BROADENING THE SCOPE OF DEBATES AROUND STEM CELL RESEARCH

Over the last decade, stem cell research has generated an enormous amount of public, political and bioethical debate. These debates have overwhelmingly tended to focus on two moral issues: the moral status of human embryos and the duty to care for the sick and vulnerable. This preoccupation, especially on the question of moral status, has not only dichotomized the debate around two fundamentally incommensurable positions, it has come at the cost of other important issues largely being ignored. In highlighting some of the bioethical and regulatory deficiencies of this fixation, we draw on recent developments in the experimental use of autologous adult stem cells to argue for a more inclusive approach to the ethical issues surrounding stem cell research.     

ON MORAL INCOHERENCE AND HIDDEN BATTLES: STEM CELL RESEARCH IN ARGENTINA

In this article, the authors focus on Argentina's activity in the developing field of regenerative medicine, specifically stem cell research. They take as a starting point a recent article by Shawn Harmon (published in this journal) who argues that attempts to regulate the practice in Argentina are morally incoherent. The authors try to show first, that there is no such ‘attempt to legislate’ on stem cell research in Argentina and this is due to a number of reasons that they explain. Second, by examining the role played by different values, conflicting legal and moral views, and the influence of various actors, they attempt to show that the legislative silence regarding stem cell research may not necessarily be a manifestation of a legal/moral disconnection but rather a survival strategy for navigating the long and heated battle on the moral status of the embryo and the kind of treatment it deserves.     

低分子量硫酸葡聚糖对小鼠造血干细胞动员作用的研究

给小鼠静脉注射低分子量（＜１０￣４ｕ）硫酸葡聚糖（ＤＳ）１５ｍｇ／ｋｇ后外周血中白细胞、单个核细胞（ｍｏｎｏｎｕｃｌｅａｒｃｅｋ,ＭＮＣ）、ＣＦＵ－ＧＭ、ＢＦＵ－Ｅ和ＣＦＵ－Ｍｉｘ产率等指标出现时相性变化。给药后１ｈ开始升高,２ｈ达到高峰、分别为药前值的２．２、２．６、３．８、４．４和３．０倍,７ｈ时趋向正常。给药后２ｈ上述各类细胞在外周血中的含量随着ＤＳ的剂量增加而增加。白细胞、ＭＮＣ计数在ＤＳ１８０ｍｇ／ｋｇ时达到峰值,均为对照组的４倍。２４０ｍｇ／ｋ８时未见明显增加。不同剂量ＤＳ对各系祖细胞均有不同程度的动员作用,ＤＳ剂量１５－３０ｍｇ／ｋｇ效果最好,每升血中ＣＦＵ－ＧＭ、ＢＦＵ－Ｅ、ＣＦＵ－Ｍｉｘ的数量分别相当于对照组的５．０、１１．９和８．８倍。其峰值出现时间与白细胞、ＭＮＣ不同,表明ＤＳ对不同类型细胞的作用机制也不尽一致。经口给小鼠投以ＤＳ２４０和４８ｏｍｇ／ｋｇ后,未见外周血中白细胞、ＭＮＣ计数有显著性升高,提示对造血干细胞没有动员作用。     

NO ETHICAL BYPASS OF MORAL STATUS IN STEM CELL RESEARCH

Recent advances in reprogramming technology do not bypass the ethical challenge of embryo sacrifice. Induced pluripotent stem cell (iPS) research has been and almost certainly will continue to be conducted within the context of embryo sacrifice. If human embryos have moral status as human beings, then participation in iPS research renders one morally complicit in their destruction; if human embryos have moral status as mere precursors of human beings, then advocacy of iPS research policy that is inhibited by embryo sacrifice concerns renders one morally complicit in avoidable harms to persons. Steps may be taken to address these complicity concerns, but in the final analysis there is no alternative to achieving clarity with respect to the moral status of the human embryo.     

EMERGING TECHNOLOGIES AND DEVELOPING COUNTRIES: STEM CELL RESEARCH REGULATION AND ARGENTINA

Given 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 (and the closely associated field of cloning), focusing on concerns relating to the wellbeing of the embryo and the wellbeing of society (the collective). 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.     

THE DENDRITIC CELL: ITS POTENT ROLE IN THE RESPIRATORY IMMUNE RESPONSE

The importance of the dendritic cell for the capture of antigens and initiating an immune response is now well recognized. Whereas much is known about their structure and function, their lineage is still not clear. Studiesin vitrohave demonstrated that the regulated maturation of function that occurs in culture explains many of thein vivoevents relating to antigen capture and presentation. The control over maturation and migration of these cells to the immune system is decisive as to whether an immune response is mounted or not. ‘Danger ’ signals provided by conserved bacterial products or by microenvironmental cytokines are important regulators. Dendritic cells have been clearly involved in the development of respiratory disease and our understanding of their involvement will have an impact on our future therapeutic strategies.     

PROVISION OF COMMUNITY‐WIDE BENEFITS IN PUBLIC HEALTH INTERVENTION RESEARCH: THE EXPERIENCE OF INVESTIGATORS CONDUCTING RESEARCH IN THE COMMUNITY SETTING IN SOUTH ASIA

Background: This article describes the types of community‐wide benefits provided by investigators conducting public health research in South Asia as well as their self‐reported reasons for providing such benefits. Methods: We conducted 52 in‐depth interviews to explore how public health investigators in low‐resource settings make decisions about the delivery of ancillary care to research subjects. In 39 of the interviews respondents described providing benefits to members of the community in which they conducted their study. We returned to our narrative dataset to find answers to two questions: What types of community‐wide benefits do researchers provide when conducting public health intervention studies in the community setting, and what reasons do researchers give when asked why they provided community‐wide benefits? Findings: The types of community‐wide benefits delivered were directed to the health and well‐being of the population. The most common types of benefits delivered were the facilitation of access to health care for individuals in acute medical need and emergency response to natural disasters. Respondents' self‐reported reasons when asked why they provided such benefits fell into 2 general categories: intrinsic importance and instrumental importance.     

THE RACE TOWARD ‘ETHICALLY UNIVERSALLY ACCEPTABLE’ HUMAN PLURIPOTENT (EMBRYONIC‐LIKE) STEM CELLS: ONLY A PROBLEM OF SOURCES?

Over the past few years, several proposals aimed at procuring human pluripotent (embryonic‐like) stem cells without involving the destruction of a human embryo have been proposed and widely discussed. This article focuses on a basic aspect of the debate, namely the plausibility of one or more of these new proposals being able to meet the ethical requirements that those who regard the human embryo as sacred have tried to impose on stem cells research in the last ten years. The thesis of the article is that focusing the discussion only on the sources of stem cells has prevented a full understanding of the foundation, meaning and scope of these ethical requirements. To substantiate this thesis, the article takes into consideration two issues: the first has to do with the potential of the cells obtained through some of the new approaches (iPS included), the second (and decisive) with the argument of the ‘indirect complicity’, applied to the use of ‘contaminated’ knowledge.     

DISPUTING THE ETHICS OF RESEARCH: THE CHALLENGE FROM BIOETHICS AND PATIENT ACTIVISM TO THE INTERPRETATION OF THE DECLARATION OF HELSINKI IN CLINICAL TRIALS

In this paper we argue that the consensus around normative standards for the ethics of research in clinical trials, strongly influenced by the Declaration of Helsinki, is perceived from various quarters as too conservative and potentially restrictive of research that is seen as urgent and necessary. We examine this problem from the perspective of various challengers who argue for alternative approaches to what ought or ought not to be permitted. Key themes within this analysis will examine these claims and argue they have implications for the interests of the research subject, research governance and regulation. Using our work with TREAT‐NMD, the neuromuscular clinical trials network, we posit that there is a place for advancing the discourse of moral rights and moral duties in the context of research, especially from the perspective of patients and their families, and for including the politics of patient activism and empowerment. At the same time we remain vigilant to the danger that the therapeutic misconception and other serious vulnerabilities for the patient population in clinical trials, are at risk of being overlooked.     

UNCERTAIN TRANSLATION,UNCERTAIN BENEFIT AND UNCERTAIN RISK: ETHICAL CHALLENGES FACING FIRST‐IN‐HUMAN TRIALS OF INDUCED PLURIPOTENT STEM (IPS) CELLS

The discovery of induced pluripotent stem (iPS) cells in 2006 was heralded as a major breakthrough in stem cell research. Since then, progress in iPS cell technology has paved the way towards clinical application, particularly cell replacement therapy, which has refueled debate on the ethics of stem cell research. However, much of the discourse has focused on questions of moral status and potentiality, overlooking the ethical issues which are introduced by the clinical testing of iPS cell replacement therapy. First‐in‐human trials, in particular, raise a number of ethical concerns including informed consent, subject recruitment and harm minimisation as well as the inherent uncertainty and risks which are involved in testing medical procedures on humans for the first time. These issues, while a feature of any human research, become more complex in the case of iPS cell therapy, given the seriousness of the potential risks, the unreliability of available animal models, the vulnerability of the target patient group, and the high stakes of such an intensely public area of science. Our paper will present a detailed case study of iPS cell replacement therapy for Parkinson's disease to highlight these broader ethical and epistemological concerns. If we accept that iPS cell technology is fraught with challenges which go far beyond merely refuting the potentiality of the stem cell line, we conclude that iPS cell research should not replace, but proceed alongside embryonic and adult somatic stem cell research to promote cross‐fertilisation of knowledge and better clinical outcomes.     

LINKING INTERNATIONAL RESEARCH TO GLOBAL HEALTH EQUITY: THE LIMITED CONTRIBUTION OF BIOETHICS

Health research has been identified as a vehicle for advancing global justice in health. However, in bioethics, issues of global justice are mainly discussed within an ongoing debate on the conditions under which international clinical research is permissible. As a result, current ethical guidance predominantly links one type of international research (biomedical) to advancing one aspect of health equity (access to new treatments). International guidelines largely fail to connect international research to promoting broader aspects of health equity – namely, healthier social environments and stronger health systems. Bioethical frameworks such as the human development approach do consider how international clinical research is connected to the social determinants of health but, again, do so to address the question of when international clinical research is permissible. It is suggested that the narrow focus of this debate is shaped by high‐income countries' economic strategies. The article further argues that the debate's focus obscures a stronger imperative to consider how other types of international research might advance justice in global health. Bioethics should consider the need for non‐clinical health research and its contribution to advancing global justice.     

CHARACTERIZATION OF A DINOFLAGELLATE CRYPTOCHROME BLUE‐LIGHT RECEPTOR WITH A POSSIBLE ROLE IN CIRCADIAN CONTROL OF THE CELL CYCLE1

Karenia brevis (C. C. Davis) G. Hansen et Moestrup is a dinoflagellate responsible for red tides in the Gulf of Mexico. The signaling pathways regulating its cell cycle are of interest because they are the key to the formation of toxic blooms that cause mass marine animal die‐offs and human illness. Karenia brevis displays phased cell division, in which cells enter S phase at precise times relative to the onset of light. Here, we demonstrate that a circadian rhythm underlies this behavior and that light quality affects the rate of cell‐cycle progression: in blue light, K. brevis entered the S phase early relative to its behavior in white light of similar intensity, whereas in red light, K. brevis was not affected. A data base of 25,000 K. brevis expressed sequence tags (ESTs) revealed several sequences with similarity to cryptochrome blue‐light receptors, but none related to known red‐light receptors. We characterized the K. brevis cryptochrome (Kb CRY) and modeled its three‐dimensional protein structure. Phylogenetic analysis of the photolyase/CRY gene family showed that Kb CRY is a member of the cryptochrome DASH (CRY DASH) clade. Western blotting with an antibody designed to bind a conserved peptide within Kb CRY identified a single band at ～55 kDa. Immunolocalization showed that Kb CRY, like CRY DASH in Arabidopsis, is localized to the chloroplast. This is the first blue‐light receptor to be characterized in a dinoflagellate. As the Kb CRY appears to be the only blue‐light receptor expressed, it is a likely candidate for circadian entrainment of the cell cycle.     

THE CONTRIBUTIONS OF EMPIRICAL EVIDENCE TO SOCIO‐ETHICAL DEBATES ON FRESH EMBRYO DONATION FOR HUMAN EMBRYONIC STEM CELL RESEARCH

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.     

WHAT PUTS THE ‘YUCK’ IN THE YUCK FACTOR?

The advances in biotechnology have given rise to a discussion concerning the strong emotional reaction expressed by the public towards biotechnological innovations. This reaction has been named the ‘Yuck‐factor’ by several theorists of bioethics. Leon Kass, the former chairman of the President's council on bioethics, has appraised this public reaction as ‘an emotional expression of deep wisdom, beyond reason's power fully to articulate it’. 1 Similar arguments have been forwarded by the Catholic Church, several Protestant denominations and the Pro‐Life movement. Several bioethicists have, however, opposed the idea of a disgust‐based morality. 2 Recent findings in cognitive science support the view that the strong negative emotions people often experience when faced with biotechnological ideas are not expressions of inner wisdom. The negative emotions may rather be the result of a cognitive violation the biotechnological innovations easily cause. Due to their evolutionary background, people have certain automatic and quick cognitive tendencies routinely used for categorizing and reasoning about nature, usually termed ‘folk biology’. Biotechnological processes like hybridisation and cloning clearly violate several of the cognitive rules people naturally apply for the explanation and categorization of their natural environment. As the cognitive tendencies routinely applied to the explanation of biological world are violated, an emotional response of fear, disgust and of something unnatural being underway is easily provoked. It is suggested in this paper that the reason behind the Yuck‐factor is not a deep inner wisdom, but a violation of natural human cognitive tendencies concerning the biological world.     

Stem‐cell‐based therapies for retinal degenerative diseases: Current challenges in the establishment of new treatment strategies

Various advances have been made in the treatment of retinal diseases, including new treatment strategies and innovations in surgical devices. However, the treatment of degenerative retinal diseases, such as retinitis pigmentosa (RP) and age‐related macular degeneration (AMD), continues to pose a significant challenge. In this review, we focus on the use of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to treat retinal diseases by harnessing the ability of stem cells to differentiate into different body tissues. The retina is a tissue specialized for light sensing, and its degradation leads to vision loss. As part of the central nervous system, the retina has very low regenerative capability, and therefore, treatment options are limited once it degenerates. Nevertheless, innovations in methods to induce the generation of retinal cells and tissues from ESCs/iPSCs enable the development of novel approaches for these irreversible diseases. Here we review some historical background and current clinical trials involving the use of stem‐cell‐derived retinal pigment epithelial cells for AMD treatment and stem cell‐derived retinal cells/tissues for RP therapy. Finally, we discuss our future vision of regenerative treatment for retinal diseases with a partial focus on our studies and introduce other interesting approaches for restoring vision.     

THE NEW MILITARY MEDICAL ETHICS: LEGACIES OF THE GULF WARS AND THE WAR ON TERROR

United States military medical ethics evolved during its involvement in two recent wars, Gulf War I (1990–1991) and the War on Terror (2001–). Norms of conduct for military clinicians with regard to the treatment of prisoners of war and the administration of non‐therapeutic bioactive agents to soldiers were set aside because of the sense of being in a ‘new kind of war’. Concurrently, the use of radioactive metal in weaponry and the ability to measure the health consequences of trade embargos on vulnerable civilians occasioned new concerns about the health effects of war on soldiers, their offspring, and civilians living on battlefields. Civilian medical societies and medical ethicists fitfully engaged the evolving nature of the medical ethics issues and policy changes during these wars. Medical codes of professionalism have not been substantively updated and procedures for accountability for new kinds of abuses of medical ethics are not established. Looking to the future, medicine and medical ethics have not articulated a vision for an ongoing military‐civilian dialogue to ensure that standards of medical ethics do not evolve simply in accord with military exigency.     

INTERACTIONS OF THE MIX‐LINKED β‐(1,3)/β‐(1,4)‐d‐XYLANS IN THE CELL WALLS OF PALMARIA PALMATA (RHODOPHYTA)1

Algal cell wall mechanical properties, crucial for biological functions and commercial applications, rely on interactions in macromolecular assemblies. In an effort to better understand the interactions of the matrix‐phase β‐(1,3)/(1,4)‐d ‐xylan in the edible seaweed Palmaria palmata ((L.) O. Kuntze, Rhodophyta, Palmariales), sequential extractions by saline, alkaline, and chaotropic solutions were done. The chemical composition and structure and the physicochemical properties of the isolated xylan revealed that it was partly acidic, probably due to the presence of sulfate (up to 5%) and phosphate groups (up to 4%). Although such acidity suggested ionic interactions of xylan in the cell walls, the high yields of polysaccharide extracted by alkali and particularly by 8 M urea and 4.5 M guanidium thiocyanate demonstrated that it was mainly hydrogen bonded in the cell wall. H‐bonds did not appear to be related to the mean proportions of β‐(1,3) and β‐(1,4)‐d ‐xylose linkages because these did not differ between extracts of increasing alkalinity. However, the decreasing molar weight and intrinsic viscosity of extracts obtained by alkaline solution containing a reducing agent used to prevent polysaccharide degradation suggested the presence of an alkali‐labile component in the xylan. These results are discussed with regard to the role of potential wall proteins as a means of control of these interactions.     

B‐cell acute lymphoblastic leukaemia: towards understanding its cellular origin

B‐cell acute lymphoblastic leukaemia (B‐ALL) is a clonal malignant disease originated in a single cell and characterized by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B‐cell differentiation. B‐ALL origin has been a subject of continuing discussion, given the fact that human disease is diagnosed at late stages and cannot be monitored during its natural evolution from its cell of origin, although most B‐ALLs probably start off with chromosomal changes in haematopoietic stem cells. However, the cells responsible for maintaining the disease appear to differ between the different types of B‐ALLs and this remains an intriguing and exciting topic of research, since these cells have been posited to be responsible for resistance to conventional therapies, recurrence and dissemination. During the last years this problem has been addressed primarily by transplantation of purified subpopulations of human B‐ALL cells into immunodeficient mice. The results from these different reconstitution experiments and their interpretations are compared in this review in the context of normal B‐cell developmental plasticity. While the results from different research groups might appear mutually exclusive, we discuss how they could be reconciled with the biology of normal B‐cells and propose research avenues for addressing these issues in the future.     

SYNCHRONIZED GROWTH OF THALASSIOSIRA PSEUDONANA (BACILLARIOPHYCEAE) PROVIDES NOVEL INSIGHTS INTO CELL‐WALL SYNTHESIS PROCESSES IN RELATION TO THE CELL CYCLE1

Cell‐cycle effects in phytoplankton have both general and specific influences over a variety of cellular processes. Understanding these effects requires that the majority of cells in a culture are progressing through the same cell‐cycle stage, which requires synchronous growth. We report the development of a silicon starvation–recovery synchrony for the first diatom with a sequenced genome, Thalassiosira pseudonana Hasle et Heimdale, which provides several novel insights into the process of cell‐wall formation. After 24 h of silicate starvation, flow cytometry measurements indicated that 80% of the cells were arrested in the early G1 phase of the cell cycle and then upon silicate replenishment progressed synchronously through the cycle. An early G1‐arrest point was not previously documented in diatoms. After silicate replenishment, girdle‐band synthesis was confined to a particular period in G1, and cells did not lengthen in accordance with each girdle band added, which has implications related to cell growth and separation processes in diatoms. Measurements of silicic acid uptake, intracellular pools, and silica incorporation into the cell wall, coupled with fluorescence visualization of newly synthesized cell‐wall structures, provide the first direct measurements of silica amounts in individual girdle bands and valves in a diatom. Fluorescence imaging indicated why valves in T. pseudonana do not have to reduce in size with each generation and enabled visualization of intermediates in structure formation. The development of a synchrony procedure for T. pseudonana enables correlation of cellular events with the cell cycle, which should facilitate the use of genomic information.