Select Committee on Science and Technology Written Evidence


APPENDIX 22

Memorandum from Dr Elizabeth Allan

NEW REPRODUCTIVE TECHNOLOGIES

1.  Executive Summary

  1.1  In re-evaluating the law in relation to reproductive technologies, it is essential that the physical and psychological wellbeing of the child takes priority over the wishes of those desiring to create a child through the highly artificial technologies in question. The future use of any technologies such as male pregnancy or the use of eggs from aborted foetuses, would amount to an unprecedented degree of psychological and physical experimentation on the future generation of children, and should not be permitted.

  1.2  There is a new EU Directive which highlights the fact that there are medical risks of using embryonic stem cell therapies (including therapeutic cloning), and which requires full protection of public health in relation to these medical risks. Specifically, embryonic stem cells have a serious risk of forming tumours or cancer for several reasons. Since there are serious limitations in the methods used to eliminate these problems and also to test safety, specific legislation should be put in place to safeguard the public.

  1.3  The use of animal eggs to create animal-human hybrid embryos for therapeutic cloning or for research into therapeutic cloning should not be permitted on both ethical and medical grounds.

2.  Eggs from aborted fetuses/Male pregnancy/Chimaeric embryos/Parthenogenesis/Eggs and sperm from embryonic stem cells/Reproductive cloning

  2.1  In examining new reproductive technologies, it is only too easy to consider the issues primarily from the perspective of the adults wishing to have a child. However, in considering the deliberate creation of a child using artificial techniques, where it would otherwise be impossible for that child to be created, it is our responsibility to place the psychological and physical welfare of the child first.

  2.2  Technologies such as the use of eggs from aborted foetuses, parthenogenesis, male pregnancy, the creation of chimaeric embryos containing cells from different embryos, reproductive cloning, or the creation of eggs and sperm from embryonic stem cells, would necessarily involve an extraordinary degree of psychological and physical experimentation on the children created, and should not be permitted. The psychological damage alone from such abnormal parentage (unborn foetus as a mother; unborn embryo as a father or mother; no genetic father; mother and grandmother being identical, etc) could be profound, quite apart from the risk of serious diseases from epigenetic abnormalities, etc. (For further information, particularly regarding medical risks of these technologies, please see the appendix, section I (not printed).)

  2.3  Even ooplasmic transfer, where the child would have two genetic mothers (albeit one mother contributing far fewer, although vitally important, genes) could cause a child to have an identity crisis, in addition to a greatly increased risk of Turner's syndrome.

  2.4  A child born naturally may of course have physical or psychological problems; but if one deliberately creates a child in such a way as to profoundly increase its risk of serious physical and/or psychological damage, then it is a form of deliberate abuse.

  2.5  Arguments based on the claim that all a child needs for psychological wellbeing is a loving home environment, reveal a remarkable lack of imagination in considering the potential effect on the child in these scenarios. It is also evident that you cannot love someone that does not yet exist. You can love the idea of having a child, but that is entirely different from loving the child itself. The wishes of a potential "parent" to have a child no matter how extraordinary and dangerous the technology, or how bizarre the parentage, is more akin to selfishness than genuine love. Genuine love sacrifices one's own desires for the benefit of the other.

  2.6  If someone genuinely wishes to show parental love towards children, it may be better to consider adoption, as an alternative which could heal already-broken lives through love, rather than deliberately creating children who could have broken lives because of the way they were created.

  2.7  Regarding the consideration of medical risks of new reproductive technologies, I appreciate that the Science and Technology Committee may wish to avoid discussions on whether a technology would be possible or safe, as indicated by the Committee secretariat in the internet debate. However, I suggest that where technologies are unsafe at least for the foreseeable future, that consideration of the medical risks is valid as an ethical issue as well as a purely medical one.

  2.8  Certainly the many ethical issues of new reproductive technologies need to be considered at this stage. However, if any technology would currently be unsafe, it should currently be legislated against on both medical and ethical grounds, since the deliberate introduction of unnecessary medical risks in the creation of children by using such technologies, is in itself an ethical argument.

  2.9  I therefore submit to the committee that now is not the time to legalise an unsafe technology, even if final permission to use the technology would still have to go through a committee such as the HFEA. This is partly because there are additional profound ethical considerations which should not be decided by a committee; and partly because the safety of these technologies would take many years to test. A robust system (law) therefore needs to be in place in the meantime to prevent abuse of new technologies.

3.  Embryonic stem cells and therapeutic cloning

  3.1  There is a new EU Directive (Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004, on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells) which states:

  3.2  "This Directive should not interfere with decisions made by Member States concerning the use or non-use of any specific type of human cells, including germ cells and embryonic stem cells. If, however, any particular use of such cells is authorised in a Member State, this Directive will require the application of all provisions necessary to protect public health, given the specific risks of these cells based on the scientific knowledge and their particular nature . . ."

  3.3  This Directive acknowledges the seriousness of the specific medical risks involved in using embryonic stem cells (whether derived from embryos created by in vitro fertilisation, cell nuclear replacement, parthenogenesis or by any other procedure), and requires that public health is fully protected if their use is permitted in any Member State. Embryonic stem cells, including those derived by cell nuclear replacement, should therefore not be used if they cannot be shown to be safe.

  3.4  There are a number of ways in which embryonic stem cells could cause tumours and cancer (further details are provided in the appendix, section II (not printed)). Unfortunately, there are extremely strong pressures to produce therapies from embryonic stem cells and therapeutic cloning as quickly as possible. Current methods of testing the safety of embryonic stem cells are, however, completely inadequate (see below). It is therefore significant that this EU Directive alerts the Member States to the fact that there are specific dangers, and requires full protection of public health.

3(a)  Embryonic stem cells—Teratomas and teratocarcinomas

  3(a).1  Embryonic stem cells are known to form specific types of tumours called teratomas or teratocarcinomas. Indeed, formation of these tumours is such a characteristic and distinguishing property of isolated, undifferentiated embryonic stem cells, that one of the main ways that embryonic stem cell scientists use to determine whether they have isolated embryonic stem cells or not is to test whether they will form these tumours (Amit et al, 2000; Evans and Kaufman,1981; Reubinoff et al, 2000; Richards et al, 2002; Thomson et al, 1998). By contrast, adult stem cells do not appear to form these tumours.

  3(a).2  A standard method of determining the quality of embryonic stem cells is therefore to make sure they form tumours—a highly unusual situation, since good quality is clearly in direct opposition to safety. Although scientists are working on ways to solve this problem, embryonic stem cells are so tumourigenic, that the standards required for safety are far higher than are likely to be reached for some time, as described below.

3(b)  Inadequacy of attempts to solve the problem of teratoma formation, since exceptionally low numbers of undifferentiated embryonic stem cells can kill

  3(b).1  Highly malignant tumours that destroy surrounding tissue, and that can kill, have already been formed when therapeutic transplantation of embryonic stem cells into animals has been attempted. Examples include stroke, a model of Parkinson's disease, and cartilage formation, as well as treatment of healthy animals (Erdo et al, 2003; Bjorklund et al, 2002; Wakitani et al, 2003).

  3(b).2  Scientists have attempted to circumvent the problem of teratoma formation by pre-differentiation. This approach has also been combined with genetic engineering to tag differentiated cells, to assist in their separation from undifferentiated cells. Genetic engineering to stop cell division has also been attempted.

  3(b).3  However, the level of differentiation and purification from the undifferentiated form needs to be exceptionally high—possibly well over 99.999%, since generally hundreds of thousands or millions, even tens of millions of cells are used in embryonic stem cell therapies; however, only a few undifferentiated embryonic stem cells are required to form virulent teratomas.

  3(b).4  Consistent with this, teratoma formation has been found to occur in animals receiving brain transplants of pre-differentiated cells derived from embryonic stem cells, using an animal model of Parkinson's disease (Nishimura et al, 2003), stroke (Erdo et al, 2003) or healthy animals (Brustle et al, 1997; Erdo et al, 2003). Teratomas could be serious enough to kill (Nishimura et al, 2003).

  3(b).5  It should be noted that the number of undifferentiated embryonic stem cells required to kill is so low, that their presence can remain undetected unless repeated experimentation is carried out (Nishimura et al, 2003).

  3(b).6  Articles claiming that pre-differentiation solves the problem of teratoma formation have been found to have a crucial design flaw (xenogeneic transplantation), since it has been found that xenogeneic transplantation unexpectedly dramatically protects against teratoma formation (Erdo et al, 2003).

  3(b).7  Erdo et al also point out that the safety of human embryonic stem cells or their pre-differentiated derivatives cannot be adequately tested in preclinical animal models, since these would be xenogeneic systems, which would be expected to give false negatives for teratoma formation. (Xenogeneic transplantation would not be carried out with human patients.)

  3(b).8  Scientists have also attempted to overcome the problem of teratoma formation by genetic engineering by inserting a "suicide" gene into embryonic stem cells to stop cell division. However, teratoma formation is characterised by uncontrolled and inappropriate cell differentiation rather than cell division; for example, with hair, gut and teeth forming in the brain. If teratomas formed in essential organs such as the brain (as has already occurred in animal experiments), severe, irreversible damage could occur irrespective of termination of cell division. Additionally, genetic engineering may have as yet undefined long-term risks, which would vary depending on the procedure used.

3(c)  Embryonic stem cells—Cancer

  There are several other ways in which embryonic stem cells could cause cancer (for details, please see appendix, section II (not printed)). These abnormalities become worse with culture, which is directly relevant to stem cell banks.

    —  Chromosomal abnormalities typical of cancerous cells:

    Human embryonic stem cells have a tendency towards recurrent gain of chromosomes 17q and 12 in culture: a feature which is characteristic of teratocarcinoma stem cells (Draper et al, 2003).

    —  Uniparental disomy:

    Uniparental disomy is a specific form of chromosomal abnormality that has been demonstrated to increase with culture of embryonic stem cells. Although rare, it is particularly dangerous since all recessive alleles on a chromosome, including tumour suppressor genes, are unmasked, thus greatly increasing the risk of cancer (Cervantes et al, 2002).

    —  Abnormal DNA methylation:

    Cultured embryonic stem cells have very abnormal and unstable DNA methylation (Dean et al, 1998; Humpherys et al, 2001). Abnormal DNA methylation is characteristic of many cancers.

3(d)  Misleading claims that embryonic stem cells would be safe

  3(d).1  It has been claimed that embryonic stem cells would be safe, on the basis that healthy mice can be generated from (isolated) embryonic stem cells (by aggregation of embryonic stem cells with tetraploid embryos).

  3(d).2  However, this is a highly misleading argument, partly since the behaviour of embryonic stem cells transplanted into adults is entirely different to those transplanted into an early embryonic environment. Teratomas do not normally form when embryonic stem cells are transplanted into early embryos (their natural environment), but do form when transplanted into adult animals (which is not their natural environment)

  3(d).3  It is also a highly misleading argument since the vast majority of embryonic stem cell lines do not produce mice, or produce mice that are deformed, or that may die before birth or shortly afterwards (for example, Nagy et al, 1993). These embryonic stem cell lines therefore appear defective in some way.

  3(d).4  With mice, however, it is easy to screen out many dangerous embryonic stem cell lines, by screening out the lines that produce mice that are deformed or that die early. Entire strains of mice that are not useful can also be screened out.

  3(d).5  By contrast, it is not possible to carry out this same screening procedure with humans: The equivalent in relation to human embryonic stem cells would be to generate large numbers of chimaeric humans by aggregating isolated human embryonic stem cells with tetraploid human embryos and allowing the resultant chimaeric humans to develop, to see which embryonic stem cell lines produced healthy adult humans. Those embryonic stem cell lines that produced abnormal children or children that died early, or that resulted in the death of the human foetus, would be discarded because they might be dangerous to use for embryonic stem cell therapies. This is clearly a totally unacceptable experiment.

  3(d).6  For a number of reasons, it is therefore invalid to use the above argument to claim that human embryonic stem cells would be safe.

3(e)  Parthenogenetic and androgenetic embryonic stem cells

  Stem cells from parthenogenetic or androgenetic embryos have been suggested as a possible source of embryonic stem cells. However, embryonic stem cells from these sources seem not only to be subject to the same medical risks as those derived from IVF embryos since they generate teratomas and teratocarcinomas (Cibelli et al, 2002; Kaufman et al, 1983), but may have even greater problems with the development of severe chromosomal abnormalities (De La Fuente and King, 1998; Slimane-Bureau and King, 2002), and also with abnormal DNA methylation and expression of imprinted genes (Dean et al, 1998; Szabo and Mann, 1994).

3(f)  Therapeutic cloning

  3(f).1  Therapeutic cloning would be liable to have even greater risks than embryonic stem cell therapies, since embryonic stem cells from nuclear transfer embryos would be used. The considerable genetic and epigenetic abnormalities inherent in cloning procedures would therefore be added to the risks of embryonic stem cell technology.

  3(f).2. These risks would include abnormal DNA methylation from both cloning procedures and embryonic stem cells, chromosomal abnormalities related to both cloning and embryonic stem cell culture, dysregulation of numerous genes, the possibility of immune rejection (albeit to a lesser extent than with IVF-derived embryonic stem cells) as a result of foreign mitochondria from the egg donor, teratoma or teratocarcinoma formation and uniparental disomy.

  3(f).3  Unfortunately, the word limit precludes providing evidence in this text; however, it is included in the appendix, section II (not printed).

  3(f).4  The problems generated in therapeutic cloning would most probably not be the same as those seen in reproductive cloning, since the developmental context would be different.

  3(f).5  For example, it has been argued that developmental diseases associated with gene imprinting disorders would not be particularly relevant for therapeutic cloning, and that therapeutic cloning would therefore be safe, even if reproductive cloning were not.

  3(f).6  However, this completely overlooks the risk of cancer from abnormal DNA methylation and abnormal expression of imprinted genes. The risk of cancer formation would be highly relevant for therapeutic cloning, although far less relevant for reproductive cloning since clones with a severely abnormal epigenetic status might not even survive to birth. However, cells from early cloned embryos with an abnormal epigenetic status might be able to survive in culture for therapeutic cloning. As they would not be screened out by foetal developmental failure or by clearly visible abnormality as seen in reproductive cloning, cells containing epigenetic (or genetic) abnormalities which could cause cancer could therefore unwittingly be used for therapeutic cloning.

  3(f).7  There is currently no successful way of screening out all the defective embryos or cells, or of identifying them. There is therefore a very high risk that embryonic stem cells used for therapeutic cloning would be seriously defective.

4.  Animal-human hybrids

  4.1  The use of enucleated animal eggs has been suggested as a source of eggs for therapeutic cloning, or for research into this field. However, the reprogramming of human DNA by reprogramming factors designed to create rabbits, cows etc, is inherently different from the insertion of a gene or two from one species to another. The ethical and medical implications are therefore far more serious (appendix, section III (not printed)).

  4.2  It should also be noted that the hybrid embryos would almost certainly combine animal mitochondria and human nuclei. Although mitochondria contain a relatively small number of genes, these organelles have a disproportionate significance as they are vital to survival: even relatively minor dysfunction of mitochondria, or functional incompatibility between mitochondria and nuclei, can lead to serious medical consequences. The degree of functional incompatibility that exists between human nuclear DNA and animal mitochondrial DNA could therefore have profound medical risks, as described in the appendix, section III.

  4.3  The main reason for using therapeutic cloning over embryonic stem cells produced by IVF is claimed to be the greater degree of immune-compatibility with the patient. The use of enucleated animal eggs would therefore be counter-productive, since a greater degree of immune reaction to animal mitochondrial histocompatibility antigens than to human mitochondria would be expected.

  4.4  Regarding the possible use of such embryos for research into therapeutic cloning, the incompatibility of gene products from animal mitochondrial DNA and human nuclear DNA, as described in the appendix (not printed), would seriously hinder and complicate the interpretation of any experiments, and would seriously compromise any clinical application utilising results from such experiments.

May 2004





 
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