The Guild of Catholic Doctors
Comments to the Chief
Expert Group on Cloning
The expert advisory group on therapeutic cloning in humans, wishes to consider whether research under UK legislation should be extended to include research to develop methods of therapy for mitochondrial diseases and therapy for diseased or damaged tissues or organs.
As Catholic laymen and women we draw inspiration from the statement: "Human life must be respected and protected absolutely from the moment of conception. From the first moment of his existence, a human being must be recognised as having the rights of a person - among which is the inviolable right of every innocent being to life." From this it follows that we are opposed in principle to destructive embryo experimentation as currently allowed by law. Despite our fundamental objection in principle, we feel that we can still offer responses to the various questions posed in the letter inviting comments.
Therapeutic cloning for mitochondrial disease - general comments
It is just over 10 years since the first mutation was identified in mitochondrial DNA. It is now being suggested that nuclear replacement may be used to avoid transmission of inherited mitochondrial diseases. From reading the many comments made about this possibility, many may not realise that the mitochondrial DNA is not an independent and separate genetic pool having complete control of mitochondrial function. The majority of mitochondrial proteins are coded by nuclear DNA and several of the mitochondrial diseases are inherited in traditional fashion by autosomal genes on nuclear chromosomes.
The scene is further complicated in that mitochondrial DNA has a high mutation rate (5-10 times that of nuclear DNA) and that the more severe mitochondrial mutations show heteroplasmy (ie. the presence of a mixture of mutant and normal mitochondrial DNA in the same cell). Furthermore it has been shown that mitochondrial diseases may be acquired in early embryonic life or induced by chemical/toxic damage; and in some cases biochemical manipulation has been shown to reverse some of the effects of mitochondrial damage. The understanding of these diseases is therefore still in its infancy. With the rate of advance in molecular medicine it is likely that effective treatment will be available within the same timescale that nuclear transfer technology might become available. It is certainly premature to suggest that the legislation should be relaxed, at the current state of knowledge, to allow nuclear replacement experimentation in humans.
Furthermore, the likely practical reality of nuclear replacement in these circumstances would have the logical consequence of undermining the consensus that reproductive cloning should not be permitted. Currently to enhance the success of IVF a number of ova are fertilised, and a limited number of embryos are replaced in the womb, with the option of cryopreservation of others. If the technique of nuclear replacement for mitochondrial disease should become a practical reality, it is likely that the scientists would wish to have several attempts at nuclear transfer into ova. It may well be that the original embryo produced by the couple, but containing the cytoplasm with defective mitochondrial DNA, is allowed to develop into a several cell stage. Then attempts at transferring each nucleus into an unfertilised egg would be made (this is the technique used in the Oregon Primate Research Centre in their cloning experiments on monkey embryos, and to date cloning from embryos has been shown to be more efficient than from adult cells). One could envisage the scenario where either only a single original embryo was available and/or the only successful nuclear transfers were from a single original embryo. It would be likely that the clinicians involved would wish to transfer several of these embryos into the woman in order to maximise the chance of a successful pregnancy. In such circumstances it would be difficult for the HFEA to resist and demand that only one embryo is used. The system would therefore have produced identical clones. Once the principle of allowing cloned identical twins to be used under one situation was permitted, what would be the justification for banning it under other circumstances? The techniques of therapeutic cloning would inevitably and logically lead to reproductive cloning and we therefore urge rejection of this type of cloning.
Another logical consequence of permitting this type of therapeutic cloning is the acceptance, in principle, of the manipulation of the germline genes. Presumably the only reason for wishing to undergo nuclear transfer to avoid mitochondrial disease is that the parents wish their childrens genetic make-up to be predominantly from their own genes - otherwise current methods using a donor ovum and its nucleus would be acceptable. Allowing therapeutic cloning for mitochondrial disease establishes the principle that it is permissible to discard part of the genetic constitution of an embryo and replace it with the genetic material from a third individual. This is a variation on germline gene therapy to which there is universal opposition. This suggestion is not unrealistic as scientists are already using lasers to remove parts of chromosomes. Logically there is no difference between discarding the native mitochondrial DNA, and replacing it with mitochondrial DNA from a third parent, and discarding nuclear genes and replacing them with others. Therefore the acceptance of therapeutic cloning for mitochondrial disease logically is also the acceptance of germline gene therapy, which many would label as the path to designer babies.
Creation of stem cells and organs - General comments
It has been argued that cloning techniques are important for the creation of stem cells which can then be used for creation of tissues and organs for transplantation. It is argued that cloning will overcome both the rejection problems of transplantation and the shortage of organs. The differentiation of stem cells into solid organs is a highly complex process and to date no-one has yet been able to generate, in vitro, a organised solid organ - such as heart, kidney, lung or liver - from a stem cell. The well publicised mouse with a human ear growing on its back was created by using an ear shaped scaffolding of porous biodegradable polyester fabric implanted with human cartilage cells.
The pioneering work of the 1995 Nobel prize winners Lewis, Nusslein-Volhard and Wieschaus, has laid the foundations of our understanding of the genetic control of early embryonic development. Much of that work was done by looking at deliberately induced mutants of Drosophila flies and by manipulation of the homeobox genes, to produce flies with eyes, legs and other body parts in abnormal positions.
Studies of the hox (homebox) genes and the pax (paired box) genes has shown remarkable interspecies homology indicating that the genetic control mechanisms of body development are fairly universal. Targeted mutations of both Hox and the Pax-2 genes, in vivo, have already revealed discrete developmental defects affecting the development of the kidney. The proteins produced by these genes have DNA binding properties and it has been shown that they play a part in the transcriptional control of other genes. As understanding increases it may be possible to selectively switch these genes on and off to stimulate production of organs from tissue culture rather than go back to the embryo and complete totipotentiality. Certainly the manipulation of early human embryos, to reproduce results done in animal experiments, would be completely unethical. It is more realistic to suggest that current and ethically acceptable molecular genetics techniques will lead to advances in transplantation, including possible production of new organs, rather than invoking a need to allow cloning in human embryos.
Stem cell research
The rationale for suggesting that cloning techniques are needed to generate stem cells needed for production of tissues and organs is not proven. The rationale is based on the assumption that stem cells are best obtained from embryonic tissue/the totipotent zygote. However, what is the evidence that this assumption is valid? It used to be biological dogma that differentiated cells, despite having the full DNA complement, had the unused/unnecessary genes permanently disabled. The cloning of Dolly and other mammals has demonstrated this is not the case, and in the right environment the full genetic complement can be made available. It appears that those promoting the idea of the necessity of cloning to produce stem cells and organs, are relying heavily on the assumption that it is only through reversal to the totipotent embryonic state, available through cloning, that the full complement of DNA will become available. However, if scientists are to going to produce stem cells from embryonic lines, they will not only have to gain an understanding of the process but develop practical techniques to allow targeted switching of the necessary genes to promote the desired differentiation. Having achieved such a level of knowledge, it would seem very likely that the same techniques could be used to control the required genes in adult tissues.
Furthermore recent literature is now revealing that the majority of adult tissues, even those classically considered to consist only of differentiated cells, do contain cells capable of behaving as stem cells1. Other references describe that bone marrow derived cells can differentiate into cardiac myocytes within the heart2. It has even been demonstrated that neural stem cells can differentiate into myeloid, lymphoid and early haemopoetic cells3. Cells from the skeletal muscle of an amputated leg of a 75 year old were stimulated to develop in tissue culture into skeletal muscle, smooth muscle, bone, cartilage and fat4.
From the earliest days of the Warnock Commission, it has been accepted that even the earliest human embryo should be treated with respect and accorded a special status. It is on this principle that the HFEA was set up. Even though society does not accept our position on the sanctity of early embryonic life, we believe that the majority would oppose the use of human embryos for basic science research which has not even yet been undertaken in animals.
Our main points are therefore:
We argue that the acceptance of cloning in cases of inherited mitochondrial diseases has the logical consequence of having to accept both reproductive cloning and the principle of germline gene therapy.
We suggest that the techniques that will need to be developed in order to stimulate stem cells along a particular line of differentiation are likely to be applicable to stem cells which can be recovered from virtually any adult tissue, so rendering the necessity of cloning through the embryonic stage unnecessary.
It is not possible to argue that the human embryo is given a special status requiring even a degree of respect if it is being used for basic science research which either has not yet been undertaken in animals, or for which animal experimental data is minimal.
We urge the expert committee to recommend to the government that human embryos are not used in any cloning experiments.
Dr Michael Jarmulowicz
Hon Secretary, Guild of Catholic Doctors
on behalf of the Guild of Catholic Doctors
29th October 1999
- Chepko G, Smith GH. Mammary epithelial stem cells: our current understanding. Journal of Mammary Gland Biology & Neoplasia. 1999:4;35-52.
- Bittner RE. Schofer C. Weipoltshammer K. et al. Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anatomy & Embryology. 1999:199;391-6.
- Bjornson CR. Rietze RL. Reynolds BA et al. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science. 1999:283;534-7.
- Williams JT. Southerland SS. Souza J. Calcutt AF. Cartledge RG. Cells isolated from adult human skeletal muscle capable of differentiating into multiple mesodermal phenotypes. American Surgeon. 1999;65:22-6.