11 September 2003
Human stem cell research
Committee on Culture, Science and Education
Rapporteur: Mr Wolfgang WODARG, Germany, Socialist Group
While confirming the Assembly’s previous stands on bioethics issues, the draft resolution encourages research on human stem cells as such research can lead to important developments in the treatment of serious diseases. Any research on human embryos should be duly authorised and monitored. Their destruction should be prevented.
The aim of stem cell research is the understanding of the mechanisms of proliferation and differentiation of these cells and their control in order to be able to use them in regenerative medicine. Controversy surrounds the reliability of embryonic and adult stem cells. Some oppose the use of embryonic stem cells and the techniques of cloning on ethical grounds.
Ethical aspects however should be given priority over those of a utilitarian and financial nature.
I. Draft resolution
1. The Parliamentary Assembly recalls its previous work on bioethics and in particular its Opinions N° 198 (1996) on the draft Convention on Human Rights and Biomedicine and N° 202 (1997) on the draft additional Protocol to that Convention on the prohibition of cloning human beings.
2. It notes that the aim of stem cell research is to add new tools for the development of treatments of several diseases which up to now have been incurable or not effectively curable.
3. Human stem cells may be derived from a growing number of tissues and fluids from human beings of any age and are not limited to embryonic sources.
4. Any therapeutic use of stem cells which are not derived from the patient himself has to surmount the barrier of rejection (which might be avoided through cloning techniques).
5. The harvesting of embryonic stem cells for the time being necessitates the destruction of human embryos.
6. Furthermore the use of xenotechnologies for growing human stem cells - for example feeder cells of animal origin or chimera cloning - increases the risk of new and dangerous infectious diseases (TSE, HIV, SARS).
7. The Assembly points out that a number of embryonic human stem cell lines suitable for scientific research are already available worldwide.
8. It recalls that article 18 of the Council of Europe Convention on Human Rights and Biomedicine (Oviedo Convention) expressly states that “where the law allows research on embryos in vitro, it shall ensure adequate protection of the embryo". The details of this regulation should be the subject of an additional protocol to be prepared by the Steering Committee on Bioethics (CDBI).
9. The same article expressly prohibits the creation of human embryos for research purposes.
10. The destruction of human beings for research purposes is against the right to life of all humans and against the moral ban on any instrumentalisation of humans.
11. Therefore the Assembly calls on member states to:
i. promote stem cell research as long as it respects the life of human beings in any state of their development;
ii. encourage scientific techniques that are not socially and ethically divisive in order to advance the use of cell pluripotency and develop new methods in regenerative medicine;
iii. sign and ratify the Oviedo Convention to make effective the prohibition of the production of human embryos and prevent their destruction for research;
iv. ensure that any research on stem cells involving the destruction of human embryos is duly authorised and monitored by the appropriate national bodies;
v. respect the decision of countries not to take part in international research programmes when there are ethical values enshrined in national legislation and not to expect such countries to contribute either directly or indirectly to such research;
vi. give priority to the ethical aspects of research over those of a purely utilitarian and financial nature.
II. Explanatory memorandum1
By Mr Wodarg
A. General considerations
1. An intensive debate is currently under way on the subject of research in embryos and human stem cells. A stream of new information in the biomedical field is feeding hopes for new therapeutic approaches in the long term for diseases that are at present untreatable. Research with all forms of stem cells is also being conducted in an attempt to gain a deeper understanding of the development of cells, tissues and organs.
2. In the past, ethical problems surrounding research in embryos have often been the subject of discussion within the scientific and political community but also in the public arena. At the political level a number of commissions have already dealt with this topic.
3. It is in the nature of ethicolegal judgements that they require general validity. However, no one has a monopoly on objective correctness. This is particularly the case where - as in research with human embryonic stem cells - high-ranking values of ethics and legal order have to be weighed against one another, because they come into conflict with each other.
4. In the ethical assessment of new research technology, such as that currently developing in the area of human stem cell research, it is desirable to follow an assessment procedure which differentiates between means and objectives. Initially the legitimacy of the objectives which the research under consideration and the potential technology are supposed to serve, should be questioned. Since even high priority aims cannot justify every means, questions should also be asked concerning the acceptability of the means used, including any unintended side effects and long term consequences. It is necessary to consider the social conditions that form the context for the objectives concerned and also to examine the social consequences to which the selected combination of objectives and means may lead.
5. Where research objectives have to be balanced against competing objectives or claims, the reasonable principle of research experimentation, that various promising paths to a research goal should be followed simultaneously, is subject to a limitation in the sense that the ethically and legally uncomplicated paths should be followed first, before investigating the feasibility of a method subject to ethical and legal criticism. This means that ethically disputed research regarded as having high priority objectives should not be given attention while ethically less controversial methods of research are being pursued.
6. In addition to the general aims of researchers - to gain information, to develop and improve the treatment of serious diseases - stem cell research can also be used for other objectives of questionable legitimacy, including objectives for which a therapeutic nature can be claimed as well as objectives outside the therapeutic spectrum. Amongst these are the use of the technologies developed by stem cell research in order to modify the germ cells that affect all progeny (germ line intervention), and in order to transfer a somatic cell nucleus into an enucleated egg cell to give birth to a cloned human (reproductive cloning).
7. The announcement of Dolly’s birth brought about a swift series of legal proclamations banning the cloning of human beings. Much work had already been done on Europe, which led to a scientific and political consensus as to the illegality and immorality of human cloning. This work had been carried out for several years, both in the Council of Europe and in the European Union.
8. In the Council of Europe, one finds Assembly Recommendations 934 (1982), 1046 (1986) and 1100 (1989), which effectively express a sanction on human cloning. The Council’s Oviedo Convention on Human Rights and Biomedicine also contains articles (1 and 18) that implicitly prohibit human cloning. However the clearest prohibition against cloning has been the addition of the first protocol to this same Convention, which deals with the explicit banning of human cloning, and was opened for signature, potentially only by the signatories of the Convention, on 12 January 1998. In Article 1, the protocol clearly states that: Any intervention seeking to create a human being genetically identical to another human being, whether living or dead, is prohibited.
9. In its first reading of the European Directive on setting standards of quality and safety for the donation, procurement, testing, processing, storage and distribution of human tissues and cells, the European Parliament has adopted an amendment in favour of banning within the European Union the use of tissues and cells from cloned human embryos.
10. In order to put a stop to any approach of creating a cloned child2, an initiative was introduced at the United Nations in 2001 by Germany and France with the aim of preparing a convention proscribing reproductive cloning as quickly as possible. Negotiations broke down in 2002 and were postponed until the next round of negotiations in 2003, because the USA and some other countries were proposing a more extensive proposal for a comprehensive ban on all forms of cloning and no suitable compromise proposal could be prepared.
11. Of the ethical criteria reflected in fundamental legal norms and in medical ethics, objectives such as the reproductive cloning of humans and intervention in the human cell line must be regarded as ethically unacceptable. Reproductive cloning aims to give rise to a human possessing the nucleus genome of an individual already born, and therefore subordinates this human being to the ends of third parties in a manner contrary to human dignity. Interventions in the human germ line are associated with uncontrollable risks and require for their introduction experiments in humans that cannot be justified. They interfere with the genome of an unforeseeable number of future carriers of this genome without their consent. This is an act of predestination with regard to the individuals affected that cannot be legitimised even by a possible therapeutic objective. Stem cell research relating to procedures such as reproductive cloning and germ line intervention is accordingly to be rejected purely on the basis of its objectives, as medically and ethically unjustifiable. The question of ethical justification of the means used in stem cell research relates in particular to the methods by which the stem cells required for research are obtained. The derivation of stem cells from human embryos is here again the main focus from the ethical point of view; the rights to protection attributable to the human embryo must be considered here and the consequences for society's dealings with unborn human life have to be taken into account.
B. Scientific status
Definition and Origin of Stem Cells
12. Stem cells are cells that renew themselves by cell division and are capable of maturing into many different cell types (differentiation). They could therefore be used for cell and tissue replacement.
Depending on their origin, a distinction is drawn between
§ embryonic stem cells (ES cells) from embryos3 derived from in-vitro fertilisation (IVF),
§ embryonic stem cells produced by cell nucleus transfer,
§ embryonic germ cells (EG cells) from terminations of pregnancy,
§ neonatal stem cells from blood taken from the umbilical cord (cord blood) and
§ adult or somatic stem cells that can be derived from many tissues of born human beings throughout their whole life (AS cells).
13. ES cells can be harvested from the inner cell mass of cells at the blastocyst stage. In mice, there are now a number of established cell lines that proliferate under the appropriate conditions in vitro and can be cultured indefinitely in their undifferentiated state. These cells can also be deep-frozen and stored for long periods. Around seven to eight cell lines are used for research in mouse ES cells throughout the world, well over 90% of this work being carried out in five cell lines. The characteristic properties of ES cells include:
§ proliferation over an indefinite period in the undifferentiated state,
§ stable, unchanged sets of chromosomes,
§ spontaneous differentiation into various cells of all three germ layers in vivo and in vitro,
§ potential differentiation into all cell types of the adult organism, including germ cells, after
§ injection into foreign blastocysts.
14. It first became possible to isolate and culture human embryonic stem cells in 1998.4 With the methods used at present, the harvesting of ES cells is inevitably connected with the destruction of the blastocyst. Some experts are of the view that, at least for the purposes of basic research, small numbers of viable cell lines would be sufficient, so that no further "consumption" of embryos would be required. In order to establish these human ES cell lines, with the present state of the art, only a limited number of embryos would therefore be needed.5 Other experts consider it likely that a larger number of cell lines will be required for therapeutic use than in mice – possibly even 100 to 1000 – since slight differences between the cell lines have been identified. This does not take into account the need to use further embryos if, for purposes of cell and tissue replacement, cell lines with different tissue characteristics are required and are to be made available in ES cell banks. Testing for tissue compatibility before stem cells are transferred can help to prevent rejection of the cells by an immune reaction in the patients concerned. For this reason, the European Science Foundation speaks of cell banks containing 4000 ES cell lines.6
15. One of the key problems in the derivation of differentiated cells from ES cells is purification. The purity of transplanted cells is crucial, since the smallest quantities of immature embryonic cells can lead after transplantation to the growth of undefined/unwanted cells foreign to the host tissue or tumours (known as teratomas or teratocarcinomas). Moreover, differentiation in cell culture leads to a mixture of various cell types. The harvesting of cells of a defined type, however, is the prerequisite for possible therapeutic applications. It has been possible to differentiate mouse ES cells in vitro into cartilage cells, epithelial cells, cells of the blood and nervous systems, insulin-producing cells and heart, skeletal and vascular muscle cells.7 In ES cells from non-human primates, spontaneous differentiation into myocardial cells and neurones has been observed and also into cells8 of the endoderm and trophoblast9. With regard to directed differentiation and the identification of the effects of various factors on ES cells from non-human primates and humans, research is still at an early stage.
16. The transfer of a diploid cell nucleus into an enucleated, unfertilised egg cell allows asexual replication even in mammals. Dolly, the cloned sheep, provided the first evidence that this cell nucleus can also be taken from adult somatic cells. Since then, offspring have also been created in cattle, goats, mice and pigs by this process of reproductive cloning.10 The environment in the egg cell makes it possible to reprogram nuclei from differentiated somatic cells in such a way that a totipotent cell is produced. In cloning experiments in animals, problems are frequently encountered during pregnancy (disturbances in placental development, increased abortion rates, foetal abnormalities) or severe damage to the health of the newborn animals. 11 One of the causes is suspected to be incomplete or defective reprogramming of the cell nuclei, leading to defective activation of genes relevant to development. Cell nucleus transfer results in the creation of individuals whose nucleus genome is identical to the original cell but who also possess the mitochondrial DNA from the cell plasma.
17. Totipotent cells created by cell nucleus transfer, after their development to the blastocyst in vitro, may also be used as a basis for establishing ES cell lines. The process has become known as "therapeutic" cloning to distinguish it from reproductive cloning, since it is hoped that use of the procedure in humans could result in the creation of embryonic stem cells with the genetic characteristics of a patient for therapeutic purposes (autologous cells). However, as with the creation of cloned animals, a large number of genetic and epigenetic defects must also be expected in those cell lines. The extent to which such cell lines could be used for cell and tissue replacement is therefore unclear.
18. In order to reprogram the nuclei of somatic cells from patients, human egg cells would need to be used. Human egg cell donation, however, is associated not only with medical risks but also with ethical problems. Since estimates suggest that, even under favourable conditions, at least 280 human egg cells could be required to establish a single ES cell line by "therapeutic" cloning12, egg cells of animal origin and enucleated ES cells or embryonic germ cells (EG cells) have been discussed as possible alternative host cells for nucleus transplantation. Groups of cells produced in this way are chimeras with regard to their genetic material because, in addition to human nucleus DNA, they also contain mitochondrial DNA of animal origin. It is uncertain whether the interaction of gene products of the nucleus genome and of the mitochondrial genome required for the building of mitochondria can take place in such cells and whether functional compatibility exists between the molecules of the different species present in the egg cell, which appears to be necessary for reprogramming.
19. Embryonic germ cells (EG cells) can be harvested from the precursor cells of egg and sperm cells, known as primordial germ cells, in the late embryonic or early foetal stage. Human embryonic germ cells can be isolated from human embryos and foetuses at several weeks of age, following termination of pregnancy.13 Because of the variation in times at which pregnancies are terminated and since the embryo or foetus dies during the termination, harvesting of EG cells is more difficult than the isolation of ES cells. For technical reasons, e.g. because of insufficiently sterile conditions, it appears unlikely that suitable EG cell lines can be established from spontaneous abortions.14 No detailed findings are yet available on the proliferation and development capabilities of human EG cells. The cells used to date show a capacity for proliferation inferior to that of ES cells, though their genetic activity exhibits a broad potential for development (differentiation potential). It is impossible at present to say whether EG cells may provide an alternative to ES cells.
20. The harvesting of stem cells from cord blood directly after parturition has been practised for some years, in order to obtain haematopoietic stem cells as an alternative to bone marrow transplantation. Around 1,500 transplant procedures using neonatal stem cells have now been performed world-wide.15 The use of somatic stem cells from cord blood offers a number of advantages: harvesting of the cells is practically risk-free for donors, the prevalence of transmissible viruses is low and cryo preservation allows the cells to be made available over a long period. Although stem cells are present in cord blood in high concentrations, the absolute number of cells is limited in view of the small quantity of cord blood. The quantities of usable blood are suitable for the treatment of children (bodyweight approx. 20 – 25 kg). The number of stem cells is frequently not sufficient to replace bone marrow transplantation in adults. However, patients with a weight of almost 100 kg have been successfully transplanted with neonatal stem cells.16 Moreover, at least for bone marrow transplantation, only half the numbers of cells are required for transplantation with the patient's own cells (autologous transplantation) compared with allogeneic (heterologous) transplantation of donor cells.17
21. Even in adult mammals, stem cells that renew themselves and are not yet finally differentiated exist for the regeneration of certain tissues. The best known examples are the haematopoietic stem cells found in the bone marrow, which are capable of differentiating into all blood cells. There are also adult stem cells in the liver, skin, hair, inner wall of the intestine and other tissues which frequently have to regenerate. Even in the lungs, retina and teeth and in tissues with low regenerative capability, such as the nervous system, the existence of such precursor cells has been demonstrated.18 Around 20 main types of adult stem cells have been discovered to date. The harvesting of such tissue-specific AS cells may be problematic, since the cells are present in organs like the heart, brain or pancreas and only in small numbers. Other researchers assume that the difficulties encountered in harvesting AS cells are due to lack of experience. However, it is suspected that the number of somatic stem cells decreases with age.
22. The potential of AS cells depends crucially on their ability to develop. For a long time it was assumed that tissue-specific AS cells were capable only of developing into their target tissue, but in recent years it has increasingly been found that differentiation into other cell types is also possible. Even without cell nucleus transfer, which leads to a complete reprogramming of differentiated somatic cells, tissue-specific AS cells can under certain conditions be made to mutate into a number of cells not within their usual development spectrum (transdifferentiation). Adult mouse neural stem cells, for example, have been found to differentiate into skeletal muscle, heart, lung, blood and skin after implantation.19 It may even be possible to convert AS cells back to a pluripotent stage, as seen in ES cells (reprogramming).20 So far however, it has not been possible to control the processes of transdifferentiation or reprogramming.
Totipotency and pluripotency
23. In general a distinction is made between totipotent and pluripotent embryonic cells. The use of the terms totipotency and pluripotency in scientific literature is however inconsistent: in classical embryology, the totipotency of a cell is understood to mean the ability to form a complete being, i.e. an individual. Pluripotent cells, however, in the context of classical embryology, are capable of developing into a variety of cells, tissues or organs but not into a complete individual. According to classical embryology, during normal development of a human, the stage of totipotency is limited to the fertilised egg cell and the daughter cells arising during the initial stages of division. Many experts therefore rule out the possibility that ES or EG cells implanted into a uterus could continue to develop into an individual. ES and EG cells are therefore classed as pluripotent. This point of view has however recently been challenged by the works of Hans Schöler, Karin Hübner et al., who were able to show, that mouse embryonic stem cells in culture can develop into oogonia that enter meiosis and recruit adjacent cells to form follicle-like structures and later develop into blastocysts.21 For ethical reasons it is impossible to investigate whether human ES cells would be capable, after implantation into a uterus, of developing into a complete individual. Nor is it possible to investigate whether human ES cells, after being returned to another blastocyst, would take part in embryonic development and enter the germ line, as is the case with mouse ES cells.
24. Understanding of the concept of totipotency based on classical embryology is called into question by the availability of the technique of cell nucleus transfer since, under certain experimental conditions, even cell nuclei from adult tissues can be used to produce a cell with totipotency (reprogramming). In this case it is only the product of cell nucleus transfer that is to be defined as totipotent and not the original cell. With the reprogramming of AS cells the question also arises as to whether these reach the level of totipotency or whether they remain pluripotent.
Therapeutic use of stem cells
25. In the context of what is known as regenerative medicine, stem cells could attain particular therapeutic importance with regard to those tissues which in adult humans exhibit only very little or no ability to regenerate. This applies in particular to the central nervous system. Possible areas of use for stem cells in cell and tissue replacement include not only neurodegenerative diseases such as Parkinson's disease and Huntington's chorea but also myocardial infarction, stroke, paralysis, epilepsy, diabetes mellitus (type I) the leukaemias and deficiencies of the immune system.
26. With respect to the use of stem cells in cell and tissue replacement, a distinction must be made from the clinical point of view between allogeneic (heterologous) and autologous cells. Whereas allogeneic cells have a genetic identity different from that of the individual receiving the tissue, in the case of autologous cells the genetic pattern is identical. ES cells and EG cells would belong to the allogeneic category. AS cells and neonatal stem cells might fall within both the allogeneic and autologous categories. ES cells produced by cell nucleus transfer would presumably behave as quasi-autologous cells. Immunological rejection reactions are to be expected with the transplantation of allogeneic cells or tissues, as seen in organ transplantation. After the transplantation of autologous cells, no immunosuppression would be required.22
27. The development from stem cells of complex organs such as the heart, kidney or liver is also under discussion within the research community. Functional structures are to be formed by the combination of living cells and three-dimensional synthetic frameworks.23 A major difficulty, however, is the need for an adequate blood supply to the organ and its connection to the nervous system. It is therefore assumed that the development of organs cannot be simulated in cell culture in the foreseeable future and that this must at present be regarded as rather unrealistic.
28. The clinical use of stem cells is currently restricted to AS cells and neonatal stem cells, used within their tissue specificity. Increasingly, however, curative studies are being conducted outside the spectrum of tissue specificity.24 Investigations in AS cells are currently at a considerably more advanced stage than research in ES cells. With AS cells, the main priority is to overcome difficulties associated with the derivation and replication of cells and those related to the purity of cell types.
Whether AS cells can be obtained in adequate quantity from elderly patients must also be clarified. In comparison to ES cells the risk of malignancy in therapeutic use is presumably lower in view of the more limited ability to proliferate.
29. The complex processes involved in the differentiation of tissues and organs are still largely not understood. Basic research – in particular with ES cells – should make a considerable contribution to our understanding of the mechanisms on which proliferation and differentiation in embryonic development are based. Opinions vary amongst researchers as to whether these investigations are a necessary prerequisite for obtaining information on the way in which the differentiation of adult stem cells can be steered in particular directions, with a view to their use in regenerative cell therapy.
30. The extent to which findings from animal experiments are applicable to humans has not yet been clarified. A number of fundamental differences have been identified in the embryonic development of mice and humans and in investigations in ES cells it has been found that various substances have an effect on human cells which is completely different from that seen in mouse cells. Research in human ES cells is therefore expected to provide important insights into the specific characteristics of human embryonic development. Insofar as this research in humans reaches boundaries which must not be crossed or is rejected for ethical reasons, there remains the possibility of obtaining general information by means of animal experimental research particularly in non-human primates (monkeys).
C. Ethical and legal problems
Objectives and means of research in human stem cells
31. After a phase of research that related to tissue-specific (adult) human stem cells and tissue-specific and embryonic stem cells of animal origin, stem cell research entered a more intensive phase from November 1998. It was then for the first time that identification and derivation of pluripotent human stem cells began from “supernumerary” embryos (ES cells) and from primordial germ cells from aborted embryos or foetuses (EG cells). This new phase involves both tissue-specific adult and also embryonic stem cells, the emphasis so far in the latter area – in accordance with the state of development of research – having been in the field of animal experimental research.
32. With regard to objectives, a distinction must be made between those towards which current research has mainly been directed and those for which the results of such research can be used beyond the intended sphere of application. When considering the objective mentioned, it is appropriate to base their ethical evaluation on the ethical standards also expressed in the norms of fundamental constitutional regulations. These include often as a priority the inviolability of human dignity, the right to life and to protection of the integrity of life and limb, rights of self-determination and personal rights and also the prohibition of discrimination. The norms established in criminal law, occupational law and in research ethics, particularly the ethics of research in humans, must also be observed. In the light of these criteria, a distinction must be drawn between objectives to which a particular priority is attached and other objectives which must be regarded as ethically questionable.
33. As is clear from the report on the current status of research, a large number of studies throughout the world are currently pursuing objectives in two areas, based on a variety of interests and evaluations:
§ One of the purposes of research is to obtain information on the circumstances of biological development, which in humans are not yet fully understood. In particular, an understanding is required of the circumstances that lead to the differentiation of embryonic cells into the various tissue-specific cell types and of the factors that cause a somatic cell nucleus to redifferentiate after implantation into an enucleated egg cell. This is research of a basic nature, without which the development of appropriate treatments is impossible.
§ There is also research that may be characterised as applied research, in that, in addition to obtaining information it also serves medical objectives. This includes in particular the development of treatments relating to diseases which medicine has so far been unable to address adequately and in which the use of tissue transplantation promises improvements in treatment. These include in particular the neurodegenerative diseases, diabetes mellitus, degenerative heart disease, etc. In differentiating between basic and applied research, it must be borne in mind that the borderline between these two forms within modern research is fluid and in many areas difficult to identify. This is not least the case in view of research sponsorship, where the benefit of application often represents one of the prerequisites for sponsorship. The difficulty of distinguishing between the two forms of research also applies in the area of stem cell research.
34. Scientific research, by its very nature, involves the risk of failure and therefore any research – depending on its level of advancement – is subject to some degree of uncertainty as to whether, and within what period, the intended objective can be reached. This is particularly true of research in the biological sciences. As is clear from the current status report, stem cell research still has a long way to approach its targets, both in relation to establishment of the fundamental principles and also to the possible applications.
35. In individual limited areas (such as the use of haematopoietic stem cells in connection with the treatment of leukaemias) research has already succeeded in crossing the borderline into application. For most of the other high priority targets mentioned for discovery and action, however, it must be assumed that their realisation, if at all achievable, will require longer periods of research possibly of between 10 and 60 years. Animal experimental research plays a particular role here, if the successful performance of animal experiments by conventional methods – initially in the form of studies in small animals, later in primates – is the prerequisite for the transition to studies in humans. Usually, modern molecular biological research, often guided by a fast-benefit research policy with the strategic use of patents as the essential research objective, tends to investigate applicability to humans at an early stage, and thereafter proceeds with animal experimental research.
36. The fundamental knowledge required for the planned derivation of stem cells by reprogramming somatic cells is largely still lacking, and the preliminary animal experimental work required for the therapeutic use of embryonic human stem cells has not yet been completed. The applicability to humans of information obtained in the animal model has not yet been sufficiently established. For objectives such as the growing of organs from stem cells or the understanding of Alzheimer's disease, the principles are still so poorly understood that doubts persist regarding their general achievability.
37. The objectives of obtaining knowledge and also of healing, alleviating and preventing disease are without doubt of particularly high ethical priority. The high priority of objectives pursued by applied research with a view to use in diagnosis, treatment and prevention, depends on the value attributed to the potential cure, alleviation and prevention of diseases in the context of health care. This in many countries is expressed in constitutional regulations for the protection of the integrity of life and limb and the principle of the welfare state. It should be borne in mind here, that there are some objectives which may be regarded as achievable in the near future and others whose achievability cannot be determined without further research.
38. When pleading objectives of medical cure and prevention, it must be remembered that the very priority of these objectives can be used to associate with this plea other objectives that are ethically of lower priority or even questionable in themselves, not to mention the possibility that such a plea may be used to justify criminal experiments in humans, such as those which occurred during the period of National Socialism in Germany. The objectives of treatment-related research can therefore only be regarded as high priority if they are desired by the patient and involve treatment for which the researcher is answerable in accordance with the rules of medical ethics.
The ontological and moral status of the human embryo
39. Due to the variety of ethical viewpoints in the assessment of the worthiness of protection of the human embryo, controverial responses have been made to the the question of justifiability of the removal of stem cells from human embryos. An ethical evaluation of research in stem cells derived from embryonic tissue is therefore impossible without referring to the various views held with regard to assessment of the ontological and moral status of the human embryo, particularly during its very early stages of development. On that basis one may examine which ethical convictions are relevant
in law and in amendment of the law. The determination of the status of the embryo created in vitro in the initial phase of its development, i.e. up to the formation of the primitive streak and nidation in the uterus, is a particularly controversial matter.
40. The variety of basic views differ as to whether the obligation to protect human rights and human dignity applies even at this early phase, i.e. giving the embryo as such and independently of evaluations by third parties unlimited protection from the begining of its existence, or whether it should have the status of an extrinsic object of protection, i.e. based on the assessment of third parties, or whether its own status as an object worthy of respect and protection depends on the degree of its development.
In this matter two basic positions may be distinguished:
1) In one view, an embryo is considered a person i.e. a human being with full human dignity and human rights from the very beginning of its existence, i.e. from fertilization on. According to this position an embryo has inviolable dignity and a right to life, which is principally not distinct from the rights and dignity of a born human being. Therefore its life could not be at the disposal of other person’s interests. This position may be called a “nongradualist position”.
2) In contrast holders of gradualist positions consider that embryos are human beings with an inferior moral and ontological status. They usually think that the dignity and the rights of an embryo or fetus grow in the course of the process of human development. Among the holders of this position, there is a broad variety of opinions on the question which criteria a human being has to meet in order to be a subject of full human dignity and human rights. Correspondingly a broad variety of development stages is being considered as determinating borderlines, i.e. formation of the primitive streak, begining of brain activity, viability of the fetus outside the mother’s womb, birth or even empirical self-consciousness some time after birth.
41. Considering different approaches in moral philosophy one may notice a certain affinity of deontological approaches to the nongradualist and of utilitarian approaches to the gradualist position. This is due to the utilitarian concept that the reason of a human person’s moral status is the fact that it has in actu wishes and interests. Deontological, i.e. Kantian approaches on the other hand mostly think that the reason of the human person’s moral status is his/her ability to act according to moral rules and ethical norms.
42. The main debates between the gradualist and the nongradualist positions concern the continuity of the process of human development, the identity of human embryo and human person, the potential of the human embryo, the role of the state, and the immanent logic of the concept of human rights and human dignity.
43. Continuity and Identity: From the nongradualist point of view the process of human development is a continuous process, in which any demarcations would be arbitrary and merely conventional. Therefore human embryos must be treated as human persons. Supporters of the gradualist position object that the continuity of a process does not implicate the identity of the starting point with the result of the process. However, this objection seems to be a misunderstanding as the nongradualist argument does not claim the identity of embryo and human person. It only claims that they have to be treated as if they were identical, because within the development process nobody can indicate a non-arbitrary point of transition from human non-person to human person.
44. Potentiality: Some supporters of the gradualist position argue that exclusively human beings who are actual persons, i.e. who have in actu self-consciousness, interests and wishes, are subjects of human rights and human dignity. Against this view nongradualists raise the objection, that in this case not only embryos and fetusses, but also comatose people, newborn children, people who suffer from dementia or even sleepers would be excluded from the scope of human dignity. They stress that it is a naturalistic fallacy to base the moral status of human persons on the actual, empirically observable characteristics and properties of a human being. In line with Kant’s idea of human dignity they claim that the reason why human beings have a distinct status, is their determination to be autonomous moral subjects. Any being having the potential to act according to moral rules and ethical norms must therefore be protected by human dignity, no matter if it ever really acts morally. As mentioned above, it would be a naturalistic fallacy to determine the scope of protected beings by empirically observable characteristics and properties. Therefore the scope must be extended to the very beginning of existence of any being, that has the potential to be a moral subject. 25 That does not mean, that a human may be taken out of the scope of human dignity, neither for the reason that he/her may not be able to factually act as a moral subject due to illness or disability, nor even if he/her was purposely created to be disabled.26 The potentiallity which is connected with human dignity, is not to be taken as a mere empirical fact. It includes all beings, which belong to the human species.
45. The Role of the State: Some gradualists have emphasized, that a modern liberal state should be absolutely neutral in bioethical questions. According to them the state should not make obligatory any religious or philosophical concept at all. Therefore, the destruction of human embryos ought to be allowed to anyone who believes, that they are not persons. Unfortunately, this argument implies a petitio principii, since the licence to destroy human embryos may only be given if human embryos are not subjects of human rights, i.e. if the gradualist position is valid. In a philosophical perspective, the basis of existing gradualist positions can be defined as positivistic, materialistic and empiristic. Materialism and Empiricism however are founded at least on as many unproven philosophical or even metaphysical assumptions as for example various religious nongradualist positions. Nongradualists might therefore argue, that the state does not leave the grounds of metaphysical and religious neutrality if it bans the destruction of human embryos, but if it allows it. Hence, nongradualists may even claim that the religious and metaphysical neutrality of a modern liberal state obliges to prohibit the destruction of embryos until it has been proved that they may not be considered to be human persons.
46. Human Dignity: One of the strongest arguments for the non gradualist position is the intrinsic logic of the concept of human dignity, which is for example stipulated in the EU Charter of Fundamental Rights. “Human Dignity“ basically signifies that a human person is not at the disposition of other persons, i.e. that a human person may not be object to other persons‘ interests, wishes and beliefs. Non gradualists stress that the concept of human dignity has two major implications: as a categorial ethical norm, there are no empirical conditions for its application, at least its validity does not depend on any properties, characteristics or stages of development. Thus, the only adequate criterion of application may be the ontological qualification of a being as a human being. Secondly, human dignity implies that nobody has the right to decide arbitrarily, which human beings have human rights and which have not. For if human dignity signifies “undisponibility“, any arbitrariness must be excluded when determining the scope of beings protected by human rights. In other words: the concept of human dignity would be undermined if people were allowed to define “human person“ according to their (private) opinions or interests. Consequently, the idea of human dignity requires a reference to the least arbitrary criterion, i.e. the criterion with the least metaphysical, religious or
philosophical premisses, when it comes to defining the beginning of human life. For this reason, the scope of being protected by human rights must include every human being from the very beginning of his/her physical existence, i.e. from fertilization on.27
Derivation of ES cell lines
47. Embryonic stem cell lines can be derived:
§ from embryos in vitro, created specifically for this purpose.
§ from embryos in vitro, created for the purpose of bringing about a pregnancy by IVF and for which, for a particular reason associated with the woman28, transplantation into the uterus of the woman is no longer possible.29
§ from pronuclear stages that have been cryo-preserved during IVF procedures and that are not yet embryos but could be developed to embryos within a short period and which, for the reasons mentioned above or because family planning is complete, are also not to be used to give rise to a pregnancy.
§ by means of "therapeutic" cloning.
48. The intention to produce embryos might be based on the fact either that there was a lack of other "resources" for ES cell derivation or that, for particular research purposes, ES cells from other sources would not meet the necessary quality requirements30 or to surpass existing patents in search of not yet protected technologies. The production of embryos for research purposes is prohibited in certain countries including Germany, Austria, Switzerland, France and Canada. It is also prohibited by Article 18 of the Bioethic Convention. Between 1990 and 1998, 118 embryos were produced in Great Britain specifically for research purposes.31 The deliberate creation of a number of embryos for the purpose of producing ES cell lines was reported from the USA for the first time in July 2001.32
49. Even for a gradualist position the question matters whether the derivation of stem cells from "supernumerary" embryos could be regarded as proportional in view of the high-priority objectives mentioned. In view of the obligation to protect each human embryo it must be demonstrated that such derivation is appropriate and necessary in order to achieve the objectives in question. This applies with regard both to whether such research could also be carried out in adult stem cells and also to whether it is necessary at the present time or whether ethically less controversial means should initially be selected for research for the high-priority purposes concerned.
50. The weight of these questions arising from ethical perspectives makes it clear that the decision concerning legal regulation could only be taken after adequate clarification of the scientific and medical circumstances involved and only after intensive public debate. These discussions should also consider the procedures and composition of the appropriate committees by which the above mentioned evidence is to be gathered and examined. This is even more the case since the dissension relating to views on the moral status of the human embryo in vitro is unlikely to be resolved within the foreseeable future.
51. The legislator must take account of the fact that the right to life of large numbers of other embryos could be jeopardised if the use of "supernumerary" embryos were permitted for the derivation of stem cells. Such jeopardy could arise – many people feel – from the fact that the number of such "supernumerary" embryos could subsequently be increased deliberately. However, this would be in contravention of the current legal position held in various countries, under which the existence of "supernumerary" embryos represents an undesirable secondary consequence of in-vitro fertilisation that should be avoided. However, an unwanted and unintentional increase in the number of "supernumerary" embryos is also feared because the evaluation of the actual situation will be difficult to separate from research interests.33 A demand for "supernumerary" embryos for research purposes could therefore result in a greater supply of such embryos. A "breach of the dam" could take place that could undermine embryo protection as a whole.
52. A change in IVF procedures, limiting the number of embryos created from three to one, does reduce the mental and physical burden on women, in so far as only one egg cell is taken without prior hormone stimulation; this procedure cannot, however, prevent the existence of "supernumerary" embryos but can only reduce their number. The possibility of freezing not only pronuclear stages but also egg cells offers another means of reducing the number of "supernumerary" embryos, only one egg cell being fertilised after thawing. With respect to the production of ES cells from pronuclear stages, it should be noted that this is possible only by means of creating embryos. There is also a view that the use of pronuclear stages for purposes that use up this material for the benefit of third parties would be equivalent to the production of embryos for research purposes.
53. Embryo adoption could in any case be regarded as a possibility for providing "supernumerary" embryos with a chance of survival in the last resort as an alternative to disposal. It may be, however, that this represents only a partial solution to the problem of "supernumerary" embryos. On the other hand, an objection to embryo adoption is that it could be associated with divided motherhood, the risk of covert surrogacy and of affecting IVF techniques, the risk of inducement to create "supernumerary embryos" and of commercialisation.
54. The method of "therapeutic" cloning differs from reproductive cloning34 not in its technique, but with regard to its intention: in reproductive cloning, genetically identical offspring ("delayed identical twins") are created. The technique of cloning is at the stage of basic research. Therapeutic applications cannot be expected within the foreseeable future.35 This is why in recent contributions the expression „therapeutic cloning“ has been criticized and more adequate expressions such as “scientific cloning“36 have been proposed.
55. The totipotent cells created by this technique, unlike embryos from natural fertilisation (of egg and stem cell) are genetically related to only one "contributing parent", the donor of the cell nucleus. The genome of the embryo is almost completely known from the outset.37 It is hoped that the genetic identity of the embryo with the cell nucleus donor will allow the production of immunologically compatible biological material which will not be rejected in the body of the donor of the cell nucleus.
56. Experience from the successful cloning of animals shows that a large number of experiments are necessary to obtain a living creature capable of survival. It is therefore assumed that even with non-reproductive cloning, a large number of cell nucleus transfers must be carried out in order to obtain a cloned ES cell line and to minimise genetic and epigenetic defects in the ES cell lines produced. Cloning requires the availability of female egg cells for nucleus transfer. Egg cell donation is an invasive intervention for the benefit of others, associated with a considerable risk of damage to health for the woman.38 The regulations allow interventions in humans for the benefit of others– as with medical experiments in humans or with organ donation from the living –only under limited circumstances even where consent has been given. A decisive factor in assessment of acceptability is the proportionality of the procedure. In spite of the existence of consent given after detailed information has been provided by a doctor, the physical intervention for the benefit of others remains contrary to law, if the burden imposed by the procedure is disproportionate as regards the purpose of the intervention.
57. If an embryo created by cell nucleus transfer represents a living human being, all the comments concerning protection of human dignity and life made above with regard to "supernumerary" embryos also apply for the embryo created by cell nucleus transfer. In the case of reproductive cloning, the individual concerned has to bear the consequences of this objective set by third parties permanently and in a way not otherwise encountered. Even if his/her genome is not completely identical with the genome of the cell nucleus donor because of the modified mitochondrial components, there is likely to be a large degree of concordance with a genome already existing in its phenotypic expression. Therefore, in the case of reproductive cloning, the embryo created is likely to be deprived by the intentional decision of third parties of the natural conditions unique to every human embryo created in the natural way, having a father and mother, that is, being a living creature which is "random" in its make-up from the two haploid sets of chromosomes of the parents and unpredictable in detail with regard to its phenotypic characteristics.39
58. Without doubt, the derivation of transplantable autologous tissue by means of the cell nucleus transfer technique described, is a high-priority therapeutic objective, if it is capable of preventing the rejection reactions otherwise to be expected. However, this objective cannot remove the ethical objection mentioned, particularly if the harvesting of transplantable tissue from AS cells – to the extent that this is possible – can lead to the same objective.
59. The aim of research to be performed in stem cells from embryos created by "therapeutic" cloning is regarded as being of high priority in so far as it concerns the understanding of the programming, reprogramming and transdifferentiation processes in embryonic and adult human stem cells. However, even this priority objective – even if definitely feasible and required by this means only for a limited period – cannot abolish the ethical concerns mentioned. This is particularly true in view of the fact that the same technique as that used for euphemistically so-called "therapeutic" cloning can also be used for reproductive cloning and an embryo created for the first purpose can at any time be used for the second purpose. Therefore, the arguments that have led reproductive cloning to be rejected worldwide also apply to cloning for other purposes.
60. A further point against the ethical acceptability of stem cell derivation by cell nucleus transfer is also the means required in this connection. In particular, the large number of egg cell donations required for successful use of the technique must be regarded as unacceptable. Not only does this represent an unreasonable burden for the woman concerned, but must also have worrying effects on the self respect and social image of women, if they are seen in this way as "suppliers of raw materials".
61. If the method of creating an embryo by cell nucleus transfer, undertaken exclusively for the derivation of stem cells, is regarded as affected by all the arguments against reproductive cloning, all the risks and side effects observed during reproductive cloning in animals must be mentioned, which make transfer of this technique to humans appear currently unjustifiable, quite apart from the other ethical problems mentioned and also apart from the question as to whether cell nucleus transfer is feasible at all in human beings. If it is assumed that even in vitro the moral status of the human embryo is not graduated and that it is therefore entitled to protection of dignity and life, and if the derivation of stem cells by "therapeutic" cloning represents not only a violation of protection of life but also of dignity, human life is being created here solely to be destroyed for the promotion of other human life. Even the undoubtedly high-priority objective cannot change these circumstances.
62. If one assumes that the worthiness of protection of the human embryo is graduated, rejection is less severe. In this case, however, the justification of proportionality is linked to strict demonstration of the appropriateness and necessity of the procedure used. The question of whether the justification relates only to a limited research phase or to broad use of the technique for treatment also plays a role. Even assuming a graduated increase in the protection of the human embryo, the problem of egg donation and the associated negative side effects would have to be given special weight.
63. Irrespective of the varying assessment of the moral status of the human embryo, the ethical legitimacy of non-reproductive cloning is also countered by the arguments that suggest that reproductive cloning is a contravention of human dignity and the associated requirement of equality. To the extent to which the technique of cell nucleus transfer can be used and misused for reproduction of a human being, these arguments must also impact on any form of cloning.
Alternatives and ethically less controversial methods of research
64. The removal of other embryonic or foetal tissues from aborted embryos or foetuses for stem cell derivation will not be analysed further in this connection here. However, it is subject to the same ethical and legal problems in relation to the harvesting of cells. Special attention should be paid to embryonic germ cells based on the observation of their pluripotency and therefore their particular suitability for stem cell production. The connection between the derivation of germ cells from embryonic of fetal tissue and the performance of termination of pregnancy was regarded as a fundamental problem in dealing with EG cells. It is essential that measures which could lead to an increase in the number of terminations of pregnancy should be avoided. There are fears, however, that the possibility of tissue donation could be seen as an additional justification for terminations of pregnancy.
65. The question of who should approve the use of embryonic or fetal tissue following terminations of pregnancy has already been discussed in detail in connection with the subject of transplantation medicine. Some authors assume that, by her decision to terminate, the woman has lost her right to decide on the further use of the aborted embryo or foetus.40 Regulations on embryonic or foetal tissue transplantation in other countries have overwhelmingly adopted the view that only the woman
can decide on possible further use after the termination of pregnancy. A clear separation of the decision to terminate pregnancy and the decision to donate the embryonic or foetal tissue is possible only if the decision on tissue donation is taken independently of termination of pregnancy.41
66. Effects on the social position of women are to be taken into account with regard to the use of embryonic or foetal tissue for the production of EG cells and also in connection with the transplantation of such tissue. It is feared that women could increasingly be regarded as "suppliers of raw materials" who make tissues available for purposes of research or transplantation. The hopes being awakened regarding therapeutic prospects for EG cells could also lead to women feeling obliged to give their consent to the use of embryonic or foetal tissue. In connection with transplant medicine it was pointed out that, particularly with an increasing demand for embryonic or foetal tissue, subtle pressures to donate tissue following termination of pregnancy could be imagined which could even lead to direct or indirect commercialisation and "a depersonalisation of women as exploitable cultivation units".42
67. After birth, the placental tissue including the residual placental blood ("cord blood") is normally discarded although, in view of its medical use, it has now become a "raw material".
The question of the right to disposal of the cord blood is still a matter of controversy with respect both to the right of ownership and to personal rights. It has also been pointed out that parents could claim ownership if they were to accept the costs of harvesting or storing the stem cells. Similar arguments could also be advanced by the operators of private cord blood banks or by the public health authority, if the derivation or storage of stem cells were publicly funded.43 Aside from the legal questions, however, parents in practice do decide on the disposal of the cord blood. They may decide on specific (named recipient) or non-specific (unspecified recipient – allogeneic) donation of the cord blood, its storage or disposal.
68. The tests performed on the blood relate mainly to characteristics necessary for safe transplantation, such as determination of the cell composition, blood group and tissue typing and the presence of infection parameters. An attempt is made by taking a careful case history to determine the existence of hereditary diseases. In theory, genetic tests could also be performed on the cells, e.g. in order to rule out the transfer of genetically transmitted diseases in transplantation. It remains to be seen whether separate permission for further genetic analysis will need to be obtained from the biological parents.44 The question of handling information obtained in this way relating to the state of health of the child and its biological parents are largely the same, with regard to data protection, right to know/right not to know, as those associated with genetic testing in general. Anonymisation of the blood preparations has been discussed in connection with the use of cord blood. This would not only solve the question of consent for specific genetic tests and the associated decision concerning utilisation or non-utilisation of the information from the test, but would also avoid the question of the obligation to divulge known genetic diagnoses to third parties (insurance companies, employers). Assuming that the storage periods for cord blood could be 20 to 30 years, donations already frozen will be affected by these developments.
69. If cord blood banks and the storage of stem cells is supported by public funds or health insurance schemes, the aim must be a just distribution of the donated stem cells amongst all patients who can profit from treatment with the cells. In order to ensure adequate access, attempts to obtain stem cells from cord blood would need to be intensified considerably. It should be born in mind here that voluntary donation of cord blood is risk-free for the donor, ethically uncontroversial and inexpensive for society. It is becoming possible to an increasing extent to derive or produce a number of different stem cells from cord blood. These can probably be used for a variety of treatments as well as for bone marrow transplantation. There therefore appears to be a need to extend the harvesting, collection and storage of donated cord blood and to standardise the costs of storage, if clinical use should be confirmed on completion of the experimental phase. The commercial offer to build up stocks of cord blood on an individual basis could give rise to unfounded expectations in the parents of newborn infants. Commercial models have been developed in recent years based on the hopes of parents that their child might in later life be cured, in the event of a serious illness, by means of the preserved neonatal stem cells. Parents could be made to feel that they were placed under moral pressure, particularly by promotional brochures, to do something apparently essential for their child that they could hardly refuse.45
70. The use of neonatal stem cells as allogeneic or autologous transplant material appears ethically less controversial. Collection of and research with neonatal stem cells should therefore be promoted in a deliberate and appropriate manner. Information obtained in this way should help to evaluate further the "neonatal stem cells" resource, to estimate the financial funding necessary for their collection and use, to discover the scope of their possible applications and to determine the possible implications for their equitable distribution. Apart from these aspects, however, the need remains for legal clarification with regard to the rights of disposal of cord blood, data protection issues and principles for the financing of cord blood banks.
71. Both the use of stem cells from cord blood for bone marrow transplantation and also the possibility of using stem cells from cord blood to create other tissue by transdifferentiation or reprogramming can be compared with the use of adult tissue-specific stem cells. Because of their immaturity, stem cells from cord blood may prove more suitable for reprogramming than adult stem cells. If neonatal cells are transformed by reprogramming to the totipotent stage, the stem cells from cord blood are subject to all the concerns mentioned with regard to ES cells.
72. The decisive advantage in using AS cells for transplantation purposes is the possibility of using the patient’s own cells, so avoiding immunological rejection reactions. Until the method is standardised, the legislation must assume treatment trials or experimental studies that require particular care in the obtaining of informed consent in view of the risk involved. However, if the transdifferentiation or reprogramming of autologous AS cells is not a possibility, allogeneic (heterologous) AS cells may also be used for the benefit of third parties. The procedure is similar in some respects to that of blood donation. If potentially risky invasive techniques are involved, however, the procedure is more closely comparable with the live donation of organs or tissues such as bone marrow.
73. If the initial indications that AS cells can also be harvested after death are confirmed, this procedure would have to be treated in the same way as organ donation, with the consequence that a specific consent procedure is necessary.
74. Should tissue specific AS cells be available for widespread medical use, methods of reprogramming (mutation back to a pluripotent stage) and transdifferentiation (development to a cell type not part of the original development spectrum of the cell) should be prohibited. The possibility of obtaining totipotent cells from adult stem cells by means of complete reprogramming is not yet documented in medical science. Should this be possible all ethical and legal considerations discussed in relation to embryonic stem cells would apply.
75. The derivation and use of adult stem cells, insofar as these occur in the autologous context and without reprogramming to totipotency, do not present legal or ethical problems. Derivation and use in the allogeneic (heterologous) context requires legal clarification of the rules of consent for the donor and recipient and also regulation of allocation and exclusion of commercial interests. In relation to the use of cadaveric tissue, experience gained in the field of organ transplantation reveals a tendency towards presumed consent so that personal consent is moving increasingly into the background while agreement by third parties is increasing. To counter this tendency, the willingness to donate organs – including the potential possibilities of treatment with stem cells – should be promoted more strongly in future by means of education and public discussion. The collection of allogeneic (heterologous) cells for the benefit of third parties from the bodies of minors should be ruled out, in order to avoid from the outset any tendency that a child might be created with a view to the derivation of AS cells for a relative.
76. From the ethical viewpoint, the promotion of research in adult stem cells, particularly their proliferation, reprogramming and transdifferentiation, should be given or should continue to be given priority.
Reporting committee: Committee on Culture, Science and Education
Reference to committee: Doc. 9581, Ref. 2767 of 18.11.2002
Draft recommendation adopted unanimously by the committee on 10 September 2003
Members of the committee: MM. de Puig (Chairman), Baronne Hooper MM. Prisacaru, Smorawinski (Vice-Persons), Apostoli, Banks, Barbieri, Berceanu (Alternate: Baciu), Braga, Buzatu (Alternate: Ionescu), Mrs Castro (Alternate: Barquero Vazquez), MM. Chaklein, Colombier, MM. Cubreacov, Dačic, Dalgaard, Mrs Damanaki (Alternate: Sfyriou), Mr Debono Grech, Mrs Delvaux-Stehres Mr Devinski, Mrs Domingues, Mrs Dromberg, Mrs Eymer, Mrs Fehr, Mrs Fernández-Capel, MM. Gadzinowski, Galchenko, Galoyan, Gentil, Mrs Glovacki-Bernardi, MM. Goris, Gündüz I, Gündüz S, Gunnarsson, Mrs Hadziahmetoviċ, MM. Hegyi, Howlin, Huseynov R, Iannuzzi, Jakic, Jakovljev, Jarab, Jurgens (Alternate: Dees), Mrs Katseli, Mrs Labucka, MM. Legendre, Lengagne, Letzgus, Libicki, Livaneli, Mrs Lucyga, MM. Lydeka (Alternate: Mincevic), Malgieri, Marxer, McNamara, Mrs Melandri, MM. Melnikov, Mestan, Mezihorak, Mrs Milotinova, Mrs Muttonen, Mr O’Hara, Mrs Ohlsson, MM. Podeschi, Rakhansky, Rockenbauer, Rybak, Mrs Samoilovska-Cvetanova (Alternate: Mrs Petrova-Mitevska), MM. Schneider, Shybko, Sizopoulos, Mrs Skarbøvik, MM. Sudarenkov (Alternate: Korobeynikov), Tusek, Vakilov , Mrs Westerlund Panke, MM. Wodarg, ZZ (Andorra), ZZ (Belgium), ZZ (Georgia), ZZ (Netherlands)
N.B. The names of those present at the meeting are printed in italics
Head of secretariat: Mr Grayson
Secretaries to the committee: Mr Ary, Mrs Theophilova-Permaul
1 Dissenting opinion: Mr O’Hara whished to have recorded his opposition to certain paragraphs in the explanatory memorandum.
2 Obscure sects and a few scientists have for years been predicting the birth of the first cloned child and are clearly bent on creating a fait accompli.
3 Embryos are defined as the early forms of human beings up to the end of organogenesis, i.e. in the first three months of development.
4 Thomson, J. A. et al., Embryonic stem cell lines derived from human blastocysts, Science, 282, 1998, pg. 1145-1147.
5 Wobus, A. M. & Brüstle, O., Humane Stammzellen: Eigenschaften, Forschungsstand und Verwendung. Stellungnahme zur Expertenanhörung der Enquete-Kommission „Recht und Ethik der modernen Medizin“ am 23. April 2001.
6 European Science Foundation (ESF), European Science Foundation Policy Briefing: Human stem cell research: Scientific uncertainties and ethical dilemmas, 2001.
7 Fuchs, E., Segre, J.A., Stem cells: A new lease on life, Cell, 1000, 2000, pg. 143-155. Odorico, J.S. et al., Multilineage differentiation from human embryonic stem cell lines, Stem Cells, 19, 2001, pg. 193-204.
8 Thompson, J. A., Marshall, V. S., Primat Embryonic Stem Cells, Current Topics in Developmental Biology, 38, 1998, pg. 133-165.
9 The possibility of developing trophoblast cells distinguishes primate cells from those of the mouse and is
interpreted by some as an indication that primate cells differ from mouse cells with regard to totipotency.
10 Wilmut, I. et al., Viable offspring derived from fetal and adult mammalian cells, Nature, 385, 1997, pg. 810-813. Wakayama, T. et al., Mice cloned from embryonic stem cells, Proceedings of the National Academy of Sciences of the United States of America, 96, 1999, pg. 14984-14989. Bethauser, J. et al., Production of cloned pigs from in vitro systems, Nature Biotechnology, 18, 2000, pg.1055-1059. Polejaeva, I. A. et al., Cloned pigs produced by nucleous transfer from adult somatic cells, Nature, 407, 2000, pg. 86-90.
11 Dolly, the cloned sheep, was the only animal born after 277 cell nucleous transfer procedures (Wilmut et al.
12 Colman, A., Kind, A., Therapeutic cloning: Concepts and practicalities, Trends in Biotechnology, 18(5), 2000, pg. 192-19.
13 The human EG cell lines described to date were derived from embryos or fetuses at 5 to 11 weeks of pregnancy. Shamblott, M. J. et al., Derivation of pluripotent stem cellsfrom cultured human primordial germ cells, Proceedings of the National Academy of Sciences of the United States of America, 95 (23) 1998, pg. 13726-13731. Shamblott, M. J. et al., Human embryonic germ cell derivates express a broad range of developmentally distinct markers and proliferate extensively in vitro, Proceedings of the National Academy of Science of the United States of America, 98(1), 2001, pg. 113-118.
14 Wobus/ Brüstle 2001.
15 Ordemann, R. et al., Dresdner Nabelschnurbank, Erfahrungen der Nabelschnurbank in Dresden, unterstützt durch die Deutsche Knochenmarkspenderdatei, Deutsche Medizinische Wochenschrift, 125(47), 2000, 1424-1428.
16 Laporte, J. P. et al., Unreleased mismatched cord blood transplantation in patients with haematological malignancies: a single institution experience, Bone Morrow Transplant, 22(1), 1998, pg. 76-77.
17 Wils, J.-P., Stammzellen-Transplantation aus Nabelschnurblut: ethische Probleme, in: Kreß, H. (Hg.) Menschenwürde, Medizin und Biotechnologie: heutige Fragen medizinischer und ökologischer Ethik, Münster, 2000, 58-75.
18 Emura, M., at al., Stem cells of the respiratory epithlium an their in vitro cultivation, In vitro animal cellular & developmental biology, 33(1), 1997, pg.3-14. Ahmad, I., et al., Identification of neural progenitors in the adult mammalian eye, Biochemical Biophysical Research Communication, 270(2), 2000, pg.517-521. Gronthos, S., et al., Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo, Proceedings of the National Academy of Sciences of the United States of America, 97(25), 2000, pg. 13625-30. Eriksson, P.S., et al., Neurogenesis in the adult human hippocampus, Nature medicine, 4(11), 1998, pg.1313-17.
19 Bjornson, C. R., et al., Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo, Science, 283, 1999, pg. 534-537. Clarke, D. L., et al., Generalized potential of adult neural stem cells, Science, 288, 2000, pg.1660-1663. Krause, D. S., et al., Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell, Cell, 105(3), 2001, pg. 369-377.
20 Watt, F.M. & Hogan, B. L. M., Out of Eden: Stem cells and their niches, Science, 282, 2000, pg. 1145-1147.
21 Schöler, H.R., Hübner, K. et al., Derivation of oocytes from mouse embryonic stem cells, Science, 300, 2003, pg. 1251-1256.
22 The possibility has been discussed that even with ES cells from cell nucleous transfer ("therapeutic" cloning),
"mild chemotherapy" might be necessary to inhibit the immune reaction caused by mitochondrial DNA from
the egg cell.
23 Kaihara, S. & Vacanti, J. P., Tissue engeneering: towards new solutions for transplantation and reconstructive surgery, Archives of surgery, 134, 1999, pg. 1184-1188.
24 Strauer, B. E. et al., Intrakoronare, humane autologe Stammzelltransplantation zur Myokardregeneration nach Herzinfarkt, Deutsche Medizinsche Wochenschrift, 126, 2001, 932-938.
25 Kant himself expresses this argument in the Metaphysics of Morals, §28 Science of Right, where he says : “For what is thus produced is a person and it is impossible to think of a being endowed with personal freedom as produced merely by a physical process. And hence, in the practical relation, it is quite a correct and even a necessary idea to regard the act of generation as a process by which a person is brought without his consent into the world and placed in it by the responsible free will of others. This act, therefore, attaches an obligation to the parents to make their children- as far as their power goes- contented with the condition thus acquired. Hence parents cannot regard their child as, in a manner, a thing of their own making; for a being endowed with freedom cannot be so regarded. Nor, consequently, have they a right to destroy it as if it were their own property, or even to leave it to chance; because they have brought a being into the world who becomes in fact a citizen of the world, and they have placed that being in a state which they cannot be left to treat with indifference, even according to the natural conceptions of right.“ (translated by W. Hastie) Kant, I, Metaphysik der Sitten, Rechtslehre § 28, A/B 112f., Königsberg 1797.
26 Occationally the idea has been formulated, that one could create an anencephalus by biomedical manipulation. According to the people who plead for this idea, the so created beings would not be able to act morally or develop a contiousness of themselves and would therefore have no human dignity. Following this idea humans would be created with the purpose to eliminate arbitrarilly their mental abilities in order to treat them like objects of instrumentalisation. To avoid even such approaches of instrumentalisation, the concept of human dignity must apply to all members of the human species.
27 The German philosopher Wolfgang Wieland explains this argument as follows: „If one takes the principle of ‚indisponibility‘ of human dignity serious, a sole consequence remains: it has to be granted to every human being because of every humans essential capacity for morality from the very beginning of his natural individual life on (also including the embryonal phase) not as a momentary but rather as a persisting disposition. This is however not an arbitrary decision but a mere consequence gained from the insight in the necessity to refrain from making such decisions in this kind of questions once and for all times and to search for a solution qualified by the outmost distance to an actual decision..“ Wieland, W., Pro Potentialitätsargument: Moralfähigkeit als Grundlage von Würde und Lebensschutz, in: Der moralische Stauts menschlicher Embryonen, Damschen, G. u. Schönecker, D. (Hg.), Berlin, NewYork, 2003, 149-168.
28 For example change of mind, illness or death of the woman.
29 These embryos are described as „supernumerary“ embryos in the following text. The use of the terms „orphande“ embryos or embryos with no prospect of life also used in the discussion could be judged as to obscure the issue.
30 Lanzendorf, J.P., et al., Use of human gametes obtained from anonymous donors for the production of human embryonic stem cell lines, Fertility and Sterility, 76(1), 2001, pg. 132-137. For example, the investigation of hereditary diseases would be possible with the use of ES cells with a defined genetic make-up.
31 Department of Health 2000, pg. 6. Relates to all types of research in embryos legal in Great Britain – not
exclusively stem cell research.
32 Gametes were used from pseudonymised donors who had given their informed consent for this use and were financially remunerated. From twelve women, 162 mature egg cells were harvested and fertilised with sperm from two donors. Of the 40 embryos successfully produced, three stem cell lines were developed. Cf. Lanzendorf et al. 2001, pg. 135.
33 The decision as to when an embryo is "supernumerary", that is, when there is no longer any question of achieving further development, depends on the personal estimation of the individuals and social circumstances involved, which are not always clearly assessable.
34 Reproductive cloning is unanimously rejected internationally, but has only been banned by law in a few countries and is not yet prohibited under international law. This, however, does not exclude the pursuance of this objective by individual researchers as demonstrated by reports from the gynaecologist Severino Antinori/Panayiotis Zavos (Scientists want to clone humans. 2001) and Brigitte Boisselier of the Raelian Sect (Boisselier 2001).
35 Apart from applications in humans, the technique of cloning by cell nucleous transfer is also being developed for animal breeding.
36 Contribution of Otfried Höffe, Klonierung beim Menschen? Der Streit um die ethischen und rechtsethischen Grenzen, lecture held on the international conference: Cloning in Biomedical research and reproduction, 14-16 May 2003, Berlin. Höffe, O, Menschen fortpflanzen, heilen und - klonen? Eine rechtsethische Zwischenbilanz, in: NZZ, 19.05.03.
37 Genetic differences between various clones from cell material from the same donor may arise as a result of
new mutations. The mitochondrial 13 genes contained in the cytoplasm of the enucleated egg cell give 99.98 to 99.99% genetic identity unless the egg cell and egg nucleus originate from the same woman. Cf. Oduncu, F.S., Klonierung von Menschen – biologisch-technische Grundlagen, ethisch rechtliche Bewertung, Ethik in der Medizin, 13(1/2), 2001, 111-126.
38 Pichlhofer, G., Groß, J. & Henke, Ch., Medizinische, rechtliche und soziokulturelle Aspekte der Eizellspende, Gutachten für das Bundesministerium für Gesundheit, Bonn, 2000, 11 ff.
39 Not a few critics regard this as a contravention of basic requirements of social ethics such as equality and the prohibition of discrimination. According to R. Dworkin (Dworkin, R., Die falsche Angst, Gott zu spielen, in: Die Zeit, 1999, 39) we are dealing here with process that intervenes deeply in the connection between nature and nurture that is constitutive for the human make-up. J. Habermas regards reproductive cloning as an intervention in the natural ‘Selbstsein” (literally, selfbeing), resulting in asymmetry of the conditions of recognition that constitute the moral subject and therefore affects generic ethics. Habermas, J., Die Zukunft der menschlichen Natur, Auf dem Wege zu einer liberalen Eugnik?, Frankfurt/Main, 2001.
40 Burtchaell, J.T., University policy on experimental use of aborted fetal tissue, Institutional Review Boards (IRB), 10(4), 1988, pg. 7-11.
41 Cf. The situation relation to transplantation: Ach, J.S., et al., Ethik der Organtranplantation, Erlangen, 2000, 155f.
42 Schneider, I., Föten, Der neue medizinische Rohstoff, Frankfurt/Main, New York, 1995, 229.
43 Gordijn, B. & Olthuis, H., Ethische Fragen zur Stammzelltherapie aus Nabelschnurblut, Ethik in der Medizin, 12, 2000, 16-29.
44 Gordijn/ Olthuis 2000.
45 Gordijn/ Olthuis 2000.