The principles of the 3Rs—replacement, refinement, and reduction—strongly shape discussion of methods for performing more humane animal research and the regulation of this contested area of ...technoscience. This special issue looks back to the origins of the 3Rs principles through five papers that explore how it is enacted and challenged in practice and that develop critical considerations about its future. Three themes connect the papers in this special issue. These are (1) the multiplicity of roles enacted by those who use and care for animals in research, (2) the distribution of “feelings that matter” across species and spaces of laboratory animal practice, and (3) the growing importance of “cultures of care” in animal research.
► The monstrous has been a central interpretative concept for critiques of biology. ► International functional genomics are increasingly using mutant mice. ► These complex biological sciences demand ...new forms of social scientific critique. ► The study is an ethnographic, artistic and etymological analysis of this endeavour.
Social scientific accounts identified in the biological grammars of early genomics a monstrous reductionism, ‘an example of brute life, the minimalist essence of things’ (Rabinow, 1996, p. 89). Concern about this reductionism focused particularly on its links to modernist notions of control; the possibility of calculating, predicting and intervening in the biological futures of individuals and populations. Yet the trajectories of the post genomic sciences have not unfolded in this way, challenging scientists involved in the production and integration of complex biological data and the interpretative strategies of social scientists honed in critiquing this reductionism. The post genomic sciences are now proliferating points from which to understand relations in biology, between genes and environments, as well as between species and spaces, opening up future possibilities and different ways of thinking about life. This paper explores the emerging topologies and temporalities of one form of post genomic research, drawing upon ethnographic research on international efforts in functional genomics, which are using mutant mice to understand mammalian gene function. Using vocabularies on the monstrous from Derrida and Haraway, I suggest an alternative conceptualisation of monstrosity within biology, in which the ascendancy of mice in functional genomics acts as a constant supplement to the reductionist grammars of genomics. Rather than searching for the minimalist essence of things, this form of functional genomics has become an exercise in the production and organisation of biological surplus and excess, which is experimental, corporeal and affective. The uncertain functioning of monsters in this contexts acts as a generative catalyst for scientists and social scientists, proliferating perspectives from which to listen to and engage with the mutating landscapes, forms of life, and languages of a post genomic biology.
This article explores the development of a novel biomedical research organism, and its potential to remake the species and spaces of translational medicine. The humanized mouse is a complex ...experimental object in which mice, rendered immunodeficient through genetic alteration, are engrafted with human stem cells in the hope of reconstituting a human immune system for biomedical research and drug testing. These chimeric organisms have yet to garner the same commentary from social scientists as other human–animal hybrid forms. Yet, they are rapidly being positioned as central to translational medicine in immunological research and pharmaceutical development. This article explores the complex relations between species and spaces they seek to enact. Humanizing mice simultaneously moves these animal forms towards the intimate geographies of corporeal equivalence with humans and the expansive geographies of translational research. These multiple trajectories are achieved by the way humanized mice function as both uncertain ‘epistemic things’ and as expansive ‘collaborative things’, articulating mouse genetics with other research, notably stem cell science. In the context of post-genomics, their indeterminacy is critical to their collaborative value; their expansive potential follows as much from their biological openness as from specific expectations. Yet, these new research organisms have both accumulative and disruptive capacities, for there are patterns of interference between these trajectories, remaking boundaries between experimental practices and clinical contexts.
Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between ...circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.
Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping ...array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10
) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.
▶ This was the first genome-wide association of a chronometric speed test battery. ▶ Suggestive association with variants in/near genes theoretically tied to speed. ▶ Cell junction and focal adhesion ...pathways shown to influence variation in speed. ▶ Candidate genes in focal adhesion pathway have been linked to Alzheimer's disease.
Processing speed is an important cognitive function that is compromised in psychiatric illness (e.g., schizophrenia, depression) and old age; it shares genetic background with complex cognition (e.g., working memory, reasoning). To find genes influencing speed we performed a genome-wide association scan in up to three cohorts: Brisbane (mean age 16 years; N=1659); LBC1936 (mean age 70 years, N=992); LBC1921 (mean age 82 years, N=307), and; HBCS (mean age 64 years, N=1080). Meta-analysis of the common measures highlighted various suggestively significant (p<1.21×10−5) SNPs and plausible candidate genes (e.g., TRIB3). A biological pathways analysis of the speed factor identified two common pathways from the KEGG database (cell junction, focal adhesion) in two cohorts, while a pathway analysis linked to the GO database revealed common pathways across pairs of speed measures (e.g., receptor binding, cellular metabolic process). These highlighted genes and pathways will be able to inform future research, including results for psychiatric disease.
Fluorescent zebrafish are the first genetically modified animals globally, if unevenly, circulated outside of laboratory environments. GloFish® were developed in Singapore. They are widely sold as ...popular pets in the United States, but their public sale is banned in Europe and elsewhere. On the trail of these animals, I trace a fragmentary biogeography through ethnographic encounters in the spaces of scientific research, animal exhibits, pet stores, and art galleries, in Europe, the USA, and Singapore. At each site, as the colour, light, and intensities of neon flicker with the potential for life, and concern for animal lives move in and out of focus, I ask: what is the proper way of knowing and living with genetically altered zebrafish? To ask the question is to open up a conversation about the changing constitution of science and space, representation, and reproduction in relation to these new forms of life. To try to answer it demands attention to a baroque patterning of scientific practices, aesthetic sensibilities, ethical responsibilities, and political spatialities. In a discursive arena typically characterised by narratives of linearity—whether of scientific progress or slippery slopes—I suggest the affective sensibilities, theatrical qualities, and unresolved elements of the baroque offer powerful, if ambivalent, resources for reflection on the intersection between the animating aesthetics and turbulent ethics of postgenomic life.
Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common ...genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.
Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic ...loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.
A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.
Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.
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