important issue. The importance of qualified information and final legislation is further emphasized by the fact that the European Union (EU) has recently installed a Working Group Human Embryo Research to work on these ethical and legal questions [70].
The present paper reports on the guidelines as they crystallized after discussions at NECTAR meetings in Le Vésinet, France (May 10-11, 1991), Milan, Italy (January 24-16, 1992) and most recently in Brussels, Belgium (August 27-29, 1993). In this presentation we will first list the set of guidelines adopted by NECTAR and subsequently explain the rationale behind the propositions in explanatory notes. Four general moral principles served as the basis for the dis-cussions: a) human beings and their autonomy should be respected, b) what is good should be done ('beneficence'), c) what is bad should be avoided ('non-maleficence') and d) what is just should be based on the fair distribution of the available means, on respect for human rights and on morally acceptable legislation [4].

GUIDELINES ADOPTED
NECTAR ethical guidelines for the retrieval and use of human embryonic or fetal donor tissue for experimental and clinical neurotransplantation and research

Clinical and experimental groups or institutions that are members of NECTAR will obey the present ethical guidelines, irrespective of the fact that national legislation may permit them to deviate from these guidelines and provided national legislation allows them to follow these guidelines.
1) Tissue for transplantation or research may be obtained from dead embryos or fetuses, their death resulting from legally induced or sponta-neous abortion. Death of an intact embryo or fetus is defined as absence of respiration and heart beats.
2) It is not allowed to keep intact embryos or fetuses alive arti-ficial-ly for the purpose of removing usable material.
3) The decision to terminate pregnancy must under no circumstances be influenced by the possible or desired sub-sequent use of the embryo or fetus and must therefore precede any introduction of the possible use of the embryonic or fetal tissue. There should be no link between the donor and the recipient, nor designation of the recipient by the donor.
4) The procedure of abortion, or the timing, must not be influenced by the requirements of the transplantation activity when this would be in con-flict with the woman's interests or would increase embryonic or fetal distress.
5) No material can be used without informed consent of the woman involved. This informed consent should, whenever possible, be obtained prior to abortion.
6) Screening of the woman for transmissible diseases requires informed consent.
7) Nervous tissue may be used for transplantation as suspended cell preparations or tissue fragments.
All members of the hospital or research staff directly involved in any of the procedures must be fully informed.
9) The procurement of embryos, fetuses or their tissue must not involve profit or remune-ration.
10) Every transplantation or research project involving the use of embryonic or fetal tissue must be approved by the local ethical committee.

EXPLANATORY NOTES
Status of guidelines
NECTAR has been initiated to stimulate collaboration of research groups with a mutual interest in the development of neurotrans-planta-tion as a possible therapy in brain diseases. The idea behind this collaboration is not that if there are ethical objections against experimental transplantation studies in one country, these studies should be carried out in another country where obtaining permission will not cause any problems. The ethical issue concerning the use of human embryos and fetuses available from legally induced abortions as well as from spontaneous abortions is considered to be universal. Therefore all NECTAR group members should adhere to the present guide-lines in order to make NECTAR a credible network within the European communities.
In Europe, legislation on elective abortion, in particular, differs widely from country to country [7,18,70] and can even change rapidly within one country as a result of dramatic political changes, as was the case in, e.g. Poland (J. Dymecki, personal communication). Moreover, there is always constant pressure on the prevailing views on elective abortion, since moral judgements differ among people, for instance on religious grounds [72]. The ethical views on the use of embryonal and fetal organs and tissue are less controversial within and among European nations, but are, as stated above, influenced by the views on elective abortion. It is the aspect of the use of legally obtained human embryonal or fetal material that is covered by the present NECTAR guidelines.
The NECTAR guidelines will obtain the status of a solid standard and a useful reference in any application for the use of embryonic and fetal tissue if each member group fully agrees with the directives given and adopts them as common practice. In that case they might also serve as a background for formal legislation on the issue in the various countries or even at the European level in the Council of Europe and the EU. The presently formulated self-adopted guidelines must not be seen as the final or definitive statement of NECTAR. Ethical aspects will remain under continuous evaluation as a result of both practical experience and further discussions with those outside the field of (neuro)transplantation.
The present ethical guidelines cannot be followed in countries where their application will lead to prosecution, but NECTAR groups from countries where legislation is more liberal than the NECTAR guidelines should still comply with the latter.

Definitions
Embryonic state is defined as between 15 days and 8 weeks post-conception of a pregnancy. In the absence of more precise information (i.e. menstrual cycle length), conception is presumed to have taken place two weeks after the beginning of the woman's last menstrual period. At 8 weeks the rudiments of nearly all the main structures have been laid down and there is a general appearance of a mammal-to-be with four limbs and a head. However, the 8-week dividing line is still arbitrary, since a firm scientific basis for the transition to the fetal stage is lacking [56]. The fetal stage is taken to be the subsequent period between 8 weeks and the time the baby is born, at approximately 38 weeks post-conception (40 weeks post-last menstrual period). The distinction of the 15-day stage as the beginning of the embryonic stage is not arbitrary: the pre-embryo is not isomorphic with the later developmental stages, since cells cannot yet be defined as contributing to the embryo or to the extra-embryonic tissue [30], and complete implantation has not yet been accomplished [56]. The possible use of pre-embryos or cells thereof (as well as of fertilized human egg cells) is not discussed within the present framework of neurotransplantation research and therapy.