Over the past several years, discoveries from mouse genetics have had direct impact on our understanding of vitamin A metabolism. Although the metabolism of vitamin A in the mouse does have some special features (for example very large stores of liver and pulmonary retinyl esters), the ability to construct knockout and transgenic mouse models has yielded an impressive amount of information directly relevant to understanding the general principles of vitamin A transport, storage and degradation. We discuss below (...) the metabolism of vitamin A through a number of genetically engineered mouse strains with alterations in genes that affect this metabolism. The novelty of this experimental approach is evidenced by the fact that the oldest of these strains was first reported only eight years ago.1) BioEssays 23:409–419, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Abstract.Since the gene splicing debates of the 1980s, the public has been exposed to an ongoing sequence of genetic and reproductive technologies. Many issue areas have outcomes that lose track of people's inner values or engender opposing religious viewpoints defying final resolution. This essay relocates the discussion of what is an acceptable application from the individual to the societal level, examining technologies that stand to address large numbers of people and thus call for policy resolution, rather than individual fiat, in (...) their application. A major source of guidance is the “Genetic Frontiers” series of professional dialogues and conferences held by the National Conference for Community and Justice from 2002 to 2004. Genetic testing, human gene therapy, genetic engineering of plants and animals, and stem cell technology are examined. While differences in perspective on the beginning of life persist, a stepwise approach to the examination of genetic testing reveals areas of general agreement. Stewardship of life, human co‐creativity with the divine, and social justice help define the bounds of application of genetic engineering and therapy; compassionate care plays a major role in establishing stem cell policy. Active, sustained dialogue is a useful resource for enabling sharing of religious values and crystallization of policies. (shrink)

This paper examines processes of translation through which molecular genetic technologies and practices are incorporated into environmental health research and regulation. Specifically, it considers how scientists, risk assessors, and regulators have used genetically modified mouse models to translate across scientific disciplines, articulate emergent molecular forms, standards, and practices with the extant? gold standard,? and establish roles for molecular knowledge in risk assessment and regulation. Noting variation both within and between regulatory agencies in responses to data from these models, (...) the article describes also the role of public-private networks and their effects on professional and institutional imperatives which shape regulators? responses to the potential applications of these models. The conclusions address the importance of translation for understanding the wider implications of the molecularization of environmental health science. (shrink)

There has always been great interest in animal models of human genetic disease, and mice provide the largest number of examples. A mutation in the homologous gene in mice does not always lead to the same phenotype as is found in man, however. Recent studies made it apparent that one mutation can have markedly different phenotypes when placed on different genetic backgrounds. This variation is due to different alleles at modifying loci in various inbred strains. Thus, if one wishes to (...) obtain the optimal mouse model for a human disease, one needs to choose the correct genetic background as well as the correct mutation. (shrink)

In-vivo phenotyping of genetically engineered mouse models for amyotrophic lateral sclerosis is established by combining BT-MRI and CASL G. Vanhoutte1, E. Storkebaum2, P. Carmeliet2, A. Van der Linden1.

Mouse models of human genetic disorders provide a valuable resource for investigating the pathogenesis of genetic disease and for testing potential therapies. The high degree of resolution of linkage mapping in the mouse allows mutant phenotypes to be mapped precisely which, combined with the accurate definition of areas of homology between the mouse and human genomes, greatly facilitates the identification of mouse models. We describe here mouse models of human single gene disorders dividing them into (...) three categories depending on the information available; phenotypic similarities, comparative mapping and identification of the underlying genetic lesion. (shrink)

There is an ongoing debate about genetic engineering (GE) in food production. Supporters argue that it makes crops more resilient to stresses, such as drought or pests, and should be considered by researchers as a technology to address issues of global food security, whereas opponents put forward that GE crops serve only the economic interests of transnational agrifood-firms and have not yet delivered on their promises to address food shortage and nutrient supply. To address discourse failure regarding the GE debate, (...) research needs to understand better what drives the divergent positions and which moral attitudes fuel the mental models of GE supporters and opponents. Hence, this study investigates moral attitudes regarding GE opposition and support in Germany. Results show that GE opponents are significantly more absolutist than supporters and significantly less likely to hold outcome-based views. Furthermore, GE opponents are more willing to donate for preventing GE admission than supporters are willing to donate for promoting GE admission. Our results shed light on why the divide between opponents and supporters in the German GE debate could remain stark and stable for so long. (shrink)

This paper spells out and discusses four assumptions of the deficit model type of thinking. The assumptions are: First, the public is ignorant of science. Second, the public has negative attitudes towards (specific instances of) science and technology. Third, ignorance is at the root of these negative attitudes. Fourth, the public’s knowledge deficit can be remedied by one-way science communication from scientists to citizens. It is argued that there is nothing wrong with ignorance-based explanations per se. Ignorance accounts at (...) least partially for many cases of opposition to specific instances of science and technology. Furthermore, more attention needs to be paid to the issue of relevance. In regard to the evaluation of a scientific experiment, a technology, or a product, the question is not only who knows best?, but also what knowledge is relevant and to what extent?. Examples are drawn primarily from the debate on genetic engineering in agriculture. (shrink)

Attention deficit hyperactivity disorder affects children, adolescents, and adults. Research suggests ADHD has a heritable component. The present article presents and assesses several genetic animal models of ADHD. The paper reviews the literature involving the following genetic animal models of ADHD: the spontaneously hypertensive rat ; the Wistar–Kyoto hyperactive rat; the coloboma mouse; the fast kindling rat; the acallosal mouse; the whirler mouse; and the genetically hypertensive rat. Research investigating animal models of ADHD has concentrated on (...) hyperactivity, but impulsiveness, learning, and attention are also being examined. The use of animal models allows for the control of possibly confounding variables and has proven very useful in the screening of new therapies. These models have not been shown to be the equivalent of the human disorder, and no model encompasses all of the symptoms of the human disorder, but they are useful nevertheless. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:FDA Releases Draft Guidance on Regulation of Genetically Engineered AnimalsJohn P. Gluck (bio) and Mark T. Holdsworth (bio)On 18 September 2008, the U.S. Food and Drug Administration (FDA) issued a draft set of guidelines for those involved in developing genetically engineered animals with heritable recombinant DNA (rDNA) constructs and is requesting comment from industry and the public about their content. The document does not impose (...) new regulations but details how existing laws and regulations apply to genetically engineered (GE) animals and offers advice to developers on how to negotiate the laws in the most efficient and productive manner. The draft guidance document is not legally enforceable at this juncture, but the guidelines are recommendations reflecting the FDA's "current thinking on a topic."The modification of GE animals being developed for commercialization, which are the focus of the document, fall into six categories: modifications intended to (1) enhance food quality—e.g., faster growing fish and meats with better nutritional profiles; (2) improve animal health via increased resistance to disease—e.g., mastitis in dairy cattle and Bovine Spongiform Encephalopathy (BSE); (3) create so-called "biopharm" animals capable of producing therapeutic products such as insulin, clotting factors, and tissues for human transplantation; (4) reduce the barriers to human animal interaction—e.g., hypoallergenic pets; (5) develop valid animal models of human disease—e.g., Parkinson's disease, Lesh-Nyhan's syndrome, and cancer; and (6) improve production of industrial or consumer products such as fiber. The timing of the guidelines coincides with the FDA's belief in an expected boon in the number of GE animals approaching the stage of commercialization.The FDA's involvement in the approval process emerges from the new animal drug provisions of the Federal Food Drug and Cosmetic Act and the definition of what constitutes a drug. The Act defines a new animal drug as "an article (other than food) intended to affect the structure or any function of the body of... animals." A rDNA construct intended to affect the structure or function of an animal meets the definition of a new animal drug, regardless of whether the resulting GE animals are intended for human food or the production of pharmaceuticals or any other substances. [End Page 393]Before proceeding to a review of the draft guidelines, it is important briefly to set the controversies around GE animals in historical and ethical context.The Ethical DebateFrom its inception, the intentional genetic modification or genetic engineering of molecules, plants, and animals by the techniques of gene splicing has consistently elicited strong responses from both the scientific community and the public. There are some data to suggest that although the concerns of scientists fall primarily into the category of possible biohazards, those of the public also reflect great concern about the intrinsic moral issues, such as whether there is something fundamentally wrong with this line of work, making it a form of forbidden knowledge (see, e.g., Gaskell 1997). When news of Paul Berg's attempts in 1970 to graft the primate tumor virus (SV 40) onto the intestinal tract bacteria Escherichia coli for the purpose of studying how normal cells may be transformed into cancerous cells was shared with colleagues, he was strongly encouraged to reflect on the potential public health risks if somehow the altered bacteria broke containment and entered the environment. Thanks to Berg's leadership, these concerns soon resulted in conferences held in Asilomar, California, and New Hampton, New Hampshire, where the ethical responsibilities of microbiologists involved in this research were discussed. These initial discussions resulted in what has come to be known as "The Moratorium Letter" (Shattuck 1996) published in the journal Science in 1974. This letter, signed by 11 leaders in the field, actually recommended restrictions on several types of experiments that were considered to be particularly risky and stated "that adherence to our major recommendations will entail postponement or possibly abandonment of certain types of scientifically worthwhile experiments" (Berg 1974). An international conference on the issues came to similar conclusions about the need for a research moratorium for the sake of public safety. Recommendations arising from conference participants led to the formation of the National Institutes... (shrink)

Societal evaluation of new technologies, specifically nanotechnology and genetically engineered organisms, challenges current practices of governance and science. When a governing body is confronted by a technology whose use has potential environmental risks, some form of risk analysis is typically conducted to help decision makers consider the range of possible benefits and harms posed by the technology. Environmental risk assessment is a critical component in the governance of nanotechnology and genetically engineered organisms because the uncertainties and (...) complexities surrounding these technologies pose such risk potential. However, GEOs are unique technologies, and there is widespread, international recognition that many traditional forms of ERA are not well-suited for evaluating them. Nanotechnology products are also likely to need different models of risk assessment, as there is very little information on their fate, transport, and impacts in the environment. (shrink)

Mitochondrial ATP synthesis, calcium buffering, and trafficking affect neuronal function and survival. Several genes implicated in mitochondrial functions map within the genomic region associated with 22q11.2 deletion syndrome (22q11DS), which is a key genetic cause of neuropsychiatric diseases. Although neuropsychiatric diseases impose a serious health and economic burden, their etiology and pathogenesis remain largely unknown because of the dearth of valid animal models and the challenges in investigating the pathophysiology in neuronal circuits. Mouse models of 22q11DS are becoming valid (...) tools for studying human psychiatric diseases, because they have hemizygous deletions of the genes that are deleted in patients and exhibit neuronal and behavioral abnormalities consistent with neuropsychiatric disease. The deletion of some 22q11DS genes implicated in mitochondrial function leads to abnormal neuronal and synaptic function. Herein, we summarize recent findings on mitochondrial dysfunction in 22q11DS and extend those findings to the larger context of schizophrenia and other neuropsychiatric diseases. (shrink)

We desperately need to know more of the biological details of the onset and progression of breast cancer. The disease is of startlingly high incidence (approaching 1 in 9 women), our current therapies for the disease are inadequate once it has metastasized, and the disease is characterized by excessive morbidity and mortality.Most of the growth and differentiation of the mammary gland occurs relatively late in life: during sexual maturation, and then cyclically during pregnancy and lactation. Normal as well as malignant (...) growth is regulated by endocrine hormones as well as by local tissue factors, such as polypeptide growth factors, Cancer seems to progress as hyperplastic ductal or lobular epithelial growth, acquiring progressive genetic changes (including those of oncogenes and tumor suppressor genes) leading to clonal outgrowths of progressively more malignant cells. The nature of proliferative controls and the relevant genetic changes are the subjects of the current review. (shrink)

This survey was conducted in 2017 to investigate factors influencing social risk perception of biotechnologists and plant breeders in training toward GM food based on a conceptual model. A random sample of 210 biotechnologists and plant breeders in training was studied. Confirmatory factor analysis and the reliability tests have been used to verify the uni-dimensionality of the measurement scale, SEM also was carried out to determine the most parsimonious models with the best fit for social risk perception of GM (...) foods and path analysis was conducted to understand the exogenous variables introduced in the research model. The findings revealed that the engineers in training had moderate social risk perception regarding GM foods. Moreover, the results of structural equation modeling showed the capability of the model in predicting the social risk perceptions of engineers in training. The psychological attributes of risks, social benefit perception, attitude toward using technology, level of religiosity, and moral and ethical beliefs emerged as the most powerful predictors of the social risk perception. The social benefit perception and attitude toward using technology also mediated the effects of psychological attributes of risks, level of religiosity, and moral and ethical beliefs. The social benefit perception also had an indirect influence on the engineers in training’s social risk perception of GM foods. Finally, we recommend the application of the model developed by this study for better understanding of social risk perception of stakeholders to have a more informed view of the development and promotion of GM foods. (shrink)

It has been argued that the Internet and social media increase the number of available viewpoints, perspectives, ideas and opinions available, leading to a very diverse pool of information. However, critics have argued that algorithms used by search engines, social networking platforms and other large online intermediaries actually decrease information diversity by forming so-called “filter bubbles”. This may form a serious threat to our democracies. In response to this threat others have developed algorithms and digital tools to combat filter bubbles. (...) This paper first provides examples of different software designs that try to break filter bubbles. Secondly, we show how norms required by two democracy models dominate the tools that are developed to fight the filter bubbles, while norms of other models are completely missing in the tools. The paper in conclusion argues that democracy itself is a contested concept and points to a variety of norms. Designers of diversity enhancing tools must thus be exposed to diverse conceptions of democracy. (shrink)

Online information intermediaries such as Facebook and Google are slowly replacing traditional media channels thereby partly becoming the gatekeepers of our society. To deal with the growing amount of information on the social web and the burden it brings on the average user, these gatekeepers recently started to introduce personalization features, algorithms that filter information per individual. In this paper we show that these online services that filter information are not merely algorithms. Humans not only affect the design of the (...) algorithms, but they also can manually influence the filtering process even when the algorithm is operational. We further analyze filtering processes in detail, show how personalization connects to other filtering techniques, and show that both human and technical biases are present in today’s emergent gatekeepers. We use the existing literature on gatekeeping and search engine bias and provide a model of algorithmic gatekeeping. (shrink)

The existence of a genetic program of development was proposed by molecular biologists in the nineteen-sixties. Historians and philosophers of science have since thoroughly criticized this notion. To fully appreciate its significance, it is interesting to consider the research which was pursued during this period by molecular biologists who proposed this notion. This study focuses on François Jacob's work and on the model of development supported by his lab in the early seventies, the T-complex model. This episode of (...) Jacob's scientific activity has since been forgotten. Characterization of this model shows that the notion of program was used in a metaphoric way and that it did not put any constraint on the work pursued in the lab at that time. Some attention is devoted to the origin of this metaphor in the context of the nineteen-seventies. (shrink)

The estrangement between genetic scientists and theologians originating in the 1960s is reflected in novel combinations of human thought (subject) and genes (investigational object), paralleling each other through the universal process known in chaos theory as self-similarity. The clash and recombination of genes and knowledge captures what Philip Hefner refers to as irony, one of four voices he suggests transmit the knowledge and arguments of the religion-and-science debate. When viewed along a tangent connecting irony to leadership, journal dissemination, and the (...) activities of the "public intellectual" and the public at large, the sequence of voices is shown to resemble the passage of genetic information from DNA to mRNA, tRNA, and protein, and from cell nucleus to surrounding environment. In this light, Hefner's inquiry into the voices of Zygon is bound up with the very subject matter Zygon covers. (shrink)

Patient-derived xenografts are currently promoted as new translational models in precision oncology. PDXs are immunodeficient mice with human tumors that are used as surrogate models to represent specific types of cancer. By accounting for the genetic heterogeneity of cancer tumors, PDXs are hoped to provide more clinically relevant results in preclinical research. Further, in the function of so-called “mouse avatars”, PDXs are hoped to allow for patient-specific drug testing in real-time. This paper examines the circulation of knowledge and bodily (...) material across the species boundary of human and personalized mouse model, historically as well as in contemporary practices. PDXs raise interesting questions about the relation between animal model and human patient, and about the capacity of hybrid or interspecies models to close existing translational gaps. We highlight that the translational potential of PDXs not only depends on representational matching of model and target, but also on temporal alignment between model development and practical uses. Aside from the importance of ensuring temporal stability of human tumors in a murine body, the mouse avatar concept rests on the possibility of aligning the temporal horizons of the clinic and the lab. We examine strategies to address temporal challenges, including cryopreservation and biobanking, as well as attempts to speed up translation through modification and use of faster developing organisms. We discuss how featured model virtues change with precision oncology, and contend that temporality is a model feature that deserves more philosophical attention. (shrink)

Many scientific models in biology are how-possibly models. These models depict things as they could be, but do not necessarily capture actual states of affairs in the biological world. In contemporary philosophy of science, it is customary to treat how-possibly models as second-rate theoretical tools. Although possibly important in the early stages of theorizing, they do not constitute the main aim of modelling, namely, to discover the actual mechanism responsible for the phenomenon under study. In the paper it is argued (...) that this prevailing picture does not do justice to the synthetic strategy that is commonly used in biological engineering. In synthetic biology, how-possibly models are not simply speculations or eliminable scaffolds towards a single how-actually model, but indispensable design hypotheses for a field whose ultimate goal is to build novel biological systems. The paper explicates this by providing an example from the study of alternative genetic systems by synthetic biologist Steven Benner and his group. The case will also highlight how the method of synthesis, even when it fails, provides an effective way to limit the space of possible models for biological systems. (shrink)

The zona pellucida is an extracellular coat that surrounds mammalian eggs and early embryos. This insoluble matrix separates germ from somatic cells during folliculogenesis and plays critical roles during fertilization and early development. The mouse and human zona pellucida contain three glycoproteins (ZP1 or ZPB, ZP2, ZP3), the primary structures of which have been deduced by molecular cloning. Targeted mutagenesis of endogenous mouse genes and transgenesis with human homologues provide models to investigate the roles of individual zona components. (...) Collectively, the genetic data indicate that no single mouse zona pellucida protein is obligatory for taxon‐specific sperm binding and that two human proteins are not sufficient to support human sperm binding. An observed post‐fertilization persistence of mouse sperm binding to “humanized” zona pellucida correlates with uncleaved ZP2. These observations are consistent with a model for sperm binding in which the supramolecular structure of the zona pellucida necessary for sperm binding is modulated by the cleavage status of ZP2. BioEssays 26:29–38, 2004. Published 2003 Wiley Periodicals, Inc. (shrink)

Mechanisms involved in the regulation of development and its genetic control are receiving ever‐increasing attention in studies of mammalian developmental genetics. The potential success of such studies is strongly enhanced by the availability of suitable systems of analysis. Such a system was identified in a series of radiation‐induced chromosomal deletions at and around the albino (c) locus of the mouse associated with cell type‐specific effects on liver differentiation. Their detailed study has aided the analysis of possible machanisms of cell (...) type‐specific gene expression. As summarized in this review, the experimental results strongly suggest that specific trans‐acting developmental regulatory genes are concerned with the differentiation of hormone‐inducible expression of a cluster of hepatocyte specific structural genes mapping in different parts of the genome. (shrink)

Against those who identify genealogy with reductive genealogical debunking or deny it any evaluative and action-guiding significance, I argue for the following three claims: that although genealogies, true to their Enlightenment origins, tend to trace the higher to the lower, they need not reduce the higher to the lower, but can elucidate the relation between them and put us in a position to think more realistically about both relata; that if we think of genealogy’s normative significance in terms of a (...) triadic model that includes the genealogy’s addressee, we can see that in tracing the higher to the lower, a genealogy can facilitate an evaluation of the higher element, and where the lower element is some important practical need rather than some sinister motive, the genealogy can even be vindicatory; and finally, that vindicatory genealogies can offer positive guidance on how to engineer better concepts. (shrink)

Mice with alterations to specific endogenous genes can be produced by gene targeting in embryonic stem cells. The field has developed rapidly over the past decade, so that large numbers of mice with different gene deficiencies have been generated. Knockout mice provide an ideal opportunity to analyse the function of individual mammalian genes and to model a range of human inherited disorders. This powerful approach has also identified numerous examples of gene redundancy and has highlighted the need to consider (...) metabolic differences between man and mouse in disease modelling. More sophisticated gene‐targeting methods are now being used to introduce subtle gene alterations. In the future, more refined genetic analysis and genome, rather than individual gene, alterations will be achieved by incorporating site‐specific recombination into targeting strategies. Gene targeting could also make a contribution to improved protocols for gene therapy. (shrink)

With the advent of the cloud computing model allowing a shared access to massive computing facilities, a surging demand emerges for the protection of the intellectual property tied to the programs executed on these uncontrolled systems. If novel paradigm as confidential computing aims at protecting the data manipulated during the execution, obfuscating techniques (in particular at the source code level) remain a popular solution to conceal the purpose of a program or its logic without altering its functionality, thus preventing (...) reverse-engineering on the program even with the help of computing resources. The many advantages of code obfuscation, together with its low cost, makes it a popular technique. This paper proposes a novel methodology for source code obfuscation that can be used together with other traditional obfuscation techniques, making the code more robust against reverse engineering attacks. Three program complexity metrics are used to define three different single-objective combinatorial optimization versions of the problem, which are solved and analysed. Additionally, three multi-objective problems are defined, those considering each of the selected metrics together with the program execution time, in order to avoid strong obfuscations penalizing the performance. The goal of the defined problems is to find sequences of LLVM optimizations that lead to highly obfuscated versions of the original code. These transformations are applied to the back-end pseudo-assembly code (i.e., LLVM Intermediate Representation), thus avoiding any further optimizations by the compiler. Classical genetic algorithms (GAs) are used to solve the studied problems, namely a basic cellular GA for the single-objective problems and the popular NSGA-II for the multi-objective ones. The promising results show the potential of the proposed technique. (shrink)

Polo‐like kinase 1 (PLK1) is a serine/threonine kinase that plays multiple and essential roles during the cell division cycle. Its inhibition in cultured cells leads to severe mitotic aberrancies and cell death. Whereas previous reports suggested that Plk1 depletion in mice leads to a non‐mitotic arrest in early embryos, we show here that the bi‐allelic Plk1 depletion in mice certainly results in embryonic lethality due to extensive mitotic aberrations at the morula stage, including multi‐ and mono‐polar spindles, impaired chromosome segregation (...) and cytokinesis failure. In addition, the conditional depletion of Plk1 during mid‐gestation leads also to severe mitotic aberrancies. Our data also confirms that Plk1 is completely dispensable for mitotic entry in vivo. On the other hand, Plk1 haploinsufficient mice are viable, and Plk1‐heterozygous fibroblasts do not harbor any cell cycle alterations. Plk1 is overexpressed in many human tumors, suggesting a therapeutic benefit of inhibiting Plk1, and specific small‐molecule inhibitors for this kinase are now being evaluated in clinical trials. Therefore, the different Plk1 mouse models here presented are a valuable tool to reexamine the relevance of the mitotic kinase Plk1 during mammalian development and animal physiology. (shrink)

The introduction of open source in the life sciences is increasingly being suggested as an alternative to patenting. This is an alternative, however, that takes its shape at the intersection of the life sciences and informatics. Numerous examples can be identified wherein open source in the life sciences refers to access, sharing and collaboration as informatic practices. This includes open source as an experimental model and as a more sophisticated approach of genetic engineering. The first section discusses the greater (...) flexibly in regard of patenting and the relationship to the introduction of open source in the life sciences. The main argument is that the ownership of knowledge in the life sciences should be reconsidered in the context of the centrality of DNA in informatic formats. This is illustrated by discussing a range of examples of open source models. The second part focuses on open source in synthetic biology as exemplary for the re-materialization of information into food, energy, medicine and so forth. The paper ends by raising the question whether another kind of alternative might be possible: one that looks at open source as a model for an alternative to the commodification of life that is understood as an attempt to comprehensively remove the restrictions from the usage of DNA in any of its formats. (shrink)

BackgroundClinical ethical practice (CEP) is required for healthcare workers (HCWs) to improve health-care delivery. However, there are gaps between accepted ethical standards and CEP in Ethiopia. There have been limited studies conducted on CEP in the country. Therefore, this study aimed to determine the magnitude and associated factors of CEP among healthcare workers in healthcare facilities in Ethiopia.MethodFrom February to April 2021, a mixed-method study was conducted in 24 health facilities, combining quantitative and qualitative methods. Quantitative (survey questionnaire) and qualitative (...) (semi-structured interviews) data were collected. For quantitative and qualitative data analysis, Stata version 14 and Atlas.ti version 7 were utilized. Multiple logistic regression and thematic analysis for quantative and qualitative respectively used.ResultsFrom a total of 432 study participants, 407 HCWs were involved in the quantitative analysis, 36 participants were involved in five focus group discussions (FGDs), and eleven key informant interviews (KIIs) were involved in the qualitative analysis. The score of good CEP was 32.68%. Similarly, the scores of good knowledge and attitude were 33.50% and 25.31%, respectively. In the multiple logistic regression models, satisfaction with the current profession, availability of functional CECs, compassionate leaders, previously thought clinical ethics in pre-service education and good attitude were significant factors associated with CEP. Among these significant factors, knowledge, compassionate leaders, poor infrastructure, a conducive environment and positive attitudes were also determinants of CEP according to qualitative findings.ConclusionsThe CEP in health care services in Ethiopia is low. Satisfaction with the current profession, functional CECs, positive attitude, compassionate leaders and previously thought clinical ethics were significant factors associated with CEP. The Ministry of Health (MoH) should integrate interventions by considering CECs, compassionate leadership, and positive attitudes and enhance the knowledge of health professionals. Additionally, digitalization, intersectoral collaboration and institutionalization are important for promoting CEP. (shrink)

M. xanthus has a complex multicellular lifestyle including swarming, predation and development. These behaviors depend on the ability of the cells to achieve directed motility across solid surfaces. M. xanthus cells have evolved two motility systems including Type‐IV pili that act as grappling hooks and a controversial engine involving mucus secretion and fixed focal adhesion sites. The necessity for cells to coordinate the motility systems and to respond rapidly to environmental cues is reflected by a complex genetic network involving at (...) least three complete sets of chemosensory systems and eukaryotic‐like signaling proteins. In this review, we discuss recent advances suggesting that motor synchronization results from spatial oscillations of motility proteins. We further propose that these dynamics are modulated by the action of multiple upstream complementary signaling systems. M. xanthus is thus an exciting emerging model system to study the intricate processes of directed cell migration. BioEssays 30:733–743, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The nomination of candidate genes underlying complex traits is often focused on genetic variations that alter mRNA abundance or result in non‐conservative changes in amino acids. Although inconspicuous in complex trait analysis, genetic variants that affect splicing or RNA editing can also generate proteomic diversity and impact genetic traits. Indeed, it is known that splicing and RNA editing modulate several traits in humans and model organisms. Using high‐throughput RNA sequencing (RNA‐seq) analysis, it is now possible to integrate the genetics (...) of transcript abundance, alternative splicing (AS) and editing with the analysis of complex traits. We recently demonstrated that both AS and mRNA editing are modulated by genetic and environmental factors, and potentially engender phenotypic diversity in a genetically segregating mouse population. Therefore, the analysis of splicing and RNA editing can expand not only the regulatory landscape of transcriptome and proteome complexity, but also the repertoire of candidate genes for complex traits. (shrink)

Synthetic biology is often understood in terms of the pursuit for well-characterized biological parts to create synthetic wholes. Accordingly, it has typically been conceived of as an engineering dominated and application oriented field. We argue that the relationship of synthetic biology to engineering is far more nuanced than that and involves a sophisticated epistemic dimension, as shown by the recent practice of synthetic modeling. Synthetic models are engineered genetic networks that are implanted in a natural cell environment. Their construction (...) is typically combined with experiments on model organisms as well as mathematical modeling and simulation. What is especially interesting about this combinational modeling practice is that, apart from greater integration between these different epistemic activities, it has also led to the questioning of some central assumptions and notions on which synthetic biology is based. As a result synthetic biology is in the process of becoming more “biology inspired.”. (shrink)

Synthetic biology is often understood in terms of the pursuit for well-characterized biological parts to create synthetic wholes. Accordingly, it has typically been conceived of as an engineering dominated and application oriented field. We argue that the relationship of synthetic biology to engineering is far more nuanced than that and involves a sophisticated epistemic dimension, as shown by the recent practice of synthetic modeling. Synthetic models are engineered genetic networks that are implanted in a natural cell environment. Their construction (...) is typically combined with experiments on model organisms as well as mathematical modeling and simulation. What is especially interesting about this combinational modeling practice is that, apart from greater integration between these different epistemic activities, it has also led to the questioning of some central assumptions and notions on which synthetic biology is based. As a result synthetic biology is in the process of becoming more “biology inspired.”. (shrink)

Theiler's virus is a picornavirus of mouse which causes an acute encephalomyelitis followed by a persistent infection of the white matter resulting in chronic inflammation and demyelination. This disease has been studied as a model for multiple sclerosis. Inbred strains of mice are either resistant--they clear the infection after the acute encephalomyelitis--or susceptible to persistent infection and demyelination. Susceptibility is a polygenic trait which has been analyzed using methods of association with “candidate” genes, and linkage analysis after a (...) complete genome scan. The H-2Db gene is responsible for an efficient CTL response which makes some strains resistant. Non H-2 genes responsible for the susceptibility of other strains have been mapped by linkage analysis to the Ifng and, possibly, the Mbp loci. The analysis of a set of congenic mice ruled out the possiblity that the relevant gene codes for interferon gamma, and showed that the region around Ifngprobably contains two susceptibility genes. The analysis of mutant mice showed further that the Mbp gene, which codes for the myelin basic protein, has a major effect on viral persistence. BioEssays 20:627–633, 1998. © 1998 John Wiley & Sons Inc. (shrink)

Different animal groups exhibit a surprisingly diversity of sex determination systems. Moreover, even systems that are superficially similar may utilize different underlying mechanisms. This diversity is illustrated by a comparison of sex determination in three well‐studied model organisms: the fruitfly Drosophila melanogaster, the nematode Caenorhabditis elegans, and the mouse. All three animals exhibit male heterogamety, extensive sexual dimorphism and sex chromosome dosage compensation, yet the molecular and cellular processes involved are now known to be quite unrelated. The similarities (...) must have arisen by convergent evolution. Studies of sex determination demonstrate that evolution can produce a variety of solutions to the same basic problems in development. (shrink)

Genetic engineering evokes a number of objections that are not directed at the negative effects the technique might have on the health and welfare of the modified animals. The concept of animal integrity is often invoked to articulate these kind of objections. Moreover, in reaction to the advent of genetic engineering, the concept has been extended from the level of the individual animal to the level of the genome and of the species. However, the concept of animal integrity was not (...) developed in the context of genetic engineering. Given this external origin, the aim of this paper is to critically examine the assumption that the concept of integrity, including its extensions to the level of the genome and the species, is suitable to articulate and justify moral objections more specifically directed at the genetic engineering of animals. (shrink)

Extrapolation from a well-understood base population to a less-understood target population can fail if the base and target populations are not sufficiently similar. Differences between laboratory mice and humans, for example, can hinder extrapolation in medical research. Mice that carry a partial or complete human physiological system, known as humanized mice, are supposed to make extrapolation more reliable by simulating a variety of human diseases. But what justifies our belief that these mice are similar enough to their human counterparts to (...) simulate human disease? I argue that, unless three requirements are met in the process of humanizing mice, very little does. My requirements are not meant to provide necessary and sufficient conditions that guarantee a particular outcome. Instead, they serve as a heuristic for guiding scientific judgments involving extrapolation. In developing each requirement, I engage with philosophical issues concerning the nature of model-based science and the mechanistic approach (and its limits) to making generalizations in the life sciences. (shrink)

Genetically engineered (GE) insects, such as the GE OX513A Aedes aegypti mosquitoes, have been designed to suppress their wild-type populations so as to reduce the transmission of vector-borne diseases in humans. Apart from the ecological and epidemiological uncertainties associated with this approach, such biotechnological approaches may be used by individual governments or the global community of nations to avoid addressing the underlying structural, systemic causes of those infections... We discuss here key ethical questions raised by the use of (...) GE mosquitoes, with the aim of fostering discussion between the public, researchers, policy makers, healthcare organizations, and regulatory agencies at the local, national, and international levels. We affect that goal by outlining a procedural approach to decision-making about the use of the “biotechnology” that goes beyond “community engagement.” The protocol we advocate for entails informed deliberations and decision-making at the community level. It is designed to ensure that the voices of the marginalized and vulnerable groups that would be disproportionately affected by the decision are heard during the community-wide discussions. Moreover, we make the case that the values embedded in the risk assessment should be identified so that the community can make an informed decision about the use of GE insects. In addition, we advocate for the involvement of a variety of actors whose responsibility would be to ensure that the community has the opportunity to make an informed decision based on deliberations about the use of the “biotechnology.”. (shrink)

This paper argues that the “long 1970s” (1969–1983) is an important though often overlooked period in the development of a rich landscape in the research of metabolism, development, and evolution. The period is marked by: shrinking public funding of basic science, shifting research agendas in molecular biology, the incorporation of new phenomena and experimental tools from previous biological research at the molecular level, and the development of recombinant DNA techniques. Research was reoriented towards eukaryotic cells and development, and in particular (...) towards “giant” RNA processing and transcription. We will here focus on three different models of developmental regulation published in that period: the two models of eukaryotic genetic regulation at the transcriptional level that were developed by Georgii P. Georgiev on the one hand, and by Roy Britten and Eric Davidson on the other; and the model of genetic sufficiency and evolution of regulatory genes proposed by Emile Zuckerkandl. These three cases illustrate the range of exploratory hypotheses that characterised the challenging landscape of gene regulation in the 1970s, a period that in hindsight can be labelled as transitional, between the biology at the laboratory bench of the preceding period, and the biology of genetic engineering and intensive data-driven research that followed. (shrink)

In this paper I will discuss three areas in which advances in human reproductive technology could occur, their uses and abuses, and their effects on society. First is the potential to drastically increase the success rate and availability of in vitro fertilization and embryo freezing. Second is the ability to perform biopsies on embryos prior to the onset of pregnancy. Finally, I will consider the adding or altering of genes in embryos, commonly referred to as genetic engineering.As new reproductive technologies (...) pass from experimental models into the potential for medical utilization, I believe that it will be important for lawmakers everywhere to avoid the impulse to outlaw procedures that a society believes to be unnatural at a first glance. Rather, I would hope that they can respond thoughtfully with legislation that serves two purposes — to protect the rights of couples to overcome infertility or to reduce the risk of genetic disease in their children-to-be, and more importantly, to protect children-to-be from the abuses that could result from some of the practices that I will discuss. (shrink)

Genetic engineering technologies are a subclass of the biotechnology family, and are concerned with the use of laboratory-based technologies to intervene with a given organism at the genetic level, i.e., the level of its DNA. This class of technologies could feasibly be used to treat diseases and disabilities, create disease-resistant crops, or even be used to enhance humans to make them more resistant to certain environmental conditions. However, both therapeutic and enhancement applications of genetic engineering raise serious ethical concerns. This (...) paper examines various objections to genetic engineering (as applied to humans) which have been raised in the literature, and presents a new way to frame these issues, and to look for solutions. Specifically, this paper frames genetic engineering technologies within the ‘design turn in applied ethics’ lens and thus situates these technologies as covarying with societal forces. The value sensitive design (VSD) approach to technology design is then appropriated as the conceptual framework in which genetic engineering technologies can be considered so that they can be designed for important human values. By doing so, this paper brings further nuance to the scholarship on genetic engineering technologies by discussing the sociotechnicity of genetic engineering systems rather than framing them as value-neutral tools that either support or constrain values based on how they are used. (shrink)

The “Model for Reaching Ethical Judgments in the context of Modern Technologies — the Case of Genetic Technology”, which is presented here, has arisen from the project “Ethical Criteria bearing upon Decisions taken in the field of Biotechnology”. This project has been pursued since 1991 in the Zentrum für interdisziplinäre Technikforschung (ZIT) of the Technical University of Darmstadt, with the purpose of examining decision-making in selected activities involving the production of transgenic plants that have a useful application. The (...) class='Hi'>model is the basis of an outline for interviews to investigate how far decisions concerning the development of such plants with genetic techniques take ethical criteria into account. It was necessary to design this new model because other models for reaching judgments of this kind were not conceptually suited for concrete application. This model represents a problem related approach and combines methodological with substantive typology. In this it differs from comparable models for reaching ethical judgments. (shrink)

Genetic engineering evokes a number of objections that are not directed at the negative effects the technique might have on the health and welfare of the modified animals. The concept of animal integrity is often invoked to articulate these kind of objections. Moreover, in reaction to the advent of genetic engineering, the concept has been extended from the level of the individual animal to the level of the genome and of the species. However, the concept of animal integrity was not (...) developed in the context of genetic engineering. Given this external origin, the aim of this paper is to critically examine the assumption that the concept of integrity, including its extensions to the level of the genome and the species, is suitable to articulate and justify moral objections more specifically directed at the genetic engineering of animals. (shrink)

In this review, we discuss the application of mouse models to the identification and pre‐clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large‐scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross‐species comparative ‘omics‐based approaches to this problem. We highlight recent progress in modelling late‐stage disease using (...) mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection. (shrink)

Vitalism was long viewed as the most grotesque view in biological theory: appeals to a mysterious life-force, Romantic insistence on the autonomy of life, or worse, a metaphysics of an entirely living universe. In the early twentieth century, attempts were made to present a revised, lighter version that was not weighted down by revisionary metaphysics: “organicism”. And mainstream philosophers of science criticized Driesch and Bergson’s “neovitalism” as a too-strong ontological commitment to the existence of certain entities or “forces”, over and (...) above the system of causal relations studied by mechanistic science, rejecting the weaker form, organicism, as well. But there has been some significant scholarly “push-back” against this orthodox attitude, notably pointing to the 18th-century Montpellier vitalists to show that there are different historical forms of vitalism, including how they relate to mainstream scientific practice. Additionally, some trends in recent biology that run counter to genetic reductionism and the informational model of the gene present themselves as organicist. Here, we examine some cases of vitalism in the twentieth century and today, not just as a historical form but as a significant metaphysical and scientific model. We argue for vitalism’s conceptual originality without either reducing it to mainstream models of science or presenting it as an alternate model of science, by focusing on historical forms of vitalism, logical empiricist critiques thereof and the impact of synthetic biology on current theorizing of vitalism. (shrink)

Spermatogenesis is an elaborate process involving both cell division and differentiation, and cell‐cell interactions. Defects in any of these processes can result in infertility, and in some cases these can be genetic in cause. Mapping experiments have defined at least three regions of the human Y chromosome that are required for normal spermatogenesis. Two of these contain the genes encoding the RNA binding proteins RBM and DAZ, suggesting that the control of RNA metabolism is likely to be an important control (...) point for human spermatogenesis. A similar analysis in mice has shown that at least two regions of the mouse Y chromosome are essential for spermatogenesis. Both genetic and reverse genetic approaches have been used to identify mouse autosomal genes required for spermatogenesis. These studies have shown that genes in a number of different pathways are essential for normal spermatogenesis, and also provide putative models of human infertility. (shrink)