Disappearing stem cells, disappearing science.

Pluripotent cells have the potential to differentiate into all of the cell types of an animal. This unique cell state is governed by an interconnected network of transcription factors. Among these, Oct4 plays an essential role both in the development of pluripotent cells in the embryo and in the self-renewal of its in vitro counterpart, embryonic stem (ES) cells. Furthermore, Oct4 is one of the four Yamanaka factors and its overexpression alone can generate induced pluripotent stem (iPS) cells. Recent reports underscore Oct4 as an essential regulator of opposing cell state transitions, such as pluripotency establishment and differentiation into embryonic germ lineages. Here we discuss these recent studies and the potential mechanisms underlying these contrasting functions of Oct4.

Controversy regarding Human embryonic Stem Cell (hESC) research is evident in the medical and scientific community, legislative, judicial, and executive branches of the government, private companies, religious affiliations, special interest groups, and among the general American public. Stem cells are derived from adult stem cell resources, which are termed non-embryonic or from the cells of immature blastocysts termed embryonic stem cells. Non-embryonic cells do not have the ability to differentiate into other specialized tissues, whereas embryonic cells are capable of differentiating into almost any type of tissue. hESC research, which is the focus of this paper, includes the direct creation and therapeutic cloning of human embryos, known as somatic cell nuclear transfer (SCNT) during the blastocyst-stage of development, the use of surplus embryos from in vitro fertilization, and from tissue derived from extracted embryos through abortion. The purpose of hESC research is threefold: (1) to advance science and medicine, (2) prevent disease, and (3) cure certain diseases. hESC research is an ethical dilemma facing the United States of America. Opponents of hESC often cite the rights of the embryo and define the embryo at conception. Supporters of hESC research include the scientific and medical community, and private hESC research companies. The unique political system of the United States has allowed for a dichotomous policy to arise, where federal funding of hESC is prohibited, but private companies and individual states are able to legally forge a path in hESC research. The prohibition of federal funds has created an abyss between states who choose to fund hESC research and those who prohibit it. It has also set the stage for yet another private corporation to advance in hESC and place profit above the American public. The embryo is the only silent member of this debate.

This paper examines the influences that congressional staff people viewed as important in shaping legislators' voting decisions on the human embryonic stem (ES) cell research bill in the 109th Congress, the first legislation vetoed by President George W. Bush. The analysis illuminates factors that impact congressional decision making on a salient issue with a strong moral component. Constituent concerns, ideology, and a desire to make good public policy all centrally affected members' choices; however, moral overtones permeated considerations relevant to the human ES cell research question. In addition, at least three influences that directly reflect or relate to members' moral claims - religious convictions, personal connections to potential beneficiaries of human ES cell research, and moral pressure from outside interests - were important also. The analysis draws on data gathered from interviews with congressional aides.

Human Embryonic Stem Cells . Edited by J. Odorico, S. Zhang and R. Pedersen . (Pp. xxii + 391 , illustrated , ISBN 18599 62785 , £80 hardback.) Abingdon, UK : BIOS Scientific/Garland Science . It is now nearly seven years since the first description of human embryonic stem (ES) cell lines was published by Jamie Thomson. That event, closely apposed to the reports of the cloning of sheep (‘Dolly’), and then mice, by somatic nuclear transfer, catalysed substantial interest in the idea of regenerative medicine and the possibility that stem cells of all sorts might be harnessed for the replacement of tissues lost to accident or disease. At about the same time, a number of papers appeared, reporting that various somatic stem cells – which were previously thought to be committed to lineages from within their tissue of origin – might indeed exhibit substantial plasticity and be able to generate terminally differentiated cells corresponding to a much wider range of cell types. Thus, the current era of stem cell biology was born, though the concept of stem cells and their application in medicine is much older. One consequence of this resurgent interest in stem cell biology has been the publishing of several multi-author volumes devoted to stem cells and their potential. The volume Human Embryonic Stem Cells, edited by J. Odorico, S. Zhang and R. Pedersen, is the latest in a series produced by different publishing houses over the past few years. Paradoxically, however, as Jamie Thomson points out in his foreword to the present volume, progress in the field has been slow over this time. Prospects for adult stem cells have been dimmed by controversy over the phenomenon of ‘plasticity’, with the suggestion that at least some of the reported cases might be artefactual, depending upon cell fusion or rare transdifferentiation events. At the same time, progress with human ES cells was initially hindered by the difficulty of access to established lines, and the complexity of maintaining and expanding the cultures when they could be obtained. Although mouse ES cells have been available for over 20 years, they have mostly been used as tools to produce transgenic mice. With notable exceptions, few have investigated their cell biology for its own sake, and so there has been relatively little experience from studies of mouse ES cells to guide the study of their human counterparts. The development of ES cell lines was a systematic progression from the study of teratocarcinomas in the 1970s, by those who thought that these tumours might provide key insights into the mechanisms of embryonic development. It is then perhaps ironic that clues about how to control the behaviour of human ES cells in culture are now being provided by our detailed knowledge of developmental genetics, especially of the mouse. However, the human ES cell field is changing. Many laboratories in many countries have now derived human ES cell lines. In the current International Stem Cell Initiative, a collaborative venture to compare the properties of human ES cell lines derived worldwide, 75 independent lines derived in 17 laboratories and ten countries have been enrolled in the study. Meanwhile, reports are now beginning to appear in prominent journals, addressing the molecular mechanisms of human ES cell proliferation and differentiation – not merely describing their characteristics and potential for diverse differentiation. The present volume, unlike many of its competitors, focuses explicitly on human ES cells, and may be thought to mark the end of the first phase of human ES cell research. It brings together a series of authors who have contributed significantly to the field and it balances chapters discussing the basic biology of ES cells with others discussing their differentiation along specific lineages and eventual application. Despite the focus on ES cells, two early chapters provide useful comparative reviews of recent studies of adult stem cell plasticity and of mesenchymal stem cells. Further chapters address potential issues that will need to be addressed as derivatives of human ES cells are developed for eventual clinical application. Included here are two interesting and useful reviews of the ethical, legal and intellectual property aspects of human ES cell research and application. Undoubtedly, research in the new field of human ES cell biology is beginning to advance rapidly, so that it might be considered that the present volume will become rapidly obsolete. However, its well-organized and well-written chapters provide a valuable reference to the current state of the field for newcomers and established human ES cell researchers alike. Although our understanding of molecular mechanisms and the means of manipulating human ES cells is likely to change significantly in the future, much of what is contained in this volume will remain fundamental, and so of value to those working in this exciting new area of research for quite a few years to come.

Embryonic stem cells are pluripotent and capable of unlimited self-renewal. Elucidation of the underlying molecular mechanism may contribute to the advancement of cell-based regenerative medicine. In the present work, we performed a large scale analysis of the phosphoproteome in mouse embryonic stem (mES) cells. Using multiplex strategies, we detected 4581 proteins and 3970 high confidence distinct phosphosites in 1642 phosphoproteins. Notably, 22 prominent phosphorylated stem cell marker proteins with 39 novel phosphosites were identified for the first time by mass spectrometry, including phosphorylation sites in NANOG (Ser-65) and RE1 silencing transcription factor (Ser-950 and Thr-953). Quantitative profiles of NANOG peptides obtained during the differentiation of mES cells revealed that the abundance of phosphopeptides and non-phosphopeptides decreased with different trends. To our knowledge, this study presents the largest global characterization of phosphorylation in mES cells. Compared with a study of ultimately differentiated tissue cells, a bioinformatics analysis of the phosphorylation data set revealed a consistent phosphorylation motif in human and mouse ES cells. Moreover, investigations into phosphorylation conservation suggested that phosphoproteins were more conserved in the undifferentiated ES cell state than in the ultimately differentiated tissue cell state. However, the opposite conclusion was drawn from this conservation comparison with phosphosites. Overall, this work provides an overview of phosphorylation in mES cells and is a valuable resource for the future understanding of basic biology in mES cells.

Embryonic stem cells in science and medicine, part II: Law, ethics, and the continuing need for dialogue

Embryonic stem (ES) cells are derived from the epiblast of the inner cell mass (ICM) of a blastocyst. These are pluripotent cells and can give rise to all derivatives of the three primary germ layers ectoderm, endoderm, and mesoderm. ES cells require specific signals for specific lineage of differentiation if injected directly into another body, ES cells will differentiate into many different types of cells, causing a teratoma (Wu et al., 2007). The techniques for culturing mouse embryonic stem (ES) cells from the inner cell mass of the preimplantation blastocyst were first done in 1981 (Martin, 1981), and versions of these standard procedures are used today in laboratories throughout the world. The first successful derivation of human ES (hES) cells was reported by Thomson et al. (Thomson et al., 1998). They isolated and plated the cells onto mitotically inactivated MEF (mouse embryonic fibroblast) cells. In 2000, Reubinoff et al. confirmed that hES cells could be efficiently derived from surplus embryos and possess the differentiation potential under in vitro conditions. Since then, there has been rapid progress made and numerous studies have described the derivation of new hES cell lines including methods of growing both undifferentiated hES cells and their differentiated progeny. In last 6 years, there has been exponential increase in methods to improve culture conditions, differentiation patterns to produce human cells for transplantation and drug testing (Trounson, 2006, Gepstein, 2002) and genetic manipulation (Draper et al., 2004, Zwaka and Thomson, 2003). Generating cultures of mouse or human ES cells that remain in a proliferating and undifferentiated state is multistep process. Typically, the inner cell mass of a preimplantation blastocyst is removed from the trophectoderm that surrounds it and cultured in the small plastic culture dishes containing growth medium supplemented with fetal calf serum. The culture dishes are sometimes coated with a layer of nondividing cells, which are often MEF cells that have been chemically inactivated so they will not divide. Mouse ES cells can be grown in vitro without feeder layers if the cytokine leukemia inhibitory factor (LIF) is added to the culture medium, but human ES cells do not respond to LIF. The process of generating an embryonic stem cell line is somewhat difficult, so lines are not produced every time from the preimplantation-stage embryo maintained in a culture dish. However, if the plated cells survive, divide and multiply enough to crowd the dish, they are removed, and plated into several fresh culture dishes. The process of re-plating or

The purpose of this chapter is to provide a comparative outline of practices, policies, and regulation of human embryonic stem cell (hESC) research in the majority of the new EU Members. First, some preliminary remarks and introductory clarifications are necessary.

Nonprofit organizations and philanthropists stepped into a funding void caused by controversies over public funding of human embryonic stem cell (hESC) research. Based on interviews of 83 representatives of 53 funders, we examine the motivations and accountability structures of public agencies, corporations, fundraising dependent nonprofit organizations and philanthropic organizations that funded hESC research in three jurisdictions: California, Sweden, and South Korea. While non-traditional forms of funding are essential in the early stages of research advancement, they are unreliable for the long timeframes necessary to advance cell therapies. Such funding sources may enter the field based on high expectations, but may exit just as rapidly based on disappointing rates of progress.

This article is a response to McLeod and Baylis (2007) who speculate on the dangers of requesting fresh ‘spare’ embryos from IVF patients for human embryonic stem cell (hESC) research, particularly when those embryos are good enough to be transferred back to the woman. They argue that these embryos should be frozen instead. We explore what is meant by ‘spare’ embryos. We then provide empirical evidence, from a study of embryo donation and of embryo donors' views, to substantiate some of their speculations about the problems associated with requesting fresh embryos. However, we also question whether such problems are resolved by embryo freezing, since further empirical evidence suggests that this raises other social and ethical problems for patients. There is little evidence that the request for embryos for research, in itself, causes patients distress. We suggest, however, that no requests for fresh embryos should be made in the first cycle of IVF treatment. Deferring the request to a later cycle ensures that potential donors are better informed (by experience and reflection) about the possible destinations of their embryos and about the definition of ‘spare embryos’. Both this article, and that by McLeod and Baylis, emphasize the need to consider the views and experiences of embryo donors when evaluating the ethics of embryo donation for hESC research.

Rethink the patentability of human embryonic stem cell research findings: Relaxation based on benefit weighing.

The governance of innovative bioscience could extensively influence the growth of science, economy, society and law of every country. Similar to many countries, Muslim nations are experiencing a variety of socio-cultural and political conflicts relating to emerging bioscience, including human embryonic stem (hES) cell research and therapy. Among Muslims, the discussion of the ethics and regulatory policy related to hES cell research is mostly seen as a restrictive position, however, some Muslim nations take an intermediate stance, e.g. Iran as a leading country among Muslim nations. Islam, similar to other religions, significantly influences the moral, social and legal debates around hES cell science. The main argument is about the level of protection of the human embryo as it is used to obtain stem cells and then destroyed. This essay broadly portrays the fundamental moral constructions of Islamic deliberations on bioscience and technology in general, and particularly hES cell science in Shi’a tradition. The paper helps us to understand how scientific knowledge, bioethical discourses and legal deliberations are produced in the Muslim countries. After introducing some background information, it delves into the core themes framing the discussion, with reference to the moral controversy surrounding hES cell science and Islamic faith. This account is intended to present the main highlighted debates and controversial questions. The essay concludes that given continuing conflicts between science, politics and religion in many countries, in some countries, for example in the Shi’a Iran, hES cell science converges with religious beliefs and government policies.

Embryonic, fetal, and adult stem cells have been extensively tested in the past decade as candidates for cell replacement therapy of severe heart failure. Among them, embryonic stem (ES) cells have been regarded as an especially valuable source of therapeutic cells due to their unlimited growth in culture and well-established cardiogenic potential in vitro. ES cell preparations that were tested in animal models of heart infarction ranged from fully undifferentiated and cardiac-committed ES cells to partially or highly enriched ES cell-derived cardiomyocytes. Here we critically review the current literature on use of fully undifferentiated ES cells for cardiac repair, elaborate on the tumorigenic risk of ES cells and pluripotent cells in general, and summarize strategies for elimination of this threat as an important step toward translation of ES cell-based therapies to clinic. This discussion is also highly relevant for clinical applicability of newly developed autologous ES cell-like stem cells, so-called induced pluripotent stem cells, which circumvent ethical and, to some extent, immunological concerns linked to the use of blastocyst-derived ES cells, but still possess high tumorigenic potential.

Embryonic Stem Cell Research (ESCR) raises ethical issues. In the process of research, embryos may be destroyed and, to some, such an act entails the 'killing of human life'. Past studies have sought the views of scientists and the general public on the ethics of ESCR. This study, however, explores multi-faith ethical viewpoints, in particular, those of Buddhists, Hindus and Catholics in Malaysia, on ESCR. Responses were gathered via semi-structured, face-to-face interviews. Three main ethical quandaries emerged from the data: (1) sanctity of life, (2) do no harm, and (3) 'intention' of the research. Concerns regarding the sanctity of life are directed at particular research protocols which interfere with religious notions of human ensoulment and early consciousness. The principle of 'do no harm' which is closely related to ahimsa prohibits all acts of violence. Responses obtained indicate that respondents either discourage research that inflicts harm on living entities or allow ESCR with reservations. 'Intention' of the research seems to be an interesting and viable rationale that would permit ESCR for the Buddhists and Hindus. Research that is intended for the purpose of alleviating human suffering is seen as being ethical. This study also notes that Catholics oppose ESCR on the basis of the inviolability of human life.

Will Human Embryonic Stem Cell Therapies Finally Grow Up?