In mice, dosage compensation of X‐linked gene expression is achieved through the inactivation of one of the two X‐chromosomes in XX female cells. The complex epigenetic process leading to X‐inactivation is largely controlled by Xist and Tsix, two non‐coding genes of opposing function. Xist RNA triggers X‐inactivation by coating the inactive X, while Tsix is critical for the designation of the active X‐chromosome through cis‐repression of Xist RNA accumulation. Recently, a plethora of trans‐acting factors and cis‐regulating elements have been suggested (...) to act as key regulators of either Xist, Tsix or both; these include ubiquitous factors such as Yy1 and Ctcf, developmental proteins such as Nanog, Oct4 and Sox2, and X‐linked regulators such as Rnf12. In this paper we summarise recent advances in our knowledge of the regulation of Xist and Tsix in embryonic stem (ES) and differentiating ES cells. (shrink)

Stem cell research is a newly emerging technology that promises a wide variety of benefits for humanity. It has, however, also caused much ethical, legal, and theological debate. While some forms of its application were prohibited in the beginning, they have now started to be used in many countries. This fact obliges us to discuss the regulation of stem cell research at national and international level. It is obvious that in order to make regulations and to draw up legislation (...) at national or international levels it helps to know the perspectives of different cultures and faith traditions. In this article the issue is explored from an Islamic perspective. Firstly, some basic information is given about Islam to explain how laws are drawn up and regulations made in this tradition. Secondly, the principles on which the laws and regulations are based are applied to stem cell research, and finally the permitted and prohibited methods of stem cell research are described. The discussions throughout the paper demonstrate that while some ethicists argue that stem cell research is unethical in the Islamic tradition, tradition permits it as long as such research is aimed at improving human health. (shrink)

Arthrogryposis multiplex congenita (AMC) is a heterogeneous syndrome where multiple joints have reduced range of motion due to contracture formation prior to birth. A common cause of AMC is reduced embryonic movement in utero. This reduction in embryonic movement can perturb molecular mechanisms and signaling pathways involved in the formation of joints during development. The absence of mechanical stimuli can impair joint cavitation, resulting in joint fusion, and ultimately eliminate function. In turn, mechanical stimuli are critical for proper (...) joint formation during development and for mitigating AMC. Studies in experimental animal models have provided a greater understanding on the molecular pathophysiology of congenital contracture formation as a consequence of embryonic immobilization. Elucidation of how the mechanical signaling environment is transduced to initiate a biological response will be necessary to gain a deeper understanding of how mechanical stimuli are intertwined in the molecular regulation of joint development. (shrink)

The differentiation of mammalian neurons during development is a highly complex process involving regulation and coordination of gene expression at multiple steps. The P19 mouse embryonal carcinoma cell line is a suitable model system with which to analyze regulation of neuronal differentiation. These multipotential cells can be maintained and propagated in tissue culture in an undifferentiated state. Exposure of aggregated P19 cells to retinoic acid results in the differentiation of cells with many fundamental phenotypes of mammalian neurons. Undifferentiated (...) P19 cells are amenable to genetic manipulations such as transfection and establishment of stable clonal cell lines expressing introduced genes. Proteins that play a key role in the neuronal differentiation of P19 cells are beginning to be identified. These include retinoic acid receptors, the epidermal growth factor receptor and the transcription factors Oct‐3 and Brn‐2. The biological and technical advantages of this system should facilitate deeper analysis of the activities of proteins that play a role in neuronal differentiation. (shrink)

Embryonic stem cells are derived from the preimplantation embryo and can differentiate into virtually any other cell type, which is governed by lineage specific transcriptions factors binding to cis regulatory elements to mediate changes in gene expression. The reliance on transcriptional regulation to maintain pluripotency makes ESCs a valuable model to study the role of distal CREs such as enhancers in modulating gene expression to affect cell fate decisions. This review will highlight recent advance on transcriptional enhancers, focusing (...) on studies performed in ESCs. In addition, we argue that the Nanog locus, which encodes for an ESC-critical TF, is particularly informative because it contains multiple co-regulated genes and enhancers in close proximity to one another. The unique landscape at Nanog permits the study of ongoing questions including whether multiple enhancers function additively versus synergistically, determinants of gene specificity, and cell-to-cell variability in gene expression. Nanog encodes a transcription factor required to maintain ESC pluripotency. The Nanog locus is an ideal model to study enhancers because it contains multiple highly potent super-enhancers within a small region. Nanog and three super-enhancers are in close physical proximity but only two SEs are required for Nanog expression. (shrink)

The mechanisms used to establish embryonic polarity are still largely unknown. A recent paper(1) describes the expression pattern of the gene glp‐1, which is required for induction events during development of the nematode Caenorhabditis elegans. Although glp‐1 RNA is found throughout the early embryo, Glp‐1 protein is only expressed in anterior cells. This negative translational regulation in posterior cells is shown to be mediated through sequences in the glp‐1 3′ untranslated region (3′UTR). Thus in nematodes, as in Drosophila, (...) translational repression is one mechanism used to establish the embryonic anterior‐posterior axis. (shrink)

The developmental history of the vertebrate eye begins at an early embryonic stage, with the formation of the body axes and induction of neural tissue. Several recent experimental embryological and genetic studies in teleost fish have produced new insights into the morphogenetic and molecular regulation of eye formation. Molecular signaling pathways and patterned expression of transcription factors implicated in eye determination are discussed, and the importance of morphogenetic cell movements is emphasized. BioEssays 24:519–529, 2002. © 2002 Wiley Periodicals, (...) Inc. (shrink)

This article contributes to the current debate on human embryonic stem cell researchers’ possible complicity in the destruction of human embryos and the relevance of such complicity for the issue of commodification of human embryos. I will discuss if, and to what extent, researchers who destroy human embryos, and researchers who merely use human embryos destroyed by others, have moral use rights, and/or moral property rights, in these embryos. I argue that the moral status of the human embryo, however (...) justified, places few restrictions on the latter researchers’ use of it, and property rights in it, once it is destroyed. I argue that the former researchers have no property rights in the destroyed embryo but use rights in it to the extent allowed by the legitimate owners of the destroyed embryo. I discuss the implications of this account for previous and current US federal law regulating human embryonic stem cell research. (shrink)

Emerging evidence suggests that microRNA (miRNA)‐mediated post‐transcriptional gene regulation plays an essential role in modulating embryonic stem (ES) cell pluripotency maintenance, differentiation, and reprogramming of somatic cells to an ES cell‐like state. Investigations from ES cell‐enriched miRNAs, such as mouse miR‐290 cluster and human miR‐302 cluster, and ES cell‐depleted miRNAs such as let‐7 family miRNAs, revealed a common theme that miRNAs target diverse cellular processes including cell cycle regulators, signaling pathway effectors, transcription factors, and epigenetic modifiers and shape (...) their protein output. The combinatorial effects downstream of miRNA action allow miRNAs to modulate cell‐fate decisions effectively. Furthermore, the transcription and biogenesis of miRNAs are also tightly regulated. Thus, elucidating the interplay between miRNAs and other modes of gene regulation will shed new light on the biology of pluripotent stem cells and somatic cell reprogramming. (shrink)

During early embryonic development in several metazoans, accurate DNA replication is ensured by high number of replication origins. This guarantees rapid genome duplication coordinated with fast cell divisions. In Xenopus laevis embryos this program switches to one with a lower number of origins at a developmental stage known as mid‐blastula transition (MBT) when cell cycle length increases and gene transcription starts. Consistent with this regulation, somatic nuclei replicate poorly when transferred to eggs, suggesting the existence of an epigenetic (...) memory suppressing replication assembly origins at all available sites. Recently, it was shown that histone H1 imposes a non‐permissive chromatin configuration preventing replication origin assembly on somatic nuclei. This somatic state can be erased by SSRP1, a subunit of the FACT complex. Here, we further develop the hypothesis that this novel form of epigenetic memory might impact on different areas of vertebrate biology going from nuclear reprogramming to cancer development. (shrink)

This paper considers the legislative debates in Australia that led to the passage of the Research Involving Human Embryos Act (Cth 2002) and the Prohibition of Human Cloning Act (Cth 2002). In the first part of the paper, we discuss the debate surrounding the legislation with particular emphasis on the ways in which demands for public consultation, public debate and the education of Australians about the potential ethical and scientific impact of human embryonic stem cells (hESC) research were deployed, (...) and the explicit and implicit framing of the scope of public consultation. We then ask whether, given the calls for public consultations, debate and understanding, current work in democratic theory could be helpful in analysing the process of policy-making in these areas. In particular, we canvass the literature relating to aggregative and deliberative models of democracy for processes that support the legitimacy of policy. We identify features of the debate that reflect the appeal of deliberative approaches as well as some of the possible hurdles or limitations to developing deliberative democratic approaches to policy in ethically contentious areas. (shrink)

Regulation of stem cell research in Europe should not take place without public and scholarly inputThe European Union has, at present, no jurisdiction over research carried out in the member states, or concerning the “ethics” of member states. This does not, however, mean that decisions made by the European institutions cannot influence such matters greatly.There has recently been a lot of focus on the decision not to fund embryonic stem cell research during the first year of the 6th (...) framework programme , but behind the scenes a much more important and wide ranging set of regulations are being prepared.The European Commission has prepared a draft directive on setting standards of quality and safety for the donation, procurement, testing, processing, storage, and distribution of human tissues and cells.1 The purpose of this directive was originally to “ensure the quality and safety of human tissues and cells for clinical use” in the EU. This is clearly a laudable objective, fully in line with the EU’s jurisdiction in consumer protection and public health.During the intricate processes of political …. (shrink)

Recent studies of early development in a number of ivertebrate and vertebrate species have suggested that growth factors and their receptors may play important roles in differentiation as well as cell proliferation. In the mouse embryo, the expression of the receptors for insulin and insulin‐like growth factors I and II (IGF‐I and ‐II) are temporally regulated. The ontogeny of receptor and ligand expression within the insulin and IGF gene family suggests that the very earliest stages of mammalian embryogenesis may be (...) subject to regulation by autocrine and paracrine factors from maternal and embryonic sources. (shrink)

We examine whether the current regulatory regime instituted in South Korea and the United States would have prevented Hwang’s potential transgressions in oocyte procurement for somatic cell nuclear transfer, we compare the general aspects and oversight framework of the Bioethics and Biosafety Act in South Korea and the US National Academies’ Guidelines for Human Embryonic Stem Cell Research, and apply the relevant provisions and recommendations to each transgression. We conclude that the Act would institute centralized oversight under governmental auspices (...) while the Guidelines recommend politically-independent, decentralized oversight bodies including a special review body for human embryonic stem cell research at an institutional level and that the Guidelines would have provided more vigorous protection for the women who had undergone oocyte procurement for Hwang’s research than the Act. We also suggest additional regulations to protect those who provide oocytes for research in South Korea. (shrink)

Zygotic gene activation (ZGA) is the critical event that governs the transition from maternal to embryonic control of development. In the mouse, ZGA occurs during the 2‐cell stage and appears to be regulated by the time following fertilization, i.e. a zygotic clock, rather than by progression through the first cell cycle. The onset of ZGA must depend on maternally inherited proteins, and post‐translational modification of these maternally derived proteins is likely to play a role in ZGA. Consistent with this (...) prediction is that protein phosphorylation catalyzed by the cAMP‐dependent protein kinase is involved in ZGA and that protein synthesis is not required for ZGA. Recent results suggest that ZGA may occur earlier than previously thought, i.e. not during the 2‐cell stage, but rather in G2 of the 1‐cell embryo. Thus ZGA may comprise a period of minor gene activation in the 1‐cell embryo that is followed by a period of major gene activation in the 2‐cell embryo. Following ZGA, the expression of constitutively activated genes may require an enhancer. (shrink)

Reproductive diseases are a long‐standing problem and have become more common in the world. Currently, 15% of the world's population suffers from infertility, and half of them are women. Maturation of oocytes, successful fertilization, and high‐quality embryos are prerequisites for pregnancy. With the development of assisted reproductive technology and advanced genetic assays, we have found that infertility in many young female patients is caused by mutations in various developmental regulators. These pathogenic factors may result in impediment of oocyte maturation, failure (...) of fertilization or early embryonic development arrest. In this review, we categorize these clinically‐identified, mutated genetic factors by their molecular characteristics: nuclear factors (PALT2, TRIP13, WEE2, TBPL2, REC114, MEI1 and CDC20), cytoplasmic factors (TLE6, PADI6, NLRP2/5, FBXO43, MOS and BTG4), a factor unique to primates (TUBB8), cell membrane factor (PANX1), and zona pellucida factors (ZP1‐3). We compared discrepancies observed in phenotypes between human and mouse models to provide clues for clinical diagnosis and treatment of related reproductive diseases. (shrink)

The successes of molecular developmental biology over the last ten years have been particularly impressive in those directions favored by its major paradigms. New technologies have both guided and been guided by the progress of the field. I review briefly some of the major insights into embryonic development that have derived from research in four specific areas: early embryogenesis of various forms; “pattern formation”; evolutionary conservation of regulatory elements; and spatial mechanisms of gene regulation. There remain many major (...) problem areas, some of which may require new orientations to solve. (shrink)

Embryogenesis involves biochemical patterning as well as mechanical morphogenetic movements, both regulated by the expression of the regulatory genes of development. The reciprocal interplay of morphogenetic movements with developmental gene expression is becoming an increasingly intense subject of investigation. The molecular processes through which differentiation patterning closely regulates the development of morphogenetic movements are today becoming well understood. Conversely, experimental evidence recently revealed the involvement of mechanical cues due to morphogenetic movements in activating mechano-transduction pathways that control both the differentiation (...) and the active morphogenesis of fundamental events in embryonic tissue development. Here I will first focus on the central role the shape of biological structures of the molecular and mesoscopic cell scales plays in mechano-transduction. Then, after a short description of the genetic regulation of the Drosophila embryo mesoderm invagination at gastrulation—one of the best-understood morphogenetic movement of embryogenesis—I will detail the processes of differentiation and of active morphogenesis of Drosophila embryo gastrulation, which require mechano-transduction. Finally, I will explore the putative consequences in evolution of these mechano-transduction events. I speculate that the first ancient multicellular organisms might have emerged from primary morphological and differentiation patterns induced by primitive mechano-sensation effects allowed by mechano-transduction in response to their physical environment, such as touch by gravity or water flows, which might have acted as primitive motor–sensorial systems, thus conditioning the emergence of our primary animal ancestors. (shrink)

In October 2015 the UK enacted legislation to permit the clinical use of two cutting edge germline-altering, IVF-based embryonic techniques: pronuclear transfer and maternal spindle transfer. The aim is to use these techniques to prevent the maternal transmission of serious mitochondrial diseases. Major claims have been made about the quality of the debates that preceded this legislation and the significance of those debates for UK decision-making on other biotechnologies, as well as for other countries considering similar legislation. In this (...) article we conduct a systematic analysis of those UK debates and suggest that claims about their quality are over-stated. We identify, and analyse in detail, ten areas where greater clarity, depth and nuance would have produced sharper understandings of the contributions, limitations and wider social impacts of these mitochondrial interventions. We explore the implications of these additional considerations for the protection of all parties involved, should the techniques transfer to clinical applications; the legitimacy of focussing on short-term gains for individuals over public health considerations, and the maintenance and improvement of public trust in medical biotechnologies. We conclude that a more measured evaluation of the content and quality of the UK debates is important and timely: such a critique provides a clearer understanding of the possible, but specific, contributions of these interventions, both in the UK and elsewhere; also, these additional insights can now inform the emerging processes of implementation, regulation and practice of mitochondrial interventions. (shrink)

van Gend, David It was to be the "new dawn" of stem cell science, but it was a false dawn. Every year for a decade the press releases of Geron Corp, a stem cell company in the US, reassured investors that their world-first treatment using embryonic stem cells in spinal injury was going to be approved "next year".1 And every year the regulating authority in the US, the FDA, failed to give approval, asking instead for further reassurance about the (...) safety of the trial. Finally, coinciding with the election of President Obama and the prospect of a new, liberated era of embryonic research, the FDA overcame its qualms and gave the go-ahead. (shrink)

Genetic studies have revealed that the antagonistic interplay between PcG and TrxG/MLL complexes is essential for the proper maintenance of vertebrate Hox gene expression in time and space. Hox genes must be silenced in totipotent embryonic stem cells and, in contrast, rapidly activated during embryogenesis. Here we discuss some recently published articles1-4 that propose a novel mechanism for the induction of Hox gene transcription. These studies report a new family of histone demethylases that remove H3K27me3/me2 repressive marks at Hox (...) promoters during differentiation of stem cells. Though the overall importance of these enzymes for proper embryogenesis was demonstrated, their precise role in Hox gene epigenetic regulation during development still remains to be firmly established. BioEssays 30:199–202, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Localized mRNA translation is a biological process that allows mRNA to be translated on‐site, which is proposed to provide fine control in protein regulation, both spatially and temporally within a cell. We recently reported that Vasa, an RNA‐helicase, is a promising factor that appears to regulate this process on the spindle during the embryonic development of the sea urchin, yet the detailed roles and functional mechanisms of Vasa in this process are still largely unknown. In this review article, (...) to elucidate these remaining questions, we first summarize the prior knowledge and our recent findings in the area of Vasa research and further discuss how Vasa may function in localized mRNA translation, contributing to efficient protein regulation during rapid embryogenesis and cancer cell regulation. (shrink)

In contrast to many countries, the political debates in the Netherlands on reproductive technologies and embryo research have paid particular attention to the issue of health risks to women. This article focuses on the question to what extent the discourse of gender has contributed to shaping the space for embryonic research in this country. The author argues that in the policy arena flexible conceptualizations of risks and burdens to women and of the identities of embryos have been crucial in (...) drawing and maintaining a discursive boundary between the domains of medically assisted reproduction and embryo research. The author shows that feminist intervention challenging this discursive strategy has had an impact on the present regulation of research. However, the main weakness of this temporary and partial feminist success is the virtual absence of a public debate on the meaning and desirability of embryo research. (shrink)

Although several theoretical approaches consider general methods for dealing with shape, recent observations and experimental data show that embryos exhibit marked changes in the properties of the biological material involved in shape development and shape regulation capacity. In vivo experiments have shown that the amphibian embryo gradually develops from a situation in which it is not able to maintain its shape to one in which it can not only maintain its shape but also possesses a maximal tolerance towards deformation (...) together with a maximal shape regulation capacity. So far two especially clear conclusions have emerged: (i) the form of the embryo appears to be determined by cell activities intrinsic to each stage, and (ii) the morphogenetic programme can be executed normally within wide limits notwithstanding dramatic deformations of the embryo during quite a long period. Thus the hypothesis may be advanced that shape and morphogenesis to some extent become independent phenomena during embryonic development. (shrink)

The closely related debates concerning abortion, the protection of the embryo and stem cell science have captured the legislative agenda in Mexico in recent years. This paper examines some contemporary debates related to stem cell science and the legal and political action that has followed in the wake of the latest Supreme Court judgment on abortion, which debates are directly linked to the degrees of protection of the embryo stipulated in the Mexican Constitution. While some Mexican states have opted to (...) take no further action, others, where conservative political forces are in the majority, have been very active in seeking to ensure that their constitutions are amended to protect human life from conception onwards. This intense legislative activity has not, however, been repeated at the federal level, where there is currently no overarching national regulatory framework governing stem cell research. Although major efforts have been made by the conservative block within the Senate to bring forward legislative proposals for the prohibition of human embryonic stem cell research, and despite the public expression by the federal government of its commitment to encourage inward investment and innovation in the area of biotechnology, stem cell science has, so far, remained unregulated. The legislative challenge is to resist the pressure that has been injected by religious leaders and to act in accordance with the values and principles adopted by the community in the Mexican Constitution. In the final analysis, Mexico faces particular difficulties in accommodating conservative political forces on one hand, while recognising on the other its need, as an emerging economy, to promote a progressive approach to innovation in biotechnology. (shrink)

The precocious induction in vivo and in culture of insect and amphibian metamorphosis by exogenous ecdysteroids and thyroid hormones, and its retardation or inhibition by juvenile hormone and prolactin, respectively, has allowed the analysis of such diverse processes of post‐embryonic development as morphogenesis, tissue remodelling, functional reorganization, and programmed cell death. Metamorphosis in vertebrates also shares many similarities with mammalian development in the late foetal and perinatal period. This review describes the regulation of expression of some of the (...) ‘adult’ gene products during metamorphosis in invertebrates and vertebrates. Recent studies on metamorphosis have revealed the important role played by auto‐induction of hormone receptor genes, based on which a model will be presented to explain the activation of ‘downstream’ genes which give rise to the adult phenotype. It will also be argued that metamorphosis is an ideal model for analyzing some of the major mechanisms governing post‐embryonic development. (shrink)

Stem cell research regulations are highly variable across nations, notwithstanding shared and common ethical concerns. Dominant in political debates has been the so-called embryo question. However, the permissibility of human embryonic stem cell research varies among national regulatory frameworks. Scholars have explained differences by resorting to notions of political culture, traditions of ethical reasoning, discursive strategies and political manoeuvring of involved actors. Explanations based on the role of religion or other cultural structural variables are also employed. This paper analyses (...) the emerging of the Italian regulatory framework on stem cell research using an analytical framework that considers the interplay between cultural structural features, political culture, traditions of ethical reasoning, institutional settings and the discursive and political agency of the actors involved. It aims also to explain the role of Roman Catholic Church in shaping the Italian stem cell research regulation not by treating religion as an autonomous causal factor, but through the analysis of the agency of Catholic and allied actors in the Italian political culture and institutional setting. (shrink)

This article explores the plausibility of an argument against embryonic stem cell research based on what the regulations already say about research on pregnant women and fetuses. The center of the argument is the notion of vulnerability and whether such a concept is applicable to human embryos. It is argued that such an argument can be made plausible. The article concludes by responding to several important objections.

The tenascins are a growing family of extracellular matrix proteins of typical multidomain structure. The prototype to be discovered was tenascin‐C. It shows a highly regulated expression pattern during embryonic development and is often transiently associated with morphogenetic tissue interactions during organogenesis. In the adult organism reexpression of tenascin‐C occurs in tumors and many other pathological conditions. Tenascin‐C expression can be regulated by many different growth factors and hormones. Furthermore, mechanical strain exerted by fibroblasts seems to induce the expression (...) of tenascin‐C. This could represent a mechanism of translating mechanical forces into protein patterns, a step of potential relevance in the organization of embryogenesis. Tenascin‐C as well as tenascin‐R are believed to counteract the cell adhesion and spreading activity of fibronectin, thereby facilitating cell movement. (shrink)

During development some cells are migratory whilst others are stationary. However, the same cell may change its behaviour depending upon its environment. Recent evidence has implicated the extracellular matrix protein fibronectin in the regulation of migratory behaviour. As the structure of this molecule becomes elucidated, it is also becoming possible to interpret this regulation in precise molecular terms.

This paper proposes a classification of hESC research regulation by shifting from the statutory content of relevant national Laws to the method of decision-making process, in order to verify whether it is possible to identify a connection between the concrete characters of that process and its outcome. A set of procedural indexes are identified and applied to the analysed legal systems. According to an increasing fulfilment of indexes, we may individuate two main regulatory families: the ‘value oriented’ and the (...) ‘procedure oriented’ ones. The latter is developing an increasing impact within European context: it is characterised by a mix of regulatory sources, each developing a specific function. Within this model, statutory law cannot infringe a regulatory space reserved to expertise and selfregulation, developing a subsidiary function; furthermore, it has to recognise the integrative role of expertise within statutory-making process. (shrink)

The coordinated expression of the Hox gene family encoding transcription factors is critical for proper embryonic development and patterning. Major efforts have thus been dedicated to understanding mechanisms controlling Hox expression. In addition to the temporal and spatial sequential activation of Hox genes, proper embryonic development requires that Hox genes get differentially silenced in a cell‐type specific manner as development proceeds. Factors contributing to Hox silencing include the polycomb repressive complexes (PRCs), which control gene expression through epigenetic modifications. (...) This review focuses on PRC‐dependent regulation of the Hox genes and is aimed at integrating the growing complexity of PRC functional properties in the context of Hox regulation. In particular, mechanisms underlying PRC binding dynamics as well as a series of studies that have revealed the impact of PRC on the 3D organization of the genome is discussed, which has a significant role on Hox regulation during development. (shrink)

Key ethical issues arise in association with the conduct of stem cell research by research institutions in the United States. These ethical issues, summarized in detail, receive no adequate translation into federal laws or regulations, also described in this article. U.S. Federal policy takes a passive approach to these ethical issues, translating them simply into limitations on taxpayer funding, and foregoes scientific and ethical leadership while protecting intellectual property interests through a laissez faire approach to stem cell patents and licenses. (...) Those patents and licenses, far from being scientifically and ethically neutral in effect, virtually prohibit commercially sponsored research that could otherwise be a realistic alternative to the federal funding gap. The lack of federal funding and related data-sharing principles, combined with the effect of U.S. patent policy, the lack of key agency guidance, and the proliferation of divergent state laws arising from the lack of Federal leadership, significantly impede ethical stem cell research in the United States, without coherently supporting any consensus ethical vision. Research institutions must themselves implement steps, described in the article, to integrate addressing ethical review with the many legal compliance issues U.S. federal and state laws create. (shrink)

Amphibian metamorphosis is a post‐embryonic process that systematically transforms different tissues in a tadpole. Thyroid hormone plays a causative role in this complex process by inducing a cascade of gene regulation. While natural metamorphosis does not occur until endogenous thyroid hormone has been synthesized, tadpoles are competent to respond to exogenous thyroid hormone shortly after hatching. In addition, even though the metamorphic transitions of individual organs are all controlled by thyroid hormone, each occurs at distinct developmental stages. Recent (...) molecular studies suggest that this competence of premetamorphic tadpoles to respond to the hormone and the developmental stage‐dependent regulation of tissue‐specific transformations are determined in part by the levels of thyroid hormone receptors and the concentrations of cellular free thyroid hormone. In addition, at least two genes, encoding a cytosolic thyroid hormone binding protein and a 5‐deiodinase, respectively, are likely to be critical players in regulating cellular free thyroid hormone concentrations. This review discusses how all of these molecuar components coordinate to induce amphibian metamorphosis in a correct spatial and temporal manner. These studies provde us with general clues as to how and why tissues become competent to respond to hormonal signals. (shrink)

Urokinase and its receptor are essential components of the cell migration machinery, providing an inducible, transient and localized cell surface proteolytic activity. This activity has been shown to be required in normal and pathological forms of cellular invasiveness (i.e. in several embryonic developmental processes, during inflammatory responses and cancer metastasis and spreading). It represents one of the best known of the protcolytic systems which are currently under investigation in this field. The urokinase receptor allows a continuous regulation of (...) the proteolytic activity at cell contacts, utilizing the different localization of urokinase and its inhibitors. The receptor, in fact, in addition to focusing the enzymatic activity at focal and cell‐cell contacts, also regulates it by internalizing and degrading only the inhibited form of urokinase. Internalized receptor releases the ligands to the lysosomes and recycles back to surface. In this way, the proteolytically active areas of the cell surface can be continuously monitored for their activity and their location modified. The cell can thus coordinate its migration efforts with a step‐wise modification of the proteolytic activity‐map of the cell surface. The urokinase cycle can be supported by one individual cell (autocrine) or by two or more cells. In the latter case, complementation and synergism of urokinase and its receptor are found. (shrink)

It will be remembered that the introductory chapter to this paper differentiated between human therapeutic cloning and embryonic stem cell research, with the former concept encapsulating the latter one. In turning to examine the current system of regulation found within the United Kingdom this has particular relevance as it is only the practice of therapeutic cloning – the creation and use of an embryo – which engages with the regulative measures adopted.

The identification of Smad proteins as molecular components of the transforming growth factor-β (TGF-β) signaling cascade has enhanced our understanding of how ligand-mediated activation of TGF-β receptors leads to modulation of target gene transcription. Recent studies have identified a distinct, structurally related class of Smads which inhibits, rather than transduces, TGF-β family signals. The molecular mechanism of action and the exact signaling pathways that are targeted by antagonistic Smads are not completely understood. These proteins appear to participate in autoregulatory negative (...) feedback loops in which signaling initiated by specific TGF-β family ligands induces the expression of an inhibitory Smad that then functions to modulate the amplitude or duration of signaling. Negative feedback circuits such as these play important roles in fine-tuning the activity of multifunctional signaling molecules during embryonic patterning and in response to pathologic stimuli in adults. BioEssays 21:382–390, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

ABSTRACTGiven its intimate relationship with the human body and its environment, biotechnology innovation, and more particularly stem cell research innovations as a part thereof, implicate diverse social and moral/ethical issues. This paper explores some of the most important and controversial moral concerns raised by human embryonic stem cell research , focusing on concerns relating to the wellbeing of the embryo and the wellbeing of society . It then considers how and whether these concerns are dealt with in regulatory instruments (...) in Argentina, a southern developing country, examining in particular whether the values underlying these concerns have been translated into practical and effective rules reflective of the primary moral positions advanced. It concludes that Argentina's current state of stem cell research governance fails to consistently reflect the moral positions that have formed and is inadequate given Argentina's activity in this field. (shrink)

The purpose of this paper is to present a critique of the current view that reduces cancer to a cellular problem caused by specific gene mutations and to propose, instead, that such a problem might become more intelligible, if it is understood as a phenomenon that results from the breakdown of the morphological plan or Gestalt of the organism. Such and organism, in Aristotelian terms, is characterized for presenting a specific morphe or logos (form) and for having a telos (end) (...) to fulfill. A malignant tumor represents an entity separated from both the organic logos and the organic telos. According to the basic postulates of Semiophysics – a blend of Aristotelian physics and Catastrophe Theory developed by René Thom – an organism is a source (original) form individuated by a dominant pregnance that corresponds to its morphogenetic field. Here it is suggested that cancer in aged individuals might result from the progressive exhaustion of developmental constraints that regulate the process of ontogeny, that it is expected to go from the fertilized non-differentiated zygote to the mature fully developed organism, because there is no further point ahead in the developmental pathway past the reproductive age. Cancer in young individuals (before their reproductive maturity) may then be consequence of the premature derangement of such fundamental developmental constraints. In all cases the result is the loss of morphological coherence within the organism. Thus representing a conflict between an organized morphology (the organism) and a part of such a morphology that drifts towards an amorphous state (the tumor). (shrink)

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can self‐renew indefinitely and contribute to all tissue types of the adult organism. Stem cell‐based therapeutic approaches hold enormous promise for the cure of regenerative diseases. Over the last few years, several studies have attempted to decipher the important role of transcription factor networks and epigenetic regulatory signals in the maintenance of ESC pluripotency, but the exact underlying mechanisms have yet to be identified. Among the epigenetic factors, chromatin dynamics (...) and structure have been found to contribute greatly to maintenance of pluripotency and regulation of differentiation in ESCs. These modifications include: covalent histone acetylation and methylation, histone bivalents and chromatin remodeling, and DNA methylation. Studies in ESCs have shown that genes associated with early development are arranged within a bivalent chromatin structure. This is thought to be a “poised yet repressed” situation, which can be activated upon differentiation. The breakthrough of iPSCs has opened a new era in stem cell biology. During reprogramming, the chromatin state of differentiated cells is reset to an embryonic form via a largely unknown mechanism. In this review, the fundamental impact of chromatin dynamic in ESCs as well as its critical role in the generation of iPSCs is discussed. (shrink)

Regeneration in arthropods and amphibians follows an analogous principle making comparisons between the two phyla possible.Larval arthropods and amphibians possess powers of epimorphic regeneration which wane for many species of these phyla with the completion of metamorphosis or the cessation of moulting. In those species which retain, post-maturationally, the ability to form a regenerative blastema, larval characteristics are carried into the adult and reproductive stages of these organisms. These include many species of: urodeles, ametabolous insects, crustaceans, myriapods and arachnids. The (...) long-standing distinction between embryonic regulation and true epimorphosis would thus appear to be a difference of degree rather than kind. (shrink)

Embryonic development in a given species is orchestrated by genes regulating growth and differentiation in a stereotyped and conserved manner, resulting in embryos of consistent size and shape. Several signaling pathways, including that of Sonic Hedgehog (SHH), have been implicated in these processes. Recent experiments with Gas1 indicate that it may act as a growth-inducing gene, challenging its previous function as a gene specifically involved in growth arrest. Moreover, GAS1, a GPI-linked membrane protein, can bind SHH, suggesting an interacting (...) link between growth and patterning through SHH and GAS1.(1-4) BioEssays 24:22–26, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

In order to reach its full potential, human embryonic stem cell (hESC) research requires the use of human oocytes. There is currently a shortage of human eggs for research, and this shortage is likely to continue, as many states and countries prohibit their sale for research purposes, while at the same time condoning unregulated markets for oocytes for use in assisted reproduction. In this essay I first explore possible alternative sources of oocytes for hESC research and conclude that, at (...) present, women are the best source. I then examine arguments about exploitation and commodification that are often raised to prohibit payment to women for oocytes in both the reproductive and research contexts and find these arguments wanting. I conclude by suggesting that ethical concerns raised about a market in oocytes do not warrant a prohibition on the sale of eggs, but that a regulated market can consistently minimize ethical concerns while respecting women and providing important resources for advances in hESC research. (shrink)

Transposable elements are no longer considered to be “junk” DNA. Here, we review how TEs can impact gene regulation systematically. TEs encode various regulatory elements that enables them to regulate gene expression. RJ Britten and EH Davidson hypothesized that TEs can integrate the function of various transcriptional regulators into gene regulatory networks. Uniquely TEs can deposit regulatory sites across the genome when they transpose, and thereby bring multiple genes under control of the same regulatory logic. Several studies together have (...) robustly established that TEs participate in embryonic development and oncogenesis. We discuss the regulatory characteristics of TEs in context of evolution to understand the extent of their impact on gene networks. Understanding these features of TEs is central to future investigations of TEs in cellular processes and phenotypic presentations, which are applicable to development and disease studies. We re-visit the Britten–Davidson “gene-battery” model and understand the genetic and transcriptional impact of TEs in innovating gene regulatory networks. Transposable elements are exogenous sequences that have either been co-opted or repurposed for host functions. The vast amounts of TE sequence in the genome provides raw material for gene expression regulation, and still remains to be fully understood; the “gene-battery” model provides the basis for understanding this. (shrink)

Embryonic development results in animals whose body plans exhibit a variety of symmetry types. While significant progress has been made in understanding the molecular events underlying the early specification of the antero‐posterior and dorso‐ventral axes, little information has been available regarding the basis for left‐right (LR) differences in animal morphogenesis. Recently however, important advances have been made in uncovering the molecular mechanisms responsible for LR patterning. A number of genes (including well‐known signaling molecules such as Sonic hedgehog and activin) (...) are asymmetrically expressed in early chick embryos, well before the appearance of morphological asymmetries. One of these, nodal, is asymmetrically expressed in frogs and mice as well, and its expression is altered in mouse mutants exhibiting defects in laterality. In the chick, these genes regulate each other in a sequential cascade, which independently determines the situs of the heart and other organs. (shrink)

Embryonic development results in animals whose body plans exhibit a variety of symmetry types. While significant progress has been made in understanding the molecular events underlying the early specification of the antero‐posterior and dorso‐ventral axes, little information has been available regarding the basis for left‐right (LR) differences in animal morphogenesis. Recently however, important advances have been made in uncovering the molecular mechanisms responsible for LR patterning. A number of genes (including well‐known signaling molecules such as Sonic hedgehog and activin) (...) are asymmetrically expressed in early chick embryos, well before the appearance of morphological asymmetries. One of these, nodal, is asymmetrically expressed in frogs and mice as well, and its expression is altered in mouse mutants exhibiting defects in laterality. In the chick, these genes regulate each other in a sequential cascade, which independently determines the situs of the heart and other organs. (shrink)

The first stage of the human embryonic stem(ES) cell research debate revolved aroundfundamental questions, such as whether theresearch should be done at all, what types ofresearch may be done, who should do theresearch, and how the research should befunded. Now that some of these questions arebeing answered, we are beginning to see thenext stage of the debate: the battle forproperty rights relating to human ES cells. The reason why property rights will be a keyissue in this debate is simple (...) and easy tounderstand: it costs a great deal of money todo this research, to develop new products, andto implement therapies; and private companies,researchers, and health professionals requirereturns on investments and reimbursements forgoods and services. This paper considersarguments for and against property rightsrelating to ES cells defends the followingpoints: (1) It should be legal to buy and sellES cells and products. (2) It should be legalto patent ES cells, products, and relatedtechnologies. (3) It should not be legal tobuy, sell, or patent human embryos. (4) Patentson ES cells, products, and related technologiesshould not be excessively broad. (5) Patents onES cells, products, and related technologiesshould be granted only when applicants statedefinite, plausible uses for their inventions. (6) There should be a research exemption in EScell patenting to allow academic scientists toconduct research in regenerative medicine. (7)It may be appropriate to take steps to preventcompanies from using patents in ES cells,products, and related technologies only toblock competitors. (8) As the field ofregenerative medicine continues to develop,societies should revisit issues relating toproperty rights on a continuing basis in orderto develop policies and develop regulations tomaximize the social, medical, economic, andscientific benefits of ES cell research andproduct development. (shrink)

Pluripotent stem cells have gained special attraction because of their almost unlimited proliferation and differentiation capacity in vitro. These properties substantiate the potential of pluripotent stem cells in basic research and regenerative medicine. Here three types of in vitro‐cultured pluripotent stem cells (embryonic carcinoma, embryonic stem and induced pluripotent stem cells) are compared in their historical context with respect to their different origin and properties. It became evident that tumourigenicity is an inherent property of pluripotent cells based on (...) p53 down‐regulation, expression of tumour‐related genes and high telomerase activity that allow unlimited proliferation. In addition, culture‐adapted genetic and epigenetic changes may induce tumourigenicity of pluripotent cells. The use of stem cells in regenerative medicine, however, requires non‐malignant cell types and strategies that circumvent stages of malignancy. Reprogramming strategies of adult somatic cells that avoid the tumourigenic state of pluripotency may offer alternatives for future biomedical application. (shrink)

DNA methylation is a repressive epigenetic modification that is essential for development and its disruption is widely implicated in disease. Yet, remarkably, ablation of DNA methylation in transgenic mouse models has limited impact on transcriptional states. Across multiple tissues and developmental contexts, the predominant transcriptional signature upon loss of DNA methylation is the de‐repression of a subset of germline genes, normally expressed in gametogenesis. We recently reported loss of de novo DNA methyltransferase DNMT3B resulted in up‐regulation of germline genes (...) and impaired syncytiotrophoblast formation in the murine placenta. This defect led to embryonic lethality. We hypothesize that de‐repression of germline genes in the Dnmt3b knockout underpins aspects of the placental phenotype by interfering with normal developmental processes. Specifically, we discuss molecular mechanisms by which aberrant expression of the piRNA pathway, meiotic proteins or germline transcriptional regulators may disrupt syncytiotrophoblast development. (shrink)