Pierre Duhem’s epistemic aims and the intellectual virtue of humility: a reply to Ivanova

David Stump (2007) has recently argued that Pierre Duhem can be interpreted as a virtue epistemologist. Stump’s claims have been challenged by Milena Ivanova (2010) on the grounds that Duhem’s ‘epistemic aims’ are more modest than those of virtue epistemologists. I challenge Ivanova’s criticism of Stump by arguing that she not distinguish between ‘reliabilist’ and ‘responsibilist’ virtue epistemologies. Once this distinction is drawn, Duhem clearly emerges as a ‘virtue-responsibilist’ in a way that complements Ivanova’s positive proposal that Duhem’s ‘good sense’ reflects a conception of the ‘ideal scientist’. I support my proposal that Duhem is a ‘virtue-responsibilist’ by arguing that his rejection of the possibility of our producing a ‘perfect theory’ reflects the key responsibilist virtue of ‘intellectual humility’.     

The Making of Modern Science: Science,Technology, Medicine and Modernity: 1789–1914

We offer a novel historical-philosophical framework for discussing experimental practice which we call ‘Generating Experimental Knowledge’. It combines three different perspectives: experimental systems, concept formation, and the pivotal role of error. We then present an historical account of the invention of the Scanning Tunnelling Microscope (STM), or Raster-Tunnelmikroskop, and interpret it within the proposed framework. We show that at the outset of the STM project, Binnig and Rohrer—the inventors of the machine—filed two patent disclosures; the first is dated 22 December 1978 (Switzerland), and the second, two years later, 12 September 1980 (US). By studying closely these patent disclosures, the attempts to realize them, and the subsequent development of the machine, we present, within the framework of generating experimental knowledge, a new account of the invention of the STM. While the realization of the STM was still a long way off, the patent disclosures served as blueprints, marking the changes that had to be introduced on the way from the initial idea to its realization.     

Common variants near MC4R are associated with fat mass, weight and risk of obesity

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.     

Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy

Digital clubbing, recognized by Hippocrates in the fifth century BC, is the outward hallmark of pulmonary hypertrophic osteoarthropathy, a clinical constellation that develops secondary to various acquired diseases, especially intrathoracic neoplasm. The pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood, but a clinically indistinguishable primary (idiopathic) form of hypertrophic osteoarthropathy (PHO) is recognized. This familial disorder can cause diagnostic confusion, as well as significant disability. By autozygosity methods, we mapped PHO to chromosome 4q33-q34 and identified mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation. Homozygous individuals develop PHO secondary to chronically elevated prostaglandin E(2) levels. Heterozygous relatives also show milder biochemical and clinical manifestations. These findings not only suggest therapies for PHO, but also imply that clubbing secondary to other pathologies may be prostaglandin mediated. Testing for HPGD mutations and biochemical testing for HPGD deficiency in patients with unexplained clubbing might help to obviate extensive searches for occult pathology.     

High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi

Isolates of Salmonella enterica serovar Typhi (Typhi), a human-restricted bacterial pathogen that causes typhoid, show limited genetic variation. We generated whole-genome sequences for 19 Typhi isolates using 454 (Roche) and Solexa (Illumina) technologies. Isolates, including the previously sequenced CT18 and Ty2 isolates, were selected to represent major nodes in the phylogenetic tree. Comparative analysis showed little evidence of purifying selection, antigenic variation or recombination between isolates. Rather, evolution in the Typhi population seems to be characterized by ongoing loss of gene function, consistent with a small effective population size. The lack of evidence for antigenic variation driven by immune selection is in contrast to strong adaptive selection for mutations conferring antibiotic resistance in Typhi. The observed patterns of genetic isolation and drift are consistent with the proposed key role of asymptomatic carriers of Typhi as the main reservoir of this pathogen, highlighting the need for identification and treatment of carriers.     

Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.     

Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA

The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.     

Testing testimony: toxicology and the law of evidence in early nineteenth-century England

Examines how, when confronted with a case of possible criminal poisoning, early-19th-century English toxicologists sought to generate and to represent their evidence in the courtroom. Contends that in both these activities, toxicologists were inextricably engaged in a complex communicative exercise. On the one hand, they distanced themselves from the instabilities of language, styling themselves as testifiers to fact alone. At the same time, they saw themselves as deeply implicated in the difficulties of forging a coherent signifying system out of a disparate collection of signs that in themselves bore no intrinsic meaning. The article suggests first, why criminal poisoning featured so prominently in the burgeoning legal literature on evidence, which provided the framework for expert testimony in English courts; next, that the scientific evidence offered by toxicologists in poisoning cases can be usefully understood as a form of (unstable) language; and finally, that this recourse to signs informed the toxicologist's encounter with another type of courtroom expert - the legal advocate - who was equally (though differently) interested in manipulating signs in order to construct (and deconstruct) legally sanctioned proof.