Select Committee on Science and Technology Written Evidence

Memorandum 27

Submission from Dr Neville Cobbe, University of Edinburgh

  1.  If one believes everything that one reads in the recent press, apparently a hybrid embryo ban "hits hopes of Alzheimer's sufferers" and "would cost patients' lives" since cloning "can beat disease" and will offer "the first effective treatments". As I have previously stated in evidence submitted to Parliament in 2004, I consider any suggestion that cells from mixed-species cloned embryos might be used in treating patients to be both naive and irresponsible. However, I note that the current focus is on research rather than direct use in therapies, even if this distinction often fails to be conveyed by the media, so I will restrict my subsequent comments accordingly. Indeed, I can at least welcome the fact that the current demand to use eggs from other species may reflect growing recognition of concerns regarding potential risks to women if eggs are required for research on such a large scale. Furthermore, such newfound recognition of risks would also be consistent with apparent trends towards minimal stimulation IVF and elective single embryo transfer. Nevertheless, one may be left wondering how feasible it is to model various non-congenital and late-onset conditions simply by studying cells from embryos in vitro, never mind the additional complications due to disrupted gene expression associated with nuclear transfer and questions of how such complications would not be exacerbated by the use of eggs from more distantly related species. I therefore hope that anyone wishing to make strong claims about the purported promise of such research should also be willing to publicly provide the fullest possible explanation of the underlying rationale, supported by appropriate reference to available evidence.

  2.  On 10 January 2007, The Times published a letter signed by 45 individuals in which the following was stated:

    "There are clear potential benefits to human health from, for example, being able to grow stem cells with specific genetic abnormalities, improving the efficiency of therapeutic cloning techniques and establishing cell lines for the testing of new treatments for diseases such as motor neuron disease, Alzheimer's disease and spinal muscular atrophy. All this can be done without having to rely on the use of human eggs which are in very short supply and are needed for treatment of patients with infertility."

  It is particularly interesting to note that Professor Alison Murdoch of the Newcastle Fertility Centre is among those who have added their names endorsing this statement, whilst she is described in this letter not as a clinician but rather as a "stem cell researcher". This inevitably begs the question as to why Professor Murdoch should be so keen to recruit additional women to provide her with as many eggs as possible in attempts to clone human embryos, as clearly revealed by the minutes of HFEA Research Licence Committee meetings, if she believes that the use of human eggs for such research is unjustified. This becomes all the more curious when the same person is engaged in the direct treatment of patients from whom eggs are obtained for such research and yet this individual now appears as a signatory to a statement acknowledging that women's eggs are in very short supply and are needed first and foremost for infertility treatment. One would therefore expect that anyone signing such a statement should also be quick to voluntarily relinquish any licence facilitating the recruitment of as many women as possible to provide eggs for cloning.

  3.  Alternatively, such discrepancies between expressed views and apparent practices might raise questions regarding how much time was available to others to read the final draft of a letter to The Times before adding their names. On discovering that the person primarily responsible for this letter was Dr Evan Harris MP, I wrote to him by e-mail on 12 January 2007, also asking who was responsible for drafting the exact wording, how many actual members of the entire scientific community were approached concerning this letter and how many of these became signatories, or else what motivated the choice of particular individuals whose signature was solicited. Unfortunately, no direct answers to these questions have yet been forthcoming. Nevertheless, Dr Harris did manage to reply within just over 10 minutes from a computer at Westminster (IP address: and offered to make a telephone call ("from a train!") but apparently would not provide answers in writing.

  4.  Regarding the ethics of research involving human/non-human entities, Dr Jason Scott Robert has recently pointed out how there may be an important tension when some studies that might be more questionable scientifically could also be those that are less likely to pose significant ethical concerns and vice versa1. To date, most attempts to clone mammals using eggs from distantly related species (such as those belonging to separate mammalian orders) have apparently only permitted limited embryonic development as far as the blastocyst stage2-10 whilst development to this stage (in order to derive embryonic stem cells) is not necessarily equivalent to full reprogramming even when performing nuclear transfer with eggs from the same species11. The species status of the resulting entity may also be open to question, despite the frequently quoted refrain that such embryos would be more than 99% human in terms of DNA content. Such a figure deals only with relative numbers of unique protein coding genes and assumes that each is present in the cell with an equal copy number. However, when the number of mitochondria typically present in an unfertilised egg is also taken into account12-15, estimates of the nuclear fraction of total DNA in the resulting product of nuclear transfer may drop to under 70% or so and estimates of the nuclear fraction of protein coding gene copies may be less than 2%. In light of issues concerning developmental potential and overall proportions of DNA from different species, how might such a presumably non-viable entity be classified as a human using either Ernst Mayr's biological species concept16 or complementary use of an evolutionary species concept17?

  5.  Even in the absence of the aforementioned empirical data concerning cross-species cloning attempts, it is doubtful how long most such mixed-species embryos and any cells derived from them would survive since it appears that host mitochondrial function is not properly supported by donor nuclei from more distantly related species18-25. This is especially relevant since oocytes with lower mitochondrial numbers seem to have lower developmental potential12-15, indicating the importance of adequate functioning mitochondria for subsequent embryonic development. Although reports differ regarding the preferential replication of donor or recipient mitochondria8, 21, 26-31, it is nonetheless possible that supplying more donor mitochondria may alleviate some incompatibility problems26. However, known differences in the reprogramming of gene expression during the earliest stages of embryonic development in different mammalian genera32-34 and similarities between defects in cloned animals and interspecific hybrids35-39 together suggest that use of eggs from more distantly related species would lead to even more defects in reprogrammed gene expression. Whereas one research group has reportedly derived embryonic stem cells following transfer of nuclei from human skin cells into rabbit eggs40, a report in the journal Nature barely a year ago described how doubt remains within the research community regarding the feasibility of this approach41, possibly aggravated by fraudulent claims about the derivation of stem cells from cloned human embryos.

  6.  Consequently, if viable offspring of particular species are extremely unlikely to be obtained when using eggs and donor nuclei from distantly related mammals, then there may be a tension between the purported scientific benefit of transferring human nuclei into eggs from various species and the moral status of the resulting entity. For example, would this mean that there are fewer ethical concerns about the use of what would seem to be intrinsically non-viable embryos of dubious species status, compared to the destruction of potentially viable human life? Conversely, would the need for more accurate reprogramming lead to subsequent demands for eggs from more closely related species, perhaps even chimpanzees? As it happens, I have already raised the question of using primate eggs in conversation with Professor Ian Wilmut. Although both of us felt that the Home Office would presently be far less likely to endorse this anyway, it may still be worth considering whether it would be wiser to also address this specific issue in current legislation before potentially raising additional public concerns. After all, if the use of numerous eggs from women for cloning research is presently considered unjustifiable due to the risks involved and the lack of personal or guaranteed benefit42, then how would the use of eggs from non-consenting members of any sentient and endangered primate species be considered more justifiable?

  7.  On the other hand, it is conceivable that the use of eggs from less closely related species might be used in more basic research to advance understanding of the factors in an egg required for reprogramming gene expression43, though a host of preliminary data also suggest that much of the desired information concerning early developmental potential can already be obtained without actually cloning embryos at all44-46. However, if it is therefore acknowledged that the transfer of human nuclei into cow or rabbit eggs is simply basic research with no clearly predictable or uniquely guaranteed clinical benefits, then questions may remain as to how this can be accommodated by the present wording of either the Human Fertilisation and Embryology Act or Statutory Instrument 2001 No 188. This is not so much a question of whether such research with mixed-species entities is necessarily illegal at present, but rather a question of whether or not it might lie outwith the scope of current regulations and how the HFEA might be qualified to handle this.

  8.  Aside from the questions above, more challenging issues may be raised through the creation of some chimeric animals in which distinct populations of cells are derived from human embryos and those of other species, especially where this involves neurons and a risk that any resulting creature might exhibit characteristics that would be considered ethically unacceptable to find in an experimental animal. There is not the space here to explore this adequately, so I would refer those interested to recommendations by the National Academy of Sciences in the U.S.A. 47 and a previous "Policy Forum" in the journal Science48. In considering the objectives of such experiments, one should consider whether a 14 day limit for chimeric embryo experimentation would necessarily be satisfactory from a scientific perspective and also examine how decisions in this area might expose inconsistencies if the termination of life may be considered by some to be more justifiable when increasingly human qualities are observed, rather than according increasing respect and rights with increasing signs of humanity in a chimera, as would seem more ethically sensible.

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  2  Dominko, T, et al, Bovine oocyte cytoplasm supports development of embryos produced by nuclear transfer of somatic cell nuclei from various mammalian species. Biol Reprod, 1999. 60 (6): p. 1496-1502.

  3  Lee, B, et al, Blastocyst development after intergeneric nuclear transfer of mountain bongo antelope somatic cells into bovine oocytes. Cloning Stem Cells, 2003. 5 (1): p 25-33.

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  9.  Zhao, Z J, et al, Rabbit oocyte cytoplasm supports development of nuclear transfer embryos derived from the somatic cells of the camel and Tibetan antelope. J Reprod Dev, 2006. 52 (3): p 449-459.

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  12  El Shourbagy, S H, et al, Mitochondria directly influence fertilisation outcome in the pig. Reproduction, 2006. 131 (2): p 233-245.

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  22  Barrientos, A, et al, Cytochrome c oxidase assembly in primates is sensitive to small evolutionary variations in amino acid sequence. Mol Biol Evol, 2000. 17 (10): p 1508-1519.

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  24  McKenzie, M and I Trounce, Expression of Rattus norvegicus mtDNA in Mus musculus cells results in multiple respiratory chain defects. J Biol Chem, 2000. 275 (40): p 31514-31519.

  25  McKenzie, M, et al, Functional respiratory chain analyses in murid xenomitochondrial cybrids expose coevolutionary constraints of cytochrome b and nuclear subunits of complex III. Mol Biol Evol, 2003. 20 (7): p 1117-1124.

  26  Chen, D Y, et al, Interspecies implantation and mitochondria fate of panda-rabbit cloned embryos. Biol Reprod, 2002. 67 (2): p 637-642.

  27  Steinborn, R, et al, Coexistence of Bos taurus and B indicus mitochondrial DNAs in nuclear transfer-derived somatic cattle clones. Genetics, 2002. 162 (2): p 823-829.

  28  Chang, K H, et al, Blastocyst formation, karyotype, and mitochondrial DNA of interspecies embryos derived from nuclear transfer of human cord fibroblasts into enucleated bovine oocytes. Fertil Steril, 2003. 80 (6): p 1380-1387.

  29  Hiendleder, S, et al, Heteroplasmy in bovine fetuses produced by intra- and inter-subspecific somatic cell nuclear transfer: neutral segregation of nuclear donor mitochondrial DNA in various tissues and evidence for recipient cow mitochondria in fetal blood. Biol Reprod, 2003. 68 (1): p 159-166.

  30  Liu, S Z, et al, Blastocysts produced by nuclear transfer between chicken blastodermal cells and rabbit oocytes. Mol Reprod Dev, 2004. 69 (3): p 296-302.

  31  Yang, C X, et al, Quantitative analysis of mitochondrial DNAs in macaque embryos reprogrammed by rabbit oocytes. Reproduction, 2004. 127 (2): p 201-205.

  32  Beaujean, N, et al, Non-conservation of mammalian preimplantation methylation dynamics. Curr Biol, 2004. 14 (7): p R266-R267.

  33  Beaujean, N, et al, The effect of interspecific oocytes on demethylation of sperm DNA. Proc Natl Acad Sci U.S.A., 2004. 101 (20): p 7636-7640.

  34  Chen, T, et al, Interspecies nuclear transfer reveals that demethylation of specific repetitive sequences is determined by recipient ooplasm but not by donor intrinsic property in cloned embryos. Mol Reprod Dev, 2006. 73 (3): p 313-317.

  35  Vrana, P B, et al, Genomic imprinting is disrupted in interspecific Peromyscus hybrids. Nat Genet, 1998. 20: p 362-365.

  36  Vrana, P B, et al, Genetic and epigenetic incompatibilities underlie hybrid dysgenesis in Peromyscus. Nat. Genet., 2000. 25 (1): p 120-124.

  37  Hiendleder, S, et al, Nuclear-cytoplasmic interactions affect in utero developmental capacity, phenotype, and cellular metabolism of bovine nuclear transfer fetuses. Biol Reprod, 2004. 70 (4): p 1196-1205.

  38  Singh, U, et al, Different molecular mechanisms underlie placental overgrowth phenotypes caused by interspecies hybridization, cloning, and Esx1 mutation. Dev. Dynamics, 2004. 230 (1): p 149-164.

  39  Zechner, U, et al, Divergent genetic and epigenetic post-zygotic isolation mechanisms in Mus and Peromyscus. J Evol Biol, 2004. 17 (2): p 453-460.

  40  Chen, Y, et al, Embryonic stem cells generated by nuclear transfer of human somatic nuclei into rabbit oocytes. Cell Res, 2003. 13 (4): p 251-263.

  41  Dennis, C, Cloning: Mining the secrets of the egg. Nature, 2006. 439 (7077): p 652-655.

  42  Minger, S, Junk medicine: therapeutic cloning. (The Times, 11 November 2006).,,8123-2446017.html.

  43  Byrne, J A, et al, Nuclei of adult mammalian somatic cells are directly reprogrammed to oct-4 stem cell gene expression by amphibian oocytes. Curr Biol, 2003. 13 (14): p 1206-1213.

  44  Ivanova, N, et al, Dissecting self-renewal in stem cells with RNA interference. Nature, 2006. 442 (7102): p 533-538.

  45  Silva, J, et al, Nanog promotes transfer of pluripotency after cell fusion. Nature, 2006. 441 (7096): p 997-1001.

  46  Takahashi, K and S Yamanaka, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006. 126 (4): p 663-676.

  47  Guidelines for Human Embryonic Stem Cell Research. 2005, National Academies Press: Washington DC. p 41.

  48  Greene, M, et al, Ethics: Moral issues of human-non-human primate neural grafting. Science, 2005. 309 (5733): p. 385-386.

January 2007

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