Cybrids and Chimeras

The authors, Sir Brian Heap and Revd. Dr Ronald Cole-Turner, were invited by the Executive Committee of the International Society for Science and Religion to prepare this statement. Through a process involving consultation with all members of the Society, the statement has now been accepted by the Executive Committee for publication as a statement made on behalf of the Society.
The Society retains the copyright of the statement, but gives general permission to reproduce it, in whole or in part, provided that the statement in the paragraph immediately preceding this is reproduced.

Summary

1. A major obstacle to embryonic stem cell research is the shortage of human eggs. A recent proposal within a multifaceted programme of research in developmental biology seeks to address the problem through the use of embryonic stem cells derived from ‘cytoplasmic hybrid embryos’ or ‘cybrids’. Cybrids would be made by the insertion of a human cell or nuclear DNA into a non-human egg (eg bovine) from which the nucleus has been removed (enucleation).

2. Another proposal which aims to understand what happens to human cells when placed in a foreign environment intends to make chimeric embryos by inserting human cells into non-human embryos. The purpose is to understand how certain human cell types behave in living systems, how they are affected by different control systems, how they respond to new types of drugs for medical treatment of rejection mechanisms, and how they function as replacements for damaged tissues.

3. Another way to produce embryonic stem cells is to induce adult cells to revert to embryonic stem cell-like properties by introducing a small number of genes (Takahashi et al., 2007; Yu et al., 2007). If these induced pluripotent stem cells (iPS; cells that can give rise to most, if not all the tissues of the body) offer a new way forward towards therapeutic measures, they may in time circumvent the need for cells obtained from the destruction of a human blastocyst and likewise obviate the need for cybrids. Nonetheless, research into cybrids and chimeras, as well as stem cells derived from embryos, is expected to continue as the fundamental mechanisms of early development in humans are probed still further.

4. In the light of these new developments, and with passage of relevant legislation by the UK Parliament in May 2008, the International Society for Science and Religion encourages further public discussion and complete openness about the status of research and the progress of regulatory procedures. The Society urges scientists to explain the technical feasibility and scientific merit of their experiments and to publish their findings in peer-reviewed journals in order to avoid undermining public confidence in the work of research. We also urge the highest level of interdisciplinary scientific, philosophical, and theological analysis of issues that will continue to arise from this work because they impinge on the significance of species boundaries and human dignity, as well as the capability to address serious medical conditions.

Cybrids

5. Cybrids can be formed by the transfer of DNA from a human cell into an egg of a non-human species (eg bovine, a readily available and wasted resource from abattoirs) from which the nucleus and its DNA have been removed (enucleated).The word ‘cybrid’ derives from ‘cytoplasmic hybrid embryo’, but it is important to note that cybrids are not hybrids in the usual sense of the word. For this reason, a preferred name adopted in UK legislation is ‘human admixed embryos’. Cybrids differ from hybrids because they are not created by cross-breeding between species, or by the mixing of nuclear DNA between species, but by inserting a human cell (or nucleus) into an enucleated non-human egg. The enucleated non-human egg would contain mitochondria which are minute organelles in the egg’s cytoplasm with their own DNA (about 99.9% of human DNA resides in the nucleus and less than 0.1% in the mitochondria which are the power plant of cell metabolism). However, the nuclear DNA of the cybrid cells would be entirely human. Once the human nucleus or cell was inserted, cybrids would be stimulated to act like an embryo with cell divisions continuing to the blastocyst stage so that embryonic stem cells might be derived.

6. Several gaps in knowledge are obvious. To what extent will the transfer of a human nucleus carry with it small numbers of human mitochondria? Will non-human cytoplasm and its mitochondrial DNA persist in cybrids? Non-human mitochondrial genes may largely but not entirely disappear after a few cell divisions so that while cybrids begin their existence with a small but significant non-human component, they would become more completely ‘humanised’ with progressive cell divisions. Incompatibilities between the nucleus and mitochondria from different species, however, may restrict development and possibly the short-term viability of cybrids (Beyhan et al., 2007), and the joining together of human and non-human mitochondrial DNA cannot be discounted. It is questions such as these that can only be answered through further research.

7. The reason commonly given for the creation of cybrids is that the field of stem cell research, which shows enormous promise in advancing basic science and leading to treatments of a wide range of diseases, such as Parkinson’s stroke, diabetes, and injury, will be advanced if researchers are able to create larger numbers of human embryonic stem cells lines, particularly if they can be ‘personalised’ so that they are more compatible with the patient and less likely to require treatment with immunosuppressive drugs. Progress is hindered in part by the lack of human eggs available for research, and in the UK permission was granted to create cybrids in certain laboratories in September 2007, and a framework of authorising legislation passed in May 2008.

8. It is important to note that in the UK it is a criminal offence to transfer cybrids into the womb or to allow them to develop beyond 14 days. The use of cybrid-derived cells in human patients will not be permitted without rigorous review.

Chimeras

9. A second proposal concerns the combination of human and non-human cells to create chimeras for research. A chimera is an animal with cells from two or more original embryos. Chimeric embryos are formed when one or more cells are injected and integrated into another animal of the same (intra-specific) or different (inter-specific) species. In the past, researchers have created intra- and inter-specific chimeras respectively in laboratory animals for the purpose of tracing the fate of different cell types during embryonic development and to understand how different organs and tissues are formed. Researchers wish to insert human pluripotent stem cells into non-human animals at the blastocyst stage of development for the same purpose.

10. Nowadays, there are important reasons for human-nonhuman chimera research. As mentioned previously, it can be used to advance knowledge about the development of pluripotent cells in living systems. It offers a conclusive test that derived human embryonic stem cells are pluripotent and can form most, if not all the tissues of the body. It should be recalled that scientists regularly transfer human genes into bacteria, plants and other animals to understand what they do and how they can be controlled. Many people are immensely grateful that clinicians have routinely replaced faulty human heart valves with healthy ones from different species such as cows or pigs.

11. When human pluripotent stem cells are inserted into non-human blastocysts, the expectation is that the human cells will multiply side-by-side with the non-human cells. This remains conjecture because when human embryonic stem cells were injected into mouse blastocysts the donor cells contributed hardly at all to enduring chimerism. In chimerism, the cells themselves do not fuse but cells of both species are present throughout the developing animal, including brain and gonads. Chimeric animals might be allowed to develop to various stages from fetus to adult depending on research purposes, and then the various tissues of the body would be examined to determine the distribution and the function of the human cells throughout the body of the chimeric animal. In this way, chimeras would be used to understand how human cells behave when deliberately introduced into foreign environments in a non-human species, how they are affected by different control systems, how they respond to new types of drugs for medical treatment of rejection mechanisms, and how they function as replacements for damaged tissues.

Issues for further consideration

12. Both experimental strategies—cybrids and chimeras—raise cultural and religious sensitivities. For some, ancient religious objections point to the strange human-nonhuman creatures of ancient myth, from which the word ‘chimera’ is taken. Bestiality and fear of developmental abnormalities leading to mistreatment as in circus entertainment are among the concerns that come to mind for others. These layers of apprehension underlie much of today’s uneasiness about cybrids and chimeras which carry the baggage that has come to be expressed as the ‘yuk’ factor.

13. On the other hand, many of today’s great religions have endorsed the core aims and strategies of biotechnological endeavour, especially in areas of human nutrition, health and the treatment of disease. Against this presumption in favour of biomedical research, some religious traditions have raised special concerns, not about the advancement of knowledge but about some of the experimental means of that advancement, particularly in respect to the earliest stages of human development.

14. The objection of the Roman Catholic Church to human embryo research extends to the creation and subsequent destruction of cybrids, where ‘humanisation’ is sufficiently ambiguous as to require the same treatment as a human embryo. The medical usefulness of cybrids has been seriously questioned (Scolding 2008), though Catholic scholars are more accepting of chimeras, even of non-human primates with human neurons providing, of course, that no chimeras shall breed. In Catholic neo-Thomism, human beings are uniquely endowed with the rational soul while non-human animals have souls unique to their kind. The presence of human cells (even human neurons) in a non-human body is not likely to cause the presence of a rational soul or to create the conditions of human rationality (Berg 2006). Protestant perspectives are varied, reflecting diverse views on the status of the human embryo and the welfare of nonhuman animals. They raise cautions about proceeding with either cybrids or chimeras too quickly. Judaism endorses these areas of research, and Islam is largely supportive as well but further contributions and clarification are required from these and other non-Western traditions.

15. In regard to chimeras, it is often observed that the insertion of human pluripotent stem cells into non-human blastocysts is the most problematical, conceptually and morally. The concern derives from human cells that may be incorporated into the non-human tissues and organs such as brain and germ (sex) cells. Whether human brain cells in a non-human brain could alter the cognitive features of the host animal is unknown. Whether these cells would develop into sex cells (eggs or sperm) also needs clarification. These and other fundamental questions may be answered by further research.

16. A somewhat higher level of concern has been expressed about the insertion of human pluripotent stem cells into a non-human primate blastocyst, such as a chimpanzee. The result might be a non-human primate with a substantial portion of human neurons. It is not known whether such an animal might exhibit what could be regarded as functionalities that are uniquely or characteristically human. Some have asked whether an enhanced primate must be treated with special regard. Because of these concerns, it is widely agreed that human pluripotent cells should not be inserted into the non-human primate blastocysts, nor should any human-nonhuman chimeras be allowed to breed. However, it should be noted that the use of non-human primate blastocysts may offer the only viable way of testing the normality and pluripotency of human embryonic stem cells.

17. While in the United Kingdom it is a criminal offence to transfer cybrids or chimeras into the womb of a woman (and researchers appear to be uniformly opposed to such an idea), it is not illegal everywhere. Chimera research is currently underway in countries lacking a strict regulatory provision, including the United States, although there are non-binding prohibitions against introducing human pluripotent into non-human primate blastocysts and against allowing any human-nonhuman chimeras to breed.

Recommendations

18. In light of these considerations, the International Society for Science and Religion encourages continued interdisciplinary reflection, public discussion, and complete openness about the status of research and of regulatory procedures applied around the world in these arenas of research. In April 2008, researchers in Newcastle reported success in creating cybrids. Their claim was made to the news media rather than in the form of a peer-reviewed report in a science journal, making the claim impossible to assess, which undermines public confidence in the work of research.

19. Researchers who succeed in creating cybrids will no doubt clarify soon whether non-human mitochondrial DNA persists in cells of cybrids and influences phenotype, and whether mitochondria in cybrids become ‘humanised’ after a few cell divisions. This will influence whether additional steps should be taken in the process of their creation such as the removal of all non-human mitochondria. Whether cybrids should also be said to become ‘humanised’ in a theological, philosophical, or legal sense is a matter on which deeper insights are urgently required.

20. Likewise regarding chimeras, we encourage the highest level of interdisciplinary scientific, philosophical, and theological analysis in respect of issues such as the meaning of species and our understanding of human dignity. We believe these proposed experiments raise questions on which several disciplines might be expected to shed insight, but only in a context of a clear understanding and analysis of the relevant scientific data. An ethical, theological, and philosophical assessment of chimeras is informed by matters such as the number and the potentiality of the inserted cells, the degree of chimerism, the developmental stage of the host animal at the time of insertion, the function of inserted cells, the evolutionary proximity of the host animal to human beings, and whether the host animal is brought to term.

21. The rapidity of research in this general area means that new developments can lead to remarkable shifts in priorities and recommendations. A case in point is research stimulated by recent reports from Japan referred to above involving the insertion of four genes into adult cells from the mouse tail that produced induced pluripotent stem (iPS) cells which looked and behaved like embryonic stem cells (Takahashi et al., 2006, 2007). Subsequently, iPS cells made from mouse skin cells were shown to contribute to chimeric embryos and produced all the body’s cells including eggs and sperm, and they were successfully used to treat a mouse model of sickle cell anaemia (Hanna et al., 2007). Induced pluripotent stem cells have also been produced using human adult cells; one of the original four genes which induced tumours having been successfully replaced by a different gene which does not (Takahashi et al., 2007; Yu et al., 2007). In addition, nuclear transfer in non-human primates has now been achieved and embryonic stem cell lines have been derived from the resulting cloned blastocysts (Byrne et al., 2007). Findings such as these appear weekly in the scientific literature because of the intensity of research in this area internationally, and therefore draw attention to the need for a continued and thorough debate as outlined here about cybrids and chimeras.

22. Finally, we urge that a prudent and respectful regard for the public concerns be maintained by researchers and policy-makers alike, in recognition of the long-term benefits to science that come from maintaining public support.

Prepared by Professor Sir Brian Heap (Cambridge, UK) and the Rev’d Dr Ronald Cole-Turner (Pittsburgh, USA)

Suggested Readings

General

Avoiding a chimaera quagmire Nature 445 7123 2007
Chimera research should be lightly regulated, not banned The Lancet 369 164 2007
‘Cybrid’ stem cells get ok New Scientist 194 49 2007
Report backs interspecies lines Science 316 1683 2007

Research

Beyhan, Z et al. Interspecies nuclear transfer: implications for embryonic stem cell biology Cell Stem Cell 1 502-512 2007
Byrne, J A et al. Producing primate embryonic stem cells by somatic cell nuclear transfer Nature 450 497-502 2007
Chen, Y et al. Embryonic stem cells generated by nuclear transfer of human somatic nuclei into rabbit oocytes Cell Research 13 251-263 2003
Hanna, J et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin Science 318 1920-1923 2007
Muotri, A et al. Development of functional human embryonic stem cell-derived neurons in mouse brain Proceedings of the National Academy of Sciences 102 18644-18648 2005
Nakagawa, M et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts Nature Biotechnology 26 101-106 2007
Okita, K T et al. Generation of germ line-competent induced pluripotent stem cells Nature 448 313-317 2007
Takahashi, K and Yamanaka, S Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors Cell 126 663-676 2006
Takahashi, K et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors Cell 131 861-872 2007
Wernig, M et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state Nature 448 318-324 2007
Yamanaka, S Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors Cell Proliferation 41 Suppl 1 51-56 2008
Yu, J et al. Induced pluripotent stem cell lines derived from human somatic cells Science 318 1917-1920 2007

Ethics and Religion

Austriaco, N P How to navigate boundaries: a reply to The American Journal of Bioethics The National Catholic Bioethics Quarterly 6 61-71 2006
Berg, T Human brain cells in animal brains: philosophical and moral considerations The National Catholic Bioethics Quarterly 6 89-107 2006
Chakrabarty, A M Crossing species boundaries and making human-nonhuman hybrids: moral and legal ramifications American Journal of Bioethics 3 20-1 2003
Cobbe, Neville Cross-species chimeras: exploring a possible Christian perspective Zygon 42, 599-628 2007
Cohen, C B Beyond the human neuron mouse to the NAS Guidelines American Journal of Bioethics 7 46-9 2007
Daley, G Q et al. Ethics: The ISSCR guidelines for human embryonic stem cell research Science 315 603-4 2007
Degrazia, D Human-animal chimeras: human dignity, moral status, and species prejudice Metaphilosophy 38 309-329 2007
Francoise, B and A Fenton Chimera research and stem cell therapies for human neurodegenerative disorders Cambridge Quarterly of Healthcare Ethics 16 195-208 2007
Greely, H T et al. Response to open peer commentaries on ‘Thinking about the human neuron mouse’ American Journal of Bioethics 7 W4-6 2007
Greely, H T et al. Thinking about the human neuron mouse American Journal of Bioethics 7 27-40 2007
Greene, M K et al. Ethics: Moral issues of human-non-human primate neural grafting Science 309 385-6 2005
Hyun, I et al. Ethical standards for human-to-animal chimera experiments in stem cell research Cell Stem Cell 1 159-63 2007
Karpowicz, P et al. It is ethical to transplant human stem cells into nonhuman embryos Nature Medicine 10 331-335 2004
Karpowicz, P et al. Developing human-nonhuman chimeras in human stem cell research: ethical issues and boundaries Kennedy Institute of Ethics Journal 15 107-34 2005
Mirkes, R Is it ethical to generate human-animal chimeras? The National Catholic Bioethics Quarterly 6 109-30 2006
Peters, T The return of the chimera Theology & Science 4 247-259 2006
Robert, J S, and F Baylis Crossing species boundaries American Journal of Bioethics 3 1-13 2003
Sagoff, M Further thoughts about the human neuron mouse American Journal of Bioethics 7 51-2 2007
Scolding, N Beware false promises The Tablet pp4-5 17 May 2008
Seyfer, T L An overview of chimeras and hybrids The National Catholic Bioethics Quarterly 6, 37-49 2006
Streiffer, R At the edge of humanity: human stem cells, chimeras, and moral status Kennedy Institute of Ethics Journal 15 347-370 2005

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