Ethical Aspects of the Use of Stem Cell Derived Gametes for Reproduction

A lot of interest has been generated by the possibility of deriving gametes from embryonic stem cells and bone marrow stem cells. These stem cell derived gametes may become useful for research and for the treatment of infertility. In this article we consider prospectively the ethical issues that will arise if stem cell derived gametes are used in the clinic, making a distinction between concerns that only apply to embryonic stem cell derived gametes and concerns that are also relevant for gametes derived from adult stem cells. At present, it appears preferable to use non-embryonic stem cells for the derivation of gametes. Adult stem cell derived gametes do not present any problems with regard to the moral status of the human embryo, bypass the safety risks linked to SCNT and do not present any ambiguity or novel problems with regard to informed consent, psychological consequences for the child or genetic parenthood. A remaining ethical concern, however, regards the safety of the procedure in terms of the welfare of the resulting children. This should spark a thorough reflection on how far one must go to accommodate a person’s wish to have a genetically related child.     

The politics and ethics of human embryo and stem cell research.

There is great promise for stem cell research to develop cells and tissues for transplantation and treatment of diseases such as Alzheimer and Parkinson disease, diabetes, and heart problems. There is also promise to advance understanding and treatment of cancer and congenital defects. Human embryo research is fundamentally the only way to understand human fertilization, implantation, and early development. For years, federal funding of human embryo research has been held hostage to a congressional prolife agenda. Any reasonable solution to these political disputes that so greatly affect women's reproductive interests and the promise of health benefits from embryo and stem cell research should mandate that governmental sponsorship proceed.     

Cell transplant and regenerative therapy with stem cells

One of the fields of medicine that has raised the most expectations in recent years is cell therapy with stem cells. The isolation of human embryo cells, the apparent and unexpected potentiality of adult stem cells and the development of gene therapy lead us to imagine a hopeful future for a significant number of diseases that are at present incurable. In this article we will sketch out the panorama of stem cell research, describing the main achievements in this field as well as some of the questions that await an answer. In spite of the great expectations, it is essential that we maintain a critical and realistic spirit when it comes to analysing the scientific advances in this area.     

From fibroblasts and stem cells: implications for cell therapies and somatic cloning

Pluripotent embryonic stem cells (ESCs) from the inner cell mass of early murine and human embryos exhibit extensive self-renewal in culture and maintain their ability to differentiate into all cell lineages. These features make ESCs a suitable candidate for cell-replacement therapy. However, the use of early embryos has provoked considerable public debate based on ethical considerations. From this standpoint, stem cells derived from adult tissues are a more easily accepted alternative. Recent results suggest that adult stem cells have a broader range of potency than imagined initially. Although some claims have been called into question by the discovery that fusion between the stem cells and differentiated cells can occur spontaneously, in other cases somatic stem cells have been induced to commit to various lineages by the extra- or intracellular environment. Recent data from our laboratory suggest that changes in culture conditions can expand a subpopulation of cells with a pluripotent phenotype from primary fibroblast cultures. The present paper critically reviews recent data on the potency of somatic stem cells, methods to modify the potency of somatic cells and implications for cell-based therapies.     

Von der Grundlagenforschung in die Klinik

The discovery of human embryonic stem cells at the end of 1998 had a strong influence on the development of stem cell research and led to controversial discussions. The first therapeutic application of adult blood stem cells began after their discovery in 1963 and was accepted as an authorized therapy in the early 1980s. The way from basic research to therapeutic use needed about 20 years and was also discussed in a controversial way similar to the discussions of today. The regulatory environment at that time, however, allowed a quick translation of the results from basic research to the clinic. Today many new stem cell therapies for a multitude of diseases are under development. Their clinical realization is regulated by the AMG (Arzneimittelgesetz). For nonclinical research as well as for clinical research, specific regulations are enacted to guarantee a structured and safe launch. Time, know how and money for planning, request for authorization and conduction of a clinical trial should not be underestimated. For clinical application of stem cell products authorization by the proper authorities is mandatory.     

Stem cell research: licit or complicit? Is a medical breakthrough based on embryonic and fetal tissue compatible with Catholic teaching?

In November 1998 biologists announced that they had discovered a way to isolate and preserve human stem cells. Since stem cells are capable of developing into any kind of human tissue or organ, this was a great scientific coup. Researchers envision using the cells to replace damaged organs and to restore tissue destroyed by, for example, Parkinson's disease, diabetes, or even Alzheimer's. But, since stem cells are taken from aborted embryonic and fetal tissue or "leftover" in vitro embryos, their use raises large ethical issues. The National Institutes of Health (NIH) recently decided to fund research employing, not stem cells, but "cell lines" derived from them. The NIH has essentially made an ethical determination, finding sufficient "distance" between cell lines and abortion. Can Catholic universities sponsoring biological research agree with this finding? Probably not. In Catholic teaching, the concept of "complicity" would likely preclude such research. However, Catholic teaching would probably allow research done with stem cells obtained from postpartum placental tissue and from adult bone marrow and tissue. These cells, which lack the pluripotency of embryonic and fetal stem cells, are nevertheless scientifically promising and do not involve the destruction of human life.     

Die Kriterien der Hochrangigkeit, der hinreichenden Vorklärung und der „Alternativlosigkeit“ nach § 5 Stammzellgesetz aus ethischer Sicht

The German Stem Cell Act forbids, in principle, the importation und use of human embryonic stem cells, but provides for exceptions under specific conditions. It is the first Federal German law that grants an ethical review authority over the approval process. The legislature has indeed established the criteria for the work of the members of the "Central Ethics Commission for Stem Cell Research" appointed by the Federal Government. The three criteria include the following: 'high priority of the research goals', sufficiencyy of research in the animal and adult human models' and 'the absence of an alternative'. Together they legitimate the importation and use of human embryonic stem cells. This paper seeks to elucidate these three criteria, to analyze their dual function as ethical and as scientific concepts, and to illustrate the ways in which they are being used.     

Human embryonic stem cells: challenges and opportunities

Human and non-human primate embryonic stem (ES) cells are invaluable resources for developmental studies, pharmaceutical research and a better understanding of human disease and replacement therapies. In 1998, subsequent to the establishment of the first monkey ES cell line in 1995, the first human ES cell line was developed. Later, three of the National Institute of Health (NIH) lines (BG01, BG02 and BG03) were derived from embryos that would have been discarded because of their poor quality. A major challenge to research in this area is maintaining the unique characteristics and a normal karyotype in the NIH-registered human ES cell lines. A normal karyotype can be maintained under certain culture conditions. In addition, a major goal in stem cell research is to direct ES cells towards a limited cell fate, with research progressing towards the derivation of a variety of cell types. We and others have built on findings in vertebrate (frog, chicken and mouse) neural development and from mouse ES cell research to derive neural stem cells from human ES cells. We have directed these derived human neural stem cells to differentiate into motoneurons using a combination of developmental cues (growth factors) that are spatially and temporally defined. These and other human ES cell derivatives will be used to screen new compounds and develop innovative cell therapies for degenerative diseases.     

Stem cell research in Germany: Ethics of healing vs. human dignity

On 25 April 2002, the German Parliament has passed a strict new law referring to stem cell research. This law took effect on July 1, 2002. The so-called embryonic Stem Cell Act (Stammzellgesetz — StZG) permits the import of embryonic stem (ES) cells isolated from surplus IvF-embryos for research reasons. The production itself of ES cells from human blastocysts has been prohibited by the German Embryo Protection Act of 1990, with the exception of the use of ES cells which exist already. The debate on the legitimate use of ES cells escalated, after the main German research funding agency, the Deutsche Forschungsgemeinschaft (DFG), unexpectedly published new guidelines recommending are stricted use of human ES cells for research. Meanwhile, the debate has ethically dividedsociety, political parties, government and church members into a group supporting and a group rejecting ES cell research. The arguments in favour of such a research can be summarized as arguments derived from a new ethics ofhealing calling for a therapeutic imperative, whereas the arguments against can be summarized as arguments violating the fundamental principle of human dignity as they imply the destruction of human embryos. This article willtry to present and evaluate various ethical arguments founded on the latest biological and medical data on the potential use of stem cell technologies. It will finally come to the conclusion that ES cell research is opposed to human dignity, since the procedures of isolating ES cells require the destruction and instrumentalization of human embryos. Human embryos are human beings at a very early stage of their development, fully possessing the ability of completing their development. At this very early stage, human embryos are extremely dependent and fragile, and thus vulnerable corporealities. Vulnerability and human dignity demand the protection of the embryo's corporeal integrity. Hence, this essay will try to propagate research with adult stem(AS) cells, a procedure which does not require the destruction of human embryos; with regard to the necessary plasticity, it should be emphasized that AS cells very much resemble ES cells.This revised version was published online in October 2005 with corrections to the Cover Date.     

Cellular therapy--the possible future of regenerative medicine

Stem cells are a unique cell population capable of self-renewal and differentiation into different cell lines. There are two main types of stem cells: embryonic stem cells (pluripotent) and somatic/adult stem cells (multipotent cells differentiated into the specific types of the tissue they originate from). Scientists are now interested in finding the sources of cells that can be used for therapeutic cloning as a method of saving human life and a new trend in regenerative medicine. Reproductive cloning, which aims at creating genetically identical human beings, is prohibited and is subject to national legislation in each country. Mesenchymal stem cells, with their capability to elude detection by the host's immune system and their relative ease of expansion in culture, are a very promising source of stem cells for regenerative medicine. This is the vast potential of cellular therapy for treating damaged and degenerating tissues.     

Genetic modification of somatic cells for producing animal models and for cellular transplantation

Great progress has been made in two technologies related to biomedical research: (1) manipulating the genomes of cells; and (2) inducing stem cells in culture to differentiate into potentially useful cell types. These technologies can be used to create animal models of human disease and to provide cells for transplantation to ameliorate human disease. Both embryonic stem cells and adult stem cells have been studied for these purposes. Genetically modified somatic cells provide another source of cells for creating animal models and for cellular transplantation.     

Forschung ja – Anwendung nein?

In exceptional cases, the German Stem Cell Act allows research on human embryonic stem cells. However, it does not allow the implementation of the research results if this in turn requires the use of further embryonic stem cell lines. It has, in the meantime, transpired that such research results could be of concrete use. Thus, in the distant future, it could be used in the clinical treatment of patients. Already in the nearer future the use of human embryonic stem cell lines can be envisaged for both the development and testing of medicines as well as in the field of toxicology. To this end, research concerning embryo toxicity and neurotoxicity is ground-breaking. The toxicological and pharmacological use of human embryonic stem cell lines should serve the protection of human health as well as the safe and reliable use of medicines. In addition, animal experiments could be reduced, which is desirable from a point of view of animal protection ethics. Since research on human embryonic stem cell lines is actually permitted in Germany, the use of the respective research results should be allowed all the more. This follows from the basic human right to health protection and health care. Legal ambiguities, which still exist in this respect, should be removed.     

生殖干细胞的研究进展

卵巢中始基卵泡是女性的基本生殖单位，也是卵细胞储备的唯一形式。传统观点认为，出生后卵母细胞数量不再增加，随着卵泡的发育、成熟和闭锁，卵母细胞不断耗竭，卵巢功能衰退，从而进入绝经期。随着人类在干细胞研究领域不断深入，应用干细胞治疗相关疾病已成为现实。在临床应用中，骨髓造血干细胞移植成为白血病等血液系统疾病患者的重要治疗方式。近年来，研究人员在成年小鼠卵巢内发现进行有丝分裂的生殖细胞，可能参与卵母细胞再生，这种细胞很可能就是生殖干细胞（GSCs）。GSCs的存在为卵巢功能不全、卵巢早衰和恶性肿瘤患者生育力保存及绝经后期女性健康维护带来希望。现就GSCs的研究进展进行综述。     

The mitochondrial contribution to stem cell biology

The distribution and functions of mitochondria in stem cells have not been examined, yet the contributions of these organelles to stem cell viability and differentiation must be vitally important in view of their critical roles in all other cell types. A key role for mitochondria in stem cells is indicated by reports that they translocate in the oocyte during fertilisation to cluster around the pronuclei and can remain in a perinuclear pattern during embryo development. This clustering appears to be essential for normal embryonic development. Because embryonic stem cells are derived from fertilised oocytes, and eventually can differentiate into 'adult' stem cells, it was hypothesised that mitochondrial perinuclear clustering persists through preimplantation embryo development into the stem cells, and that this localisation is indicative of stem cell pluripotency. Further, it was predicted that mitochondrial activity, as measured by respiration and adenosine triphosphate (ATP) content, would correlate with the degree of perinuclear clustering. It was also predicted that these morphological and metabolic measurements could serve as indicators of 'stemness.' This article reviews the distribution and metabolism of mitochondria in a model stem cell line and how this information is related to passage number, differentiation and/or senescence. In addition, it describes mitochondrial DNA deletions in oocytes and embryos that could adversely affect stem cell performance.     

The derivation and potential use of human embryonic stem cells

Human embryonic stem cells lines can be derived from human blastocysts at high efficiency (>50%) by immunosurgical isolation of the inner cell mass and culture on embryonic fibroblast cell lines. These cells will spontaneously differentiate into all the primary embryonic lineages in vitro and in vivo, but they are unable to form an integrated embryo or body plan by themselves or when combined with trophectoderm cells. They may be directed into a number of specific cell types and this enrichment process requires specific growth factors, cell-surface molecules, matrix molecules and secreted products of other cell types. Embryonic stem (ES) cells are immortal and represent a major potential for cell therapies for regenerative medicine. Their use in transplantation may depend on the formation of a large bank of suitable human leucocyte antigen (HLA) types or the genetic erasure of their HLA expression. Successful transplantation may also require induction of tolerance in recipients and ongoing immune suppression. Although it is possible to customize ES cells by therapeutic cloning or cytoplasmic transfer, it would appear unlikely that these strategies will be used extensively for producing ES cells compatible for transplantation. Embryonic stem cell research may deliver a new pathway for regenerative medicine.     

干细胞研究进展及相关伦理学问题思考

始于上世纪末,迄今仍方兴未艾的干细胞研究,由于其特殊的细胞分化,组织再生,甚至可能的器官再造特性,引起了又一次生物医学革命,被视为20世纪末最重要的生物医学成就。但同时由于胚胎干细胞涉及的人类胚胎生命及组织、器官的再生成等伦理学问题,干细胞研究从问世的第一天起,就在生物医学家、哲学家、法学家、政治家间引起广泛的争论。文章简要复习了近年来干细胞研究成果及干细胞研究引起的相关伦理学争论,并就干细胞研究引发的伦理学问题及对未来医疗发展的影响提出作者的观点。     

Adult stem cells

One of the fields of medicine that has created the greatest expectations in recent years is cellular therapy with stem cells. The isolation of human embryo cells, the apparent and unexpected potential of adult stem cells, and the development of gene therapy lead us to imagine a hopeful future for a significant number of diseases that are at present incurable. In the following pages we offer a sketch of the panorama of research with stem cells, describing the main achievements in this field as well as some of the questions awaiting answers. In spite of the great expectations, it is essential that we maintain a critical and realistic spirit when it comes to analysing the scientific advances in this area.     

A European discussion about stem cells for therapeutic use

Stem cells as a source material for growing cellular transplants to repair dysfunctional organs appear to be a new challenge for medical science. Though stem cells are also present in foetal and adult organs, embryonic stem cells from the pre-implantation embryo in particular have the potency to proliferate easily in vitro and the capacity to differentiate into all the body's organ-specific cells. Therefore, these are the ideal cells for developing new cell transplantation therapies for diseases such as Parkinson's disease, diabetes mellitus and heart failure. The use of spare in vitro fertilization (IVF) embryos or pre-implantation embryos specially created to harvest human embryonic stem cells is, however, controversial and an ethical problem. In a European discussion platform organised by the European Commission Research Directorate-General, the status quo of the progress was presented and subsequently commented upon and discussed in terms of medical-ethical, social, industrial and patient interests. The expectations of this new medical technology were high, but clinical trials seem only acceptable once the in vitro differentiation of stem cells can be adequately controlled and once it is known how in vitro prepared stem cells behave after implantation. The ethical justification of the use of in vitro pre-implantation embryos remains controversial. The prevailing view is that the interests of severely ill patients for whom no adequate therapy exists, surmounts the interest of protection of a human in vitro pre-implantation embryo, regardless of whether it was the result of IVF or of transplantation of a somatic cell nucleus of the patient in an enucleated donor egg cell (therapeutic cloning).