Volume 20, Issue 10, October 2020, Page 44-47.

BackgroundHIV molecular epidemiology is increasingly recognized as a vital source of information for understanding HIV transmission dynamics. Despite extensive use of these data-intensive techniques in both research and public health settings, the ethical issues associated with this science have received minimal attention. As the discipline evolves, there is reasonable concern that existing ethical and legal frameworks and standards might lag behind the rapid methodological developments in this field. This is a follow-up on our earlier work that applied a (...) predetermined analytical framework to examine the perspectives of a sample of scientists from the fields of epidemiology, public health, virology and bioethics on key ethical issues associated with HIV molecular epidemiology in HIV network research.MethodsFourteen in-depth interviews were conducted with scientists from the fields of molecular epidemiology, public health, virology and bioethics. Inductive analytical approaches were applied to identify key themes that emerged from the data.ResultsOur interviewees acknowledged the potential positive impact of molecular epidemiology in the fight against HIV. However, they were concerned that HIV phylogenetics research messages may be incorrectly interpreted if not presented at the appropriate level. There was consensus that HIV phylogenetics research presents a potential risk to privacy, but the probability and magnitude of this risk was less obvious. Although participants acknowledged the social value that could be realized from the analysis of HIV genetic sequences, there was a perceived fear that the boundaries for use of HIV sequence data were not clearly defined.ConclusionsOur findings highlight distinct ethical issues arising from HIV molecular epidemiology. As the discipline evolves and HIV sequence data become increasingly available, it is critical to ensure that ethical standards keep pace with biomedical advancements. We argue that the ethical issues raised in this study, whether real or perceived, require further conceptual and empirical examination. (shrink)

In the last decades, Systems Biology (including cancer research) has been driven by technology, statistical modelling and bioinformatics. In this paper we try to bring biological and philosophical thinking back. We thus aim at making diferent traditions of thought compatible: (a) causality in epidemiology and in philosophical theorizing—notably, the “sufcient-component-cause framework” and the “mark transmission” approach; (b) new acquisitions about disease pathogenesis, e.g. the “branched model” in cancer, and the role of biomarkers in this process; (c) the burgeoning of (...) omics research, with a large number of “signals” and of associations that need to be interpreted. In the paper we summarize frst the current views on carcinogenesis, and then explore the relevance of current philosophical interpretations of “cancer causes”. We try to ofer a unifying framework to incorporate biomarkers and omic data into causal models, referring to a position called “evidential pluralism”. According to this view, causal reasoning is based on both “evidence of diference-making” (e.g. associations) and on “evidence of underlying biological mechanisms”. We conceptualize the way scientists detect and trace signals in terms of information transmission, which is a generalization of the mark transmission theory developed by philosopher Wesley Salmon. Our approach is capable of helping us conceptualize how heterogeneous factors such as micro and macro-biological and psycho-social—are causally linked. This is important not only to understand cancer etiology, but also to design public health policies that target the right causal factors at the macro-level. (shrink)

It is estimated that typhoid fever (TF) annually affects more than 12 million persons, worldwide. TF is the result of a generalized infection by the enterobacterium Salmonella typhi. Patients with TF, most of whom live in developing countries have impaired activity for several weeks resulting in an important loss in productivity and welfare. Death may occur, with the single most frequent cause being intestinal perforation. While the first priority must be to develop better methods of disease prevention, there is also (...) an urgent need to devise easy, accurate, and inexpensive diagnostic assays that will allow early routine distinction of TF from other febrile illnesses. Research on TF offers the opportunity to explore many aspects of pathogenesis and the host immune response, as well as to contribute toward the development of new vaccines and diagnostic laboratory tests. (shrink)

In current philosophical discussions on evidence in the medical sciences, epidemiology has been used to exemplify a specific version of evidential pluralism. According to this view, known as the Russo–Williamson Thesis, evidence of both difference-making and mechanisms is produced to make causal claims in the health sciences. In this paper, I present an analysis of data and evidence in epidemiological practice, with a special focus on research on the exposome, and I cast doubt on the extent to which evidential (...) pluralism holds in this case. I start by focusing on the claim that molecular data allows for the production of mechanistic evidence. On the basis of a close look at the ways in which molecular data is used in exposome research, I caution against interpretations in terms of mechanistic evidence. Secondly, I expand my critical remarks on the thesis by addressing the conditions under which data is categorised as evidence in exposome research. I argue that these show that the classification of a dataset as a type of evidence is dependent on the ways in which the data is used. This is in contrast with the approach of evidential pluralism, where evidence is classified in different types on the basis of its intrinsic properties. Finally, I come back to what I consider the core of the thesis and suggest that the epidemiological research analysed in the paper indicates different interpretations of evidential pluralism and its applicability in the health sciences. (shrink)

New data of recent researches on genetics and epidemiology imply the idea of rapidly evolving viruses through DNA recombination, which leads to the establishment of new virus families, eventually adapted to the environmental conditions. Consequently the framework of the epidemiological studies widens, replacing the classic aspect of the bilateral virus—host coexistence.An holistic evolutionary approach, considering all the complex interrelationship among viruses, parasites and hosts, in conjugation with the environmental changes is developing.Molecular epidemiology and updated population models renew (...) the health strategy bringing together experts from the fields of population biology, evolution and infectious diseases.The related ethical issues, which consequently emerge should be faced accordingly. (shrink)

Frederick Griffith was an English bacteriologist at the Pathological Laboratory of the Ministry of Health in London who believed that progress in the epidemiology and control of infectious diseases would come only with more precise knowledge of the identity of the causative microorganisms. Over the years, Griffith developed and expanded a serological technique for identifying pathogenic microorganisms, which allowed the tracing of the sources of infectious disease outbreaks: slide agglutination. Yet Griffith is not remembered for his contributions to the (...) biology and epidemiology of infectious diseases so much as for discovering the phenomenon known as ‘transformation’. Griffith’s discovery, for many, was a pure case of serendipity whose biological relevance had also largely escaped him. In this paper, I argue that the key to understanding the significance of bacterial transformation – and the scientific legacy of Fred Griffith – rests not only on it initiating a cascade of events leading to molecular genetics but also on its implications for epidemiology based on the biology of host–parasite interactions. Looking at Griffith’s entire career, instead of focusing only on the transformation study, we can better appreciate the place of the latter within Griffith’s overall contributions. Presented in this way, Griffith’s experiment on bacterial transformation also ceases to appear as an anomaly, which in turn leads us to rethink some of the most prevalent historical conceptions about his work. (shrink)

It is estimated that 300,000 children 0–14 years of age are diagnosed with cancer worldwide each year. While the absolute risk of cancer in children is low, it is the leading cause of death due to disease in children in high‐income countries. In spite of this, the etiologies of pediatric cancer are largely unknown. Environmental exposures have long been thought to play an etiologic role. However, to date, there are few well‐established environmental risk factors for pediatric malignancies, likely due to (...) technical barriers in collecting biological samples prospectively in pediatric populations for direct measurements. In this review, we propose the use of novel or underutilized biospecimens (dried blood spots and teeth) and molecular approaches for exposure assessment (epigenetics, metabolomics, and somatic mutational profiles). Future epidemiologic studies of pediatric cancer should incorporate novel exposure assessment methodologies, data on molecular features of tumors, and a more complete assessment of gene‐environment interactions. (shrink)

Since the second half of the twentieth century, biomedical research has made increasing use of epidemiological methods to establish empirical evidence on a population level. This paper is about practices with data in epidemiological research, based on a case study in Denmark. I propose an epistemology of record linkage that invites exploration of epidemiological studies as heterogeneous assemblages. Focusing on data collecting, sampling and linkage, I examine how data organisation and processing become productive beyond the context of their collection. The (...) case study looks at how a local population database established in 1976 to investigate possibilities for the prevention of cardiovascular disease is used thirty years later to test hypotheses on the aetiology of breast cancer. For two breast cancer investigations based on the same core data set, I follow the underlying record linkage practice and describe how research objects such as molecular markers become relevant with respect to public health through information networking. Epidemiological association studies function as tools that performatively enrol different contexts into statistical risk estimation, thereby configuring options for research as well as for clinical testing and public health policy. (shrink)

This case for discussion highlights some of the ethical difficulties that may arise in the use of molecular typing techniques in the control of infectious diseases. Molecular typing techniques offer evidence (stronger than regular epidemiological exploration of sources and contacts) for claims about infection routes. Such evidence will mean that public health authorities need to think about how to respond ethically to causal responsibility for contagion. In this context, questions are raised about the use of molecular typing (...) methods for source and contact tracing in the control of infectious diseases. (shrink)

The two significant zoonotic bacterial infections that have remained a concern due to the complex dynamics involved in transmission and global prevalence are anthrax and brucellosis. The present paper attempts to address some of the most important zoonotic pathogens, highlighting their epidemiology, clinical manifestations, diagnosis, treatment, and prevention strategies. Anthrax is largely transmitted through direct contact with the infected animals or their products resulting in cutaneous, inhalational, and gastrointestinal forms, all with specific clinical outcomes and approaches for treatment. Similarly, (...) the genus Brucella primarily transmits brucellosis to humans by occupational exposure and consumption of contaminated animal products. Its presentation may be acute, chronic, or in relapse. Diagnosis is made by a combination of serological, molecular, and culture-based techniques, while the treatment focuses on antimicrobial regimens specific to the pathogen. However, this increases the problem of antimicrobial resistance, which makes their effective management challenging, necessitating an integrated approach. Mitigating risks through biosecurity measures, vaccination, public health education, and a One Health approach that includes human, animal, and environmental health, all facilitate prevention and control of an outbreak. Advanced surveillance and diagnostic technologies further support the prompt interventions to contain outbreaks. It then goes on to highlight the importance of interdisciplinarity for decreasing the global burden of zoonotic bacterial diseases. (shrink)

The contribution of inherited non‐genetic factors to complex diseases is of great current interest. The ways in which mothers and fathers can affect their offspring's health clearly differ as a result of the intimate interactions between mother and offspring during pre‐ and postnatal life. There is, however, potential for some overlap in mechanisms, particularly epigenetic mechanisms. A small number of epidemiological studies and animal models have investigated the non‐genetic contribution of the parents to offspring health. Discovering new mechanisms of disease (...) inheritance is technically difficult, especially in genetically, socially and environmentally heterogeneous human populations. Therefore, rigorous experimental design, appropriate sample numbers and the use of high‐throughput technologies are necessary to provide convincing evidence. Based on recent examples from the literature, here we propose several ways to improve human studies that aim to identify the underlying mechanisms of transgenerational inheritance of metabolic disease. (shrink)

Current research in molecular epidemiology uses biomarkers to model the different disease phases from environmental exposure, to early clinical changes, to development of disease. The hope is to get a better understanding of the causal impact of a number of pollutants and chemicals on several diseases, including cancer and allergies. In a recent paper Russo and Williamson address the question of what evidential elements enter the conceptualisation and modelling stages of this type of biomarkers research. Recent research in (...) causality has examined Ned Hall’s distinction between two concepts of causality: production and dependence. In another recent paper, Illari examined the relatively under-explored production approach to causality, arguing that at least one job of an account of causal production is to illuminate our inferential practices concerning causal linking. Illari argued that an informational account solves existing problems with traditional accounts. This paper follows up this previous work by investigating the nature of the causal links established in biomarkers research. We argue that traditional accounts of productive causality are unable to provide a sensible account of the nature of the causal link in biomarkers research, while an informational account is very promising. (shrink)

Epidemiological evidence supports a health‐promoting effect of the Mediterranean Diet (MedDiet), especially in the prevention of cardiovascular diseases. These cardiovascular benefits have been attributed to a number of components of the MedDiet such as monounsaturated fatty acids, antioxidant vitamins and phytochemicals. However, the underlying mechanisms remain unknown. Likewise, little is known about the genes that define inter‐individual variation in response to the MedDiet, although the TCF7L2 gene is emerging as an illustrative candidate for determining relative risk of cardiovascular events in (...) response to the MedDiet. Moreover, omics technologies are providing evidence supporting potential mechanisms, some of them implicating epigenetics (i.e. microRNAs, methylation), and certain data suggest that some traditional foods could contribute via microRNAs possibly acting as exogenous regulators of gene expression. Future research should aim at increasing and consolidating the nutrigenetic and nutrigenomic knowledge of the MedDiet in order to provide sound, personalized and optimized nutritional recommendations. (shrink)

Large part of contemporary science is in fact technoscience, in the sense that it crucially depends on several technologies for the generation, collection, and analysis of data. This prompts a re-examination of the relations between science and technologies. In this essay, I advance the view that we’d better move beyond the ‘subordination view’ and the ‘instrumental’ view. The first aims to establish the primacy of science over technology, and the second uses technology instrumentally to support a realist position about theoretical (...) entities. I suggest that we should instead concentrate on how science and technology interact. This will reveal that technology has a poietic character, namely it actively partakes in the production of knowledge. But this poietic character can only be understood within the cognitive activity of scientific communities. Current research in molecular epidemiology, notably the projects funded within the ‘European exposome initiative’, serves as a motivation for such discussion and as an illustration of the claims made. (shrink)

Antibiotic resistance in bacteria has become a great threat to global public health. Tigecycline is a next‐generation tetracycline that is the final line of defense against severe infections by pan‐drug‐resistant bacterial pathogens. Unfortunately, this last‐resort antibiotic has been challenged by the recent emergence of the mobile Tet(X) orthologs that can confer high‐level tigecycline resistance. As it is reviewed here, these novel tetracycline destructases represent a growing threat to the next‐generation tetracyclines, and a basic framework for understanding the molecular (...) class='Hi'>epidemiology and resistance mechanisms of them is presented. However, further large‐scale epidemiological and functional studies are urgently needed to better understand the prevalence and dissemination of these newly discovered Tet(X) orthologs among Gram‐negative bacteria in both human and veterinary medicine. (shrink)

The environment can elicit biological responses such as oxidative stress (OS) and inflammation as a consequence of chemical, physical, or psychological changes. As population studies are essential for establishing these environment-organism interactions, biomarkers of OS or inflammation are critical in formulating mechanistic hypotheses. By using examples of stress induced by various mechanisms, we focus on the biomarkers that have been used to assess OS and inflammation in these conditions. We discuss the difference between biomarkers that are the result of a (...) chemical reaction (such as lipid peroxides or oxidized proteins that are a result of the reaction of molecules with reactive oxygen species) and those that represent the biological response to stress, such as the transcription factor NRF2 or inflammation and inflammatory cytokines. The high-throughput and holistic approaches to biomarker discovery used extensively in large-scale molecular epidemiological exposome are also discussed in the context of human exposure to environmental stressors. We propose to consider the role of biomarkers as signs and to distinguish between signs that are just indicators of biological processes and proxies that one can interact with and modify the disease process. (shrink)

This is an ethnographic exploration into the meanings of contaminated blood. Intense commercial harvesting of human plasma, a blood component, in rural central China during the 1990s resulted in extensive HIV infection among donors. The lack of viral diversity among these infected donors, as revealed by research in molecular epidemiology, confirms that this epidemic took hold and spread rapidly with deadly efficiency through unsanitary plasmapheresis. The distinction in viral strains between this epidemic and the spread of HIV via (...) other routes of transmission in other parts of China serves also to promote claims to victimhood by infected rural commercial donors in the ambiguous geography of moral ambivalence towards carriers of the virus. Through a series of vignettes from field research among rural plasma donors in China, this article examines the tensions between solidarity and distinction, victimhood and responsibility, alliance and strife as they play out in meanings derived from contaminated blood, within their everyday experience and also within their participation in the broader HIV/aids activism, in which their distinction is inevitably challenged. (shrink)

The reduced costs of DNA sequencing and the use of such data for HIV‐1 clinical management and phylogenetic analysis have led to a massive increase of HIV‐1 sequences in the last few years. Phylogenetic analysis has shed light on the origin, spread and characteristics of HIV‐1 epidemics and outbreaks. Phylogenetic analysis is now also being used to advance our knowledge of the drivers of HIV‐1 transmission in order to design effective interventions. However, HIV phylogenetic analysis presents unique ethical challenges, which (...) have not been fully explored. This review presents an analysis of what appear to be key ethical issues in HIV phylogenetics in the hope of stimulating further conceptual and empirical work in this rapidly emerging area. We structure the review using the Emanuel Framework, a systematic, holistic framework, which has been adapted for use in developing countries, which bear the brunt of the HIV‐1 pandemic. (shrink)

Numerous clinical, epidemiological and molecular findings link some types of Human Papillomaviruses (HPV) with cancer of the genital tract. They share a common pathway of transformation with a number of DNA tumour viruses, such as Adenovirus and SV40. Although all these viruses are termed ‘DNA tumour viruses’ and have similar in vitro transforming activities, Human Papillomavirus is the only one so far clearly involved in human cancer. Extensive studies on HPV E6 and E7 proteins have demonstrated their involvement in (...) malignant transformation. E6 and E7 bind the products of tumour suppressor genes, p53 and Rb1, respectively, modifying or inactivating their normal functions. The Rb1 and p53 genes are deleted or mutated in several cancers and both proteins regulate the transcription of genes involved in cell cycle progression control. The E6/p53 and E7/Rb1 interactions result in a deregulation of the cell cycle with loss of control of crucial cellular events, such as DNA replication, DNA repair and apoptosis. (shrink)

This book explores a variety of conceptual and methodological questions about cancer and cancer research: Is cancer one disease, or many? If many, how many exactly? How is cancer classified? What does it mean, exactly, to say that cancer is “genetic,” or “familial”? What exactly are the causes of cancer, and how do scientists come to know about them? When do we have good reason to believe that this or that is a risk factor for cancer? How is cancer a (...) product or byproduct of multilevel evolution? Is cancer research unified? What sort of models, or theories, govern cancer research? This book takes a close look at these philosophical questions, by examining work in disciplines as diverse as cell and molecular biology, epidemiology, clinical medicine, and evolutionary biology. (shrink)

Precision medicine and molecular systems medicine (MSM) are highly utilized and successful approaches to improve understanding, diagnosis, and treatment of many diseases from bench-to-bedside. Especially in the COVID-19 pandemic, molecular techniques and biotechnological innovation have proven to be of utmost importance for rapid developments in disease diagnostics and treatment, including DNA and RNA sequencing technology, treatment with drugs and natural products and vaccine development. The COVID-19 crisis, however, has also demonstrated the need for systemic thinking and transdisciplinarity and (...) the limits of MSM: the neglect of the bio-psycho-social systemic nature of humans and their context as the object of individual therapeutic and population-oriented interventions. COVID-19 illustrates how a medical problem requires a transdisciplinary approach in epidemiology, pathology, internal medicine, public health, environmental medicine, and socio-economic modeling. Regarding the need for conceptual integration of these different kinds of knowledge we suggest the application of general system theory (GST). This approach endorses an organism-centered view on health and disease, which according to Ludwig von Bertalanffy who was the founder of GST, we call Organismal Systems Medicine (OSM). We argue that systems science offers wider applications in the field of pathology and can contribute to an integrative systems medicine by (i) integration of evidence across functional and structural differentially scaled subsystems, (ii) conceptualization of complex multilevel systems, and (iii) suggesting mechanisms and non-linear relationships underlying the observed phenomena. We underline these points with a proposal on multi-level systems pathology including neurophysiology, endocrinology, immune system, genetics, and general metabolism. An integration of these areas is necessary to understand excess mortality rates and polypharmacological treatments. In the pandemic era this multi-level systems pathology is most important to assess potential vaccines, their effectiveness, short-, and long-time adverse effects. We further argue that these conceptual frameworks are not only valid in the COVID-19 era but also important to be integrated in a medicinal curriculum. (shrink)

Written for non-experts, this volume introduces the mechanisms that underlie reticulate evolution. Chapters are either accompanied with glossaries that explain new terminology or timelines that position pioneering scholars and their major discoveries in their historical contexts. The contributing authors outline the history and original context of discovery of symbiosis, symbiogenesis, lateral gene transfer, hybridization or divergence with gene flow, and infectious heredity. By applying key insights from the areas of molecular (phylo)genetics, microbiology, virology, ecology, systematics, immunology, epidemiology and (...) computational science, they demonstrate how reticulate evolution impacts successful survival, fitness and speciation. Reticulate evolution brings forth a challenge to the standard Neo-Darwinian framework, which defines life as the outcome of bifurcation and ramification patterns brought forth by the vertical mechanism of natural selection. Reticulate evolution puts forward a pattern in the tree of life that is characterized by horizontal mergings and lineage crossings induced by symbiosis, symbiogenesis, lateral gene transfer, hybridization or divergence with gene flow, and infective heredity, making the “tree of life” look more like a “web of life.” On an epistemological level, the various means by which hereditary material can be transferred horizontally challenges our classic notions of units and levels of evolution, fitness, modes of transmission, linearity, communities, and biological individuality. The case studies presented examine topics including the origin of the eukaryotic cell and its organelles through symbiogenesis; the origin of algae through primary and secondary symbiosis and dinoflagellates through tertiary symbiosis; the superorganism and holobiont as units of evolution; how endosymbiosis induces speciation in multicellular life forms; transferrable and non-transferrable plasmids and how they symbiotically interact with their host; the means by which pro- and eukaryotic organisms transfer genes laterally (bacterial transformation, transduction and conjugation as well as transposons and other mobile genetic elements); hybridization and divergence with gene flow in sexually-reproducing individuals; current (human) microbiome and viriome studies that impact our knowledge concerning the evolution of organismal health and acquired immunity; and how symbiosis and symbiogenesis can be modelled in computational evolution. (shrink)

The catch 22 situation in psychiatry is that for precise diagnostic categories/criteria, we need precise investigative tests, and for precise investigative tests, we need precise diagnostic criteria/categories; and precision in both diagnostics and investigative tests is nonexistent at present. The effort to establish clarity often results in a fresh maze of evidence. In finding the way forward, it is tempting to abandon the scientific method, but that is not possible, since we deal with real human psychopathology, not just concepts to (...) speculate over. Search for clear-cut definitions/diagnostic criteria in psychiatry must be relentless. There is a greater need to be ruthless and blunt in this, rather than being accommodative of diverse opinions. Investigative tests - psychological, serum, CSF, or neuroimaging - are only corroborative at present; they need to become definitive. Medicalisation appears most prominent in psychiatry; so, diagnostic proliferation and fuzziness appear inevitable. And yet, the established diagnostic entities need to forward greater and conclusive precision. Also, the need for clarity and precision must outweigh pandering to and mollifying diverse interests, moreso in the upcoming revision of diagnostic manuals. This is specially because the DSM-5, being an Association manual, may need to accommodate powerful member lobbies; and ICD-11 may similarly need to cater to diverse country lobbies. Finding precise biological correlates of psychiatric phenomena, whether through neuroimaging, molecular neurobiology and/or neurogenomics, is the right way forward. It is in the 1.5-kg structure in the cranium that all secrets of psychiatric conditions lie. Social forces, behavioural modification, psychosocial restructuring, study of intrapsychic processes, and philosophical insights are not to be discounted, but they are supplementary to the primary goal - studying and deciphering those brain processes that result in psychiatric malfunction. Experimental breakthroughs, both in psychiatric aetiology and therapeutics, will come mainly from biology and its adjunct, psychopharmacology; while supplementary and complementary breakthroughs will come from the psychosocial, cognitive and behavioural approaches; the support base will come from phenomenology, epidemiology, nosology and diagnostics; while insights and leads can hopefully come from many fields, especially the psychosocial, the behavioural, the cognitive and the philosophical. Major energies must now be marshalled towards finding biomarkers and deciphering the precise phenotype-genotype-endophenotype axis of psychiatric disorders. Energies also need to be focussed on unravelling those critical processes in the brain that tip the scale towards psychiatric disorders. At how those critical processes are set into motion by forces de novo, in utero, in the genes and their expression, by the environment's psychopathological social forces - stress, peer pressure, poverty, deprivation, alienation, malnutrition, discrimination of various types (caste, gender, race, etc.), mass conflicts (war, terror attacks, etc.), disasters (natural and man-made), religious/ideological fascism - or social institutions like marriage, family, work place, political governance, etc. Ultimately, we must decipher how the brain goes into malfunction when such varied forces impinge on it, which precise cortical areas and neuronal cellular and molecular processes are involved in such malfunction and its manifestation, as also which of these are involved when malfunction ceases and health is restored, and the psychosocial processes and institutions which aid such health restoration, as also those which promote well-being and help in primary prevention. Emphasis on the brain and its intimate neurological and molecular mechanisms will not impinge on, or nullify, importance of the 'mind,' wherein subtle and gross brain functions in the form of behaviour, thought and emotions in all their ramifications will continue to be the focus of psychological, cognitive, sociological, psychopharmacological, behavioural and philosophical research. Progress in brain research must move in tandem with progress in 'mind' research. (shrink)

SummaryHeterozygous 4.1 hereditary elliptocytosis results from the absence of one haploid set of protein 4.1, a major component of the red cell skeleton. Two successive epidemiological investigations revealed fifteen probands in the French Northern Alps. The frequency of this disease seems to be very high in four small villages isolated in the Aravis mountains. The genealogical study shows that eleven probands share common ancestors who lived eight or ten generations ago in these villages. Thus there was probably a founder effect (...) from one pair of ancestors, strengthened by endogamy. In contrast, four probands originate from another area and are not genealogically related. Recent results in molecular genetics support the present data. (shrink)

General knowledge of the role of vitamin D3 in human physiology has been shaped by its discovery as a preventive agent of nutritional rickets, a defect in bone development due to inadequate uptake of dietary calcium. Studies on the function of the hormonal form of vitamin D3, 1α,25‐dihydroxyvitamin D3, have been greatly accelerated by the molecular cloning and structural analysis of the vitamin D3 receptor, which is a ligand‐activated regulator of gene transcription. Molecular genetic techniques including genomics have (...) helped reveal that 1α,25‐dihydroxyvitamin D3 can control more than calcium homeostasis. It has widespread effects on cellular differentiation and proliferation, and can modulate immune responsiveness, and central nervous system function. Moreover, accumulating epidemiological and molecular evidence suggests that 1α,25‐dihydroxyvitamin D3 acts as a chemopreventive agent against several malignancies including cancers of the prostate and colon. Here, we survey the most‐recent findings and discuss their implications for the potential therapeutic uses of vitamin D analogues. BioEssays 26:21–28, 2004. © 2003 Wiley Periodicals, Inc. (shrink)

The cause of Paget's disease is still unknown, despite many years of intensive study. During this time, evidence has sporadically emerged to suggest that the disease may result from a slow viral infection by one or more of the Paramyxoviruses. More recently, epidemiologic and molecular studies have suggested that the canine paramyxovirus, canine distemper virus, is the virus responsible for the disease. If true, then along with rabies, this would be a further example of a canine virus causing human (...) disease. Studies in the natural host have now supported these findings. Further investigations have proposed that the bony abnormalities seen in Paget's disease are due to the effects of the virus on osteoclastic interleukin‐6 and c‐FOS production, possibly via the transcription factor NF‐kB. (shrink)

It is customary to distinguish experimental from purely observational sciences. The former include physics and molecular biology, the latter astronomy and palaeontology. Experiments involve actively intervening in the course of nature, as opposed to observing events that would have happened anyway. When a molecular biologist inserts viral DNA into a bacterium in his laboratory, this is an experiment; but when an astronomer points his telescope at the heavens, this is an observation. Without the biologist’s handiwork the bacterium would (...) never have contained foreign DNA; but the planets would have continued orbiting the sun whether or not the astronomer had directed his telescope skyward. The observational/experimental distinction would probably be difficult to make precise 1, as the notion of an ‘intervention’ is not easily defined, but it is intuitively fairly clear, and is frequently invoked by scientists and historians of science. Experimentation, or ‘putting questions to nature’, is often cited as a hallmark of the modern scientific method, something that permitted the enormous advances of the last 350 years. And it is sometimes said that the social sciences lag behind the natural because controlled experiments cannot be done so readily in the former. Moreover in certain sciences, e.g. epidemiology, students are explicitly taught that experimental data is preferable to observational data, particularly for doing causal inference. So the distinction between observational and experimental science has quite wide currency, and is often regarded as methodologically significant. Surprisingly, mainstream philosophy of science has had rather little to say about the observational/experimental distinction. 2 For example, discussions of confirmation usually invoke a notion of ‘evidence’, to be contrasted with ‘theory’ or ‘hypothesis’; the aim is to understand how the evidence bears on the hypothesis. But whether this ‘evidence’ comes from observation or experiment generally plays no role in the discussion; this is true …. (shrink)

We compared two digital humanities methods in the analysis of a contested scientific term. “Epigenetics” is as enigmatic as it is popular. Some authors argue that its meaning has diluted over time as this term has come to describe a widening range of entities and mechanisms (Haig, International Journal of Epidemiology 41:13–16, 2012). Others propose both a Waddingtonian “broad sense” and a mechanistic “narrow sense” definition to capture its various scientific uses (Stotz and Griffiths, History and Philosophy of the (...) Life Sciences 38:22, 2016). We evaluated these proposals by first replicating a recent analysis by (Linquist and Fullerton, Theoretical Medicine and Bioethics 42:137–154, 2021). We analyzed the 1100 most frequently cited abstracts on epigenetics across four disciplines: proximal biology, biomedicine, general biology, and evolution. Each abstract was coded for its heritability commitments (if any) and functional interpretation. A second study applied LDA topic modelling to the same corpus, thus providing a useful methodological comparison. The two methods converged on a discipline-relative ambiguity. Within such disciplines as biomedicine or molecular biology that focus on proximate mechanisms, “epigenetic(s)” refers to a range of molecular structures while specifying nothing in particular about their heritability. This proximal conception was primarily associated with the functions of gene regulation and disease. In contrast, a second relatively uncommon sense of “epigenetic(s)” is restricted to a small proportion of evolutionary abstracts. It refers to many of the same molecular structures, but regards them as trans-generationally inherited and associated with adaptive phenotypic plasticity. This finding underscores the benefit of digital tools in complementing traditional conceptual analysis. Philosophers should be cautious not to conflate the relatively uncommon evolutionary sense of epigenetics with the more widely used proximal conception. (shrink)

Adverse childhood experiences (ACEs) have become a topic of public and scientific attention. ACEs denote a range of negative experiences in early life, from sexual abuse to emotional neglect, that are thought to impact health over the life course. The term was coined in the CDC-Kaiser ACE Study, an epidemiological study that surveyed 17,421 adults about ACEs and correlated the responses with participants’ current health records. Shortly after the study was published in 1998, the US CDC deemed ACEs an important (...) public health target; however, it is only recently that ACEs feature prominently in scientific and public discourses. We contend that this rise in popularity is linked to the adoption of epigenetic explanations for how ACEs affect health. Based on a literature analysis, we trace the evolution of explanatory frameworks for ACEs—from coping behaviors to allostatic load to epigenetics—and analyze how each of these explanations not only reconsiders the mechanisms by which ACEs affect health, but also who should be held responsible for addressing ACEs and how. Epigenetics provides distinctly different discursive possibilities than previous frameworks: firstly, it offers one distinct molecular mechanism for how ACEs work, lending “molecular credibility” to epidemiological findings; secondly, it raises the possibility of reversing the negative effects of ACEs on the biological level. This epigenetic articulation makes ACEs attractive for new actors in science and society. Particularly, it facilitates novel interdisciplinary collaborations and attracts actors in health advocacy who are interested in non-deterministic readings of ACEs that counteract stigma and support positive health interventions and healing. (shrink)

Ultraviolet (UV) radiation is a very common carcinogen in our environment, but epidemiological data on the relationship between skin cancers and ambient solar UV radiation are very restricted. In hairless mice the process of UV carcinogenesis can be studied in depth. Experiments with this animal model have yielded quantitative data on how tumor development depends on dose, time and wavelength of the UV radiation. In combination with epidemiological data, these experimental results can be transposed to humans. Comparative studies on (...) class='Hi'>molecular, cellular and physiological changes in mouse and man can further our fundamental understanding of UV carcinogenesis in man. This is likely to improve risk assessments such as those related to a stratospheric ozone depletion, and to yield well‐targeted intervention schemes, e.g. prescribing a specific drug or diet, for high‐risk individuals. (shrink)

Vaccine research, as well as the development, testing, clinical trials, and commercial uses of vaccines involve complex processes with various biological data that include gene and protein expression, analysis of molecular and cellular interactions, study of tissue and whole body responses, and extensive epidemiological modeling. Although many data resources are available to meet different aspects of vaccine needs, it remains a challenge how we are to standardize vaccine annotation, integrate data about varied vaccine types and resources, and support advanced (...) vaccine data analysis and inference. To address these problems, the community-based Vaccine Ontology (VO) has been developed through collaboration with vaccine researchers and many national and international centers and programs, including the National Center for Biomedical Ontology (NCBO), the Infectious Disease Ontology (IDO) Initiative, and the Ontology for Biomedical Investigations (OBI). VO utilizes the Basic Formal Ontology (BFO) as the top ontology and the Relation Ontology (RO) for definition of term relationships. VO is represented in the Web Ontology Language (OWL) and edited using the Protégé-OWL. Currently VO contains more than 2000 terms and relationships. VO emphasizes on classification of vaccines and vaccine components, vaccine quality and phenotypes, and host immune response to vaccines. These reflect different aspects of vaccine composition and biology and can thus be used to model individual vaccines. More than 200 licensed vaccines and many vaccine candidates in research or clinical trials have been modeled in VO. VO is being used for vaccine literature mining through collaboration with the National Center for Integrative Biomedical Informatics (NCIBI). Multiple VO applications will be presented. (shrink)

We received 23 spirited commentaries on our target article from across the disciplines of philosophy, economics, evolutionary genetics, molecular biology, criminology, epidemiology, and law. We organize our reply around three overarching questions: (1) What is a cause? (2) How are randomized controlled trials (RCTs) and within-family genome-wide association studies (GWASs) alike and unalike? (3) Is behavior genetics a qualitatively different enterprise? Throughout our discussion of these questions, we advocate for the idea that behavior genetics shares many of the (...) same pitfalls and promises as environmentally oriented research, medical genetics, and other arenas of the social and behavioral sciences. (shrink)

Few diseases are extensively diffused as influenza, but though flu pandemics occur with regularity throughout history the bibliography is dominated by the 1918-1919 “Spanish influenza” pandemic. This review argues that this preoccupation is largely a product of historical epidemiology and retrospective statistical analysis which has made the Spanish flu the reference point against which other modern respiratory pandemics, including COVID-19, are measured—hence the Spanish flu’s importance for the 21st century pandemic imaginary. The review identifies six distinct thematic areas within (...) the historiography of H1N1 Spanish influenza. These include medical writings which attempt to read the history of the Spanish flu backwards to “learn” public health “lessons” for the mitigation of future pandemics, and ecological writings in which influenza is seen as the paradigm of an emerging infectious disease and a model for the genesis of epidemics and pandemics from zoonotic reservoirs. Scholarship since 1997 also reflects a growing interdisciplinarity, one in which bioarchaeology and molecular dating techniques have furnished new insights into the history of influenza and the Spanish flu’s evolutionary origins, bringing the life sciences into closer dialogue with the medical and environmental humanities. These scientific insights have spurred both academic and popular writings on the Spanish flu, rendering its characterization as the “forgotten pandemic” something of an oxymoron. Indeed, if anything, the centenary of the Spanish flu in 2018 and the 2019-2023 COVID pandemic have provoked renewed interest in several of the themes identified in this review: including, most particularly, the writings of social historians of medicine, cultural historians, and disease demographers. (shrink)

Centuries of scientific progress have been devoted to reducing uncertainty. Newtonian physics, introduced over 300 years ago, allowed for precise prediction of planetary and tidal motion, falling bodies and infinitely more, in addition to allowing the construction of the material world. The 20th century witnessed a revolution in our understanding of organ and cellular function and dysfunction, elucidation of pathways, mediators, receptors, and molecular interactions, and breakthroughs in the characterization of replication, transcription, and translation, all of which has been (...) integral to our understanding of human physiology and pathophysiology. Clinical epidemiology has had a revolutionary impact on our .. (shrink)

Causation has multiple distinct meanings in genetics. One reason for this is meaning slippage between two concepts of the gene: Mendelian and molecular. Another reason is that a variety of genetic methods address different kinds of causal relationships. Some genetic studies address causes of traits in individuals, which can only be assessed when single genes follow predictable inheritance patterns that reliably cause a trait. A second sense concerns the causes of trait differences within a population. Whereas some single genes (...) can be said to cause population-level differences, most often these claims concern the effects of many genes. Polygenic traits can be understood using heritability estimates, which estimate the relative influences of genetic and environmental differences to trait differences within a population. Attempts to understand the molecular mechanisms underlying polygenic traits have been developed, although causal inference based on these results remains controversial. Genetic variation has also recently been leveraged as a randomizing factor to identify environmental causes of trait differences. This technique—Mendelian randomization—offers some solutions to traditional epidemiological challenges, although it is limited to the study of environments with known genetic influences. (shrink)

In this rapid commentary, a mini-review is given of the present state-of-knowledge regarding the etiology and epidemiology of the new coronavirus 2019-nCoV and the risks for developing Acute respiratory distress syndrome. The available knowledge on the viral genomics, molecular biology and pathogenicity of viruses of the Coronaviridae family and other Nidovirales, forms a helpful template for understanding the present pandemic outbreak. However, important questions remain unanswered about the underlying mechanism causing the very high case fatality ratios and mechanisms (...) regarding severe reactions like ARDS, fatal cardiac and renal failures, associated with a number of important comorbidity factors. Immunological reactions to lung alveoles in particular in late phase ARDS in SARS-like CoV diseases, so far may not have received enough attention. Finally a shortlist of questions for high priority further research is suggested. (shrink)

Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene–nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not (...) intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient–genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries. (shrink)

It is well established that chronic infections can lead to cancer. Almost unknown is that, in contrast, acute brief viral and bacterial infections may have beneficial effects in cases of established neoplastic disease, while exposure to pathogenic products by infection, vaccination, and inhalation can cause prophylactic effects. In the following I will align evidence from case studies of spontaneous regression and from epidemiological studies with recent immunology to conclude that pathogenic substances belonging to the group of “pathogen‐associated molecular patterns” (...) can trigger the innate immune system to establish anti‐neoplastic immune responses. A better understanding of the protective role of the innate immune system might leverage considerable prophylactic potential. (shrink)

The rapidly changing field of genetics affects society through advances in health-care and through implications of genetic research. This study addresses the impacts of new genetic discoveries and technologies on different segments of today's society. The book begins with a chapter on genetic complexity, and subsequent chapters discuss moral and ethical questions arising from today's genetics from the perspectives of health care professionals, the media, the general public, special interest groups and commercial interests.

The ArgumentThe paper is divided into the two parts. In the first, I examine the relations among molecular biology, gene technology, and medicine as some aspect of the consequences of these relations with respect to the human genome project of the consequences of these relations with respect to the human genome project. I argue that the prevailing momentum of early molecular biology resided in argue that the prevailing momentum of relay molecular biology resided in crating the technical (...) means for an extracellular representation of intracellular configurations. Assuch, its medical impact was rather limited. With the advent of recombinant DNA technology is based on the prospects of an intracellular representation of extracellular projects—the “rewriting” of life. Its medical impact is potentially unlimited. In the second part, I question the very opposition between nature and culture that implicitly underlies the notion of medicine as a “cultural system.” I argue that both on a macroscopic level and on a microscopic level, the “natural” and the “social” are no longer to be seen as ontologically different.In its uncanny oscillation between retrospection and foresight, between description and proclamation, and between assertion and hesitation, this essay translates an uneasiness that I have not been able to overcome while writing it. The essay conveys the tangled views of a hybrid author who himself cannot but oscillate between the perspectives of an actor in the field of molecular biology, a participant in the field of science studies, and a citizen. (shrink)

Journal of Social Philosophy, EarlyView.

Philosophers have proposed various kinds of relations between Mendelian genetics and molecular biology: reduction, replacement, explanatory extension. This paper argues that the two fields are best characterized as investigating different, serially integrated, hereditary mechanisms. The mechanisms operate at different times and contain different working entities. The working entities of the mechanisms of Mendelian heredity are chromosomes, whose movements serve to segregate alleles and independently assort genes in different linkage groups. The working entities of numerous mechanisms of molecular biology (...) are larger and smaller segments of DNA plus related molecules. Discovery of molecular DNA mechanisms filled black boxes that were noted, but unilluminated, by Mendelian genetics. (shrink)

Christopher Boorse’s bio-statistical theory of health and disease argues that the central discipline on which theoretical medicine relies is physiology. His theory has been much discussed but little has been said about its focus on physiology or, conversely, about the role that other biomedical disciplines may play in establishing a theoretical concept of health. Since at least the 1950s, epidemiology has gained in strength and legitimacy as an independent medical science that contributes to our knowledge of health and disease. (...) Indeed, it not only provides important information about disease distribution and aetiology, but the risk-factor approach it employs seems to challenge BST’s binary conception of health and disease. The objective of the article is to show, firstly, how important information deriving from descriptive and analytical epidemiology forms part of our contemporary medical concepts of health and disease, and secondly, that these elements are not taken into account by BST in a satisfactory way. The article’s central contention, therefore, is that if the project of defining the theoretical concept of health is to be maintained, more importance should be accorded to the contribution made by epidemiology—alongside physiology—in defining health. (shrink)

I have not attempted to provide here an analysis of the methodology of molecular biology or molecular genetics which would demonstrate at what specific points a more reductionist aim would make sense as a research strategy. This, I believe, would require a much deeper analysis of scientific growth than philosophy of science has been able to provide thus far. What I have tried to show is that a straightforward reductionist strategy cannot be said to be follwed in important (...) cases of theory development in molecular biology, and that in at least one important case, the Jacob-Monod operon theory, the methodology followed was more biological than chemical. It should be noted in closing, however, that since biological systems are thought by molecular biologists to be nothing but chemical systems, in the long run detailed investigations of such systems will be in full accord with the dictates suggested by the general reduction model. (shrink)