A number of novel gene detection techniques all revolve around the ligation of synthetic nucleic acid probes. In such ligase‐assisted gene detection reactions, specific DNA or RNA sequences are investigated by using them as guides for the covalent joining of pairs of probe molecules. The probes are designed to hybridize immediately next to each other on the target nucleic acid strand. Demonstration of ligated probes results in highly specific detection of and efficient distinction between similar sequence variants under standard reaction (...) conditions. Accordingly, the principle has been applied in automated genetic screening procedures. Ligation reactions are also integral to a number of amplification procedures and they will be of value in an expanding range of genetic analyses. (shrink)

The introduction of recombinant DNA technology into the field of genetics has led to a rapid advancement of our knowledge of genes and genome structure. Such technology, applied to the human genome, has provided valuable information concerning the nature and possible treatment of inherited disorders. The possibility that this knowledge will pave the way for the correction of at least some of these disorders has captured the imagination of the informed public. In this review we look at the accomplishments of (...) molecular pathologists to date and how new techniques are being applied to the study of inherited disease. (shrink)

Since its advent, predictive DNA testing has been perceived as a technology that may have considerable impact on the quality of people’s life. The decision whether or not to use this technology is up to the individual client. However, to enable well considered decision making both the negative as well as the positive freedom of the individual should be supported. In this paper, we argue that current professional and public discourse on predictive DNA-testing is lacking when it comes to supporting (...) positive freedom, because it is usually framed in terms of risk and risk management. We show how this ‘risk discourse’ steers thinking on the good life in a particular way. We go on to argue that empirical research into the actual deliberation and decision making processes of individuals and families may be used to enrich the environment of personal deliberation in three ways: (1) it points at a richer set of values that deliberators can take into account, (2) it acknowledges the shared nature of genes, and (3) it shows how one might frame decisions in a non-binary way. We argue that the public sharing and discussing of stories about personal deliberations offers valuable input for others who face similar choices: it fosters their positive freedom to shape their view of the good life in relation to DNA-diagnostics. We conclude by offering some suggestions as to how to realize such public sharing of personal stories. (shrink)

Although DNA microarrays are now widely used in research settings, they have been slow to penetrate clinical practice in spite of their apparent advantages. This is due to the very different requirements for a clinical test in contrast to a research tool, and to a strict necessity for demonstrated clinical utility. There is a clear differentiation between two types of DNA array tests: “genomic” diagnostics, developed to ascertain the presence or absence of mutations, deletions or duplications, and for which (...) clinical evidence is already established, and tests using expression profiling for prognosis or predictive purposes, in which case the clinical correlate must be proven. Most array diagnostics currently used belong, understandably, to the “genomic” variety. It is to be expected that future improvements in tailored technology, as well as a logical trend towards measuring an ever‐increasing number of parameters, will ensure an important diagnostic role for DNA arrays in the coming decade. BioEssays 29:699–705, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

We argue that the most‐promising area of clinical application of microarrays in the foreseeable future is the diagnostics and monitoring of infectious diseases. Microarrays for the detection and characterization of human pathogens have already found their way into clinical practice in some countries. After discussing the persistent, yet often underestimated, importance of infectious diseases for public health, we consider the technologies that are best suited for the detection and clinical investigation of pathogens. Clinical application of microarray technologies for the (...) detection of mycobacteria, Bacillus anthracis, HIV, hepatitis and influenza viruses, and other major pathogens, as well as the analysis of their drug‐resistance patterns, illustrate our main thesis. BioEssays 30:673–682, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Since its advent, predictive DNA testing has been perceived as a technology that may have considerable impact on the quality of people’s life. The decision whether or not to use this technology is up to the individual client. However, to enable well considered decision making both the negative as well as the positive freedom of the individual should be supported. In this paper, we argue that current professional and public discourse on predictive DNA-testing is lacking when it comes to supporting (...) positive freedom, because it is usually framed in terms of risk and risk management. We show how this ‘risk discourse’ steers thinking on the good life in a particular way. We go on to argue that empirical research into the actual deliberation and decision making processes of individuals and families may be used to enrich the environment of personal deliberation in three ways: (1) it points at a richer set of values that deliberators can take into account, (2) it acknowledges the shared nature of genes, and (3) it shows how one might frame decisions in a non-binary way. We argue that the public sharing and discussing of stories about personal deliberations offers valuable input for others who face similar choices: it fosters their positive freedom to shape their view of the good life in relation to DNA-diagnostics. We conclude by offering some suggestions as to how to realize such public sharing of personal stories. (shrink)

Whether, and to what degree, do patents granted on human genes cast a shadow of uncertainty over genomics and its applications? Will owners of patents on individual genes or clusters of genes sue those performing whole-genome analyses on human samples for patent infringement? These are related questions that have haunted molecular diagnostics companies and services, coloring scientific, clinical, and business decisions. Can the profusion of whole-genome analysis methods proceed without fear of patent infringement liability?Whole-genome sequencing is proceeding apace. Academic (...) centers have been performing whole-genome and -exome sequencing in research for at least five years, and academic clinical laboratories with national reach have been doing sequencing for clinical applications for almost as long. Companies have also been offering WGS and WES as a clinical service for a few years now. So far as we know, no one has been sued for infringement of “gene patents” for performing WGS. (shrink)

The ability to improve diagnosis and refine prognosis in children with acute leukaemia is improving steadily. A growing number of tests can and are being performed on leukaemic cells. These include surface-marker analysis, DNA content, cytogenetics and studies of gene rearrangements. Increasingly large bone-marrow samples, now usually obtained under general anaesthesia, are required to make secure diagnoses. Ethical issues arise from three major areas. 1) Current research on leukaemia cells requested by the Medical Research Council is considered by local research (...) ethics committees, but parents are not regularly given detailed information about or asked specifically to consent to such research; 2) substantial quantities of excess cells are stored indefinitely. This archive of stored material is a valuable resource for research but there has been little consideration of the ethical issues which arise from this practice, and 3) there is a potential for pressure to obtain increasingly large samples. 'Creeping growth' in sample size is likely to continue unless ethics committees consider future research proposals in more detail. These issues deserve attention in order that worthwhile research and its publication are not impeded for want of ethical consideration. The implications extend beyond the field of childhood leukaemia. (shrink)

Gene-technology was developed in the eighties and stimulated an overmuch heated social debate. Let's think such problems as cloning, transgenic organisms, Human Genom Project, DNA diagnostics and therapy, the geneticalisation of society etc. While the gene manipulation develops rapidly the necessary social control is missing. Regarding the social co-ordination of gene technology, the decision-makers still excessively trust in the institution of market and in the experts' competence.

In two recent papers, Rose and Nichols present evidence in favor of the view that humans represent category essences in terms of a telos, such as honey-making, and not in terms of scientific essences, such as bee DNA. In this paper, I challenge their interpretation of the evidence, and show that it is directly predicted by the main theory they seek to undermine. I argue that their results can be explained as instances of diagnostic reasoning about scientific essences.

DNA arrays are now widely used in academia and industry, and expression profiling is recognised as a major tool for basic research as well as for drug development. It is also likely, in the near future, that DNA arrays will be used in clinical laboratories for diagnostic and prognostic purposes. Since several types of arrays are being used, the coherence of results obtained using these diverse platforms becomes an important issue: to what extent can data obtained in different laboratories and (...) with different equipment be combined? Several recent papers address this issue and demonstrate that the expected agreement is not necessarily found. Consistent results can be obtained, but this requires careful identification of the genes assessed by the arrays, and scrupulous adherence to strict experimental procedures. BioEssays 26:1236–1242, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The increasing availability of DNA-based diagnostic tests has raised issues about whether these should be applied to the population at large in order to identify, treat or prevent a range of diseases. DNA tests raise concerns in the community for several reasons. There is the possibility of stigmatisation and discrimination between those who test positive and those who don't. High-risk individuals may be identified for whom no proven effective intervention is possible, or conversely may test "positive" for a disease that (...) does not eventuate. Controversy concerning prenatal diagnosis and termination of affected pregnancies may arise. Haemochromatosis, however, is a disease that is not only treatable but also preventable if those at high risk are identified presymptomatically. This paper will identify and discuss key issues regarding DNA-based population screening for haemochromatosis, and argue that population-based genetic screening for haemochromatosis should be supported when a number of contentious issues are addressed. In the context of a health system with limited resources haemochromatosis is the paradigm of a disorder where there is an ethical and clinical imperative to encourage presymptomatic DNA testing for all in ethnically relevant communities. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Religion and the Body in Medical ResearchCourtney S. Campbell (bio)AbstractReligious discussion of human organs and tissues has concentrated largely on donation for therapeutic purposes. The retrieval and use of human tissue samples in diagnostic, research, and education contexts have, by contrast, received very little direct theological attention. Initially undertaken at the behest of the National Bioethics Advisory Commission, this essay seeks to explore the theological and religious questions embedded (...) in nontherapeutic use of human tissue. It finds that the “donation paradigm” typically invoked in religious discourse to justify uses of the body for therapeutic reasons is inadequate in the context of nontherapeutic research, while the “resource paradigm” implicit in scientific discourse presumes a reductionist account of the body that runs contrary to important religious values about embodiment. The essay proposes a “contribution paradigm” that provides a religious perspective within which research on human tissue can be both justified and limited.The retrieval and use of human tissue samples for diagnostic, therapeutic, research, and educational purposes represent further developments in scientific study of the human body as a source of medical information. Following the completion of its examination of the ethical and policy issues pertaining to human cloning in the spring of 1997, the National Bioethics Advisory Commission (NBAC) returned to the set of questions for which it had been originally constituted, including ethical issues that arise in human subjects research. One issue that proved controversial for the human genetics subcommittee of NBAC was the scientific, philosophical, and legal status of tissue and other body parts (usually surgical specimens) that had been retrieved from patients (not research subjects) who had given general consent to the use of their body materials for research and educational purposes. The subcommittee addressed questions about the adequacy of general versus specific [End Page 275] consent, the scientific merits of identifiable versus anonymous samples and claims about patient confidentiality, and the justification for patient refusals and requests that the materials be returned to the patient or discarded rather than made available for scientific research. In an effort to better understand the ramifications of research on human tissue, the subcommittee commissioned several background papers that examined these questions from ethical, legal, research, and religious perspectives. What follows is a modified version of the report on religious considerations originally presented to the genetics subcommittee of NBAC.The central question examined in this article is whether tissue banking for purposes of research presents distinctive theological issues or prompts objections from religious communities or scholars. Religious discussion of human organs and tissues has focused largely on donation for therapeutic purposes (what I describe as the “donation paradigm”); hence, there is very little direct consideration of nontherapeutic uses of such tissue. It is possible, however, to describe implications and suggest inferences by considering (1) religious attitudes to the human body and to organs, tissues, and cells removed from the body, and (2) religious discussions of modes of transfer of body parts, such as donations, offerings, sales, and abandonment. By and large, this discussion will reflect themes that emerge from the central Western religious traditions, with some attention given to Eastern and Native perspectives.The Body: Religious Holism, Scientific Reductionism, Private PropertyThe human body as an organic totality has long been the subject of theological reflection and a symbol for religious communities. However, much less attention has been devoted to the religious status of organs, tissues, cells, and DNA. The reflection of religious scholars and communities on the status of body parts has been prompted by the necessity to confront practical questions in personal and public health and in communal life, such as justifications for surgery, autopsies, organ donation, or burial. Scientific and research interest in parts of the body can sometimes conflict with religious values about bodily integrity. Indeed, E. Richard Gold cites the “disparate claims of scientific investigation and religious belief on the body” as the exemplary case of incommensurate values regarding the body. According to Gold (1996, p. 149), “The body, from a scientific viewpoint, is a source of knowledge of physical development, aging, and disease. From a religious perspective, the body is understood [End Page 276] as a sacred object, being created in the image... (shrink)

Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated Abeta1-40 (...) localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (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)

Increasing evidence indicates that extracellular vesicles (EVs) secreted from tumor cells play a key role in the overall progression of the disease state. EVs such as exosomes are secreted by a wide variety of cells and transport a varied population of proteins, lipids, DNA, and RNA species within the body. Gliomas constitute a significant proportion of all primary brain tumors and majority of brain malignancies. Glioblastoma multiforme (GBM) represents grade IV glioma and is associated with very poor prognosis despite the (...) cumulative advances in diagnostic procedures and treatment strategies. Here, the authors describe the progress in understanding the role of EVs, especially exosomes, in overall glioma progression, and how new research is unraveling the utilities of exosomes in glioma diagnostics and development of next‐generation therapeutic systems. Finally, based on an understanding of the latest scientific literature, a model for the possible working of therapeutic exosomes in glioma treatment is proposed. (shrink)

Sequenom Inc., a developer of medical diagnostic products, recently made their noninvasive test for Down syndrome available for clinical practice.1 The DNA-based test—given the name “MaterniT21”—requires only a simple maternal blood sample as early as 10 weeks of gestation. In recent clinical trials involving thousands of pregnant women, the MaterniT21 test identified 99.1% of cases of Down syndrome, and gave the correct result in 99.9% of cases when the fetus did not have Down syndrome. Sequenom’s test is thought to be (...) an improvement on previous prenatal testing techniques because of its. (shrink)

Background Inadequate knowledge among health care providers (HCPs) and parents of affected children limits the understanding and utility of secondary genetic findings (SFs) in under-represented populations in genomics research. SFs arise from deep DNA sequencing done for research or diagnostic purposes and may burden patients and their families despite their potential health importance. This study aims to evaluate the perspective of both groups regarding SFs and their choices in the return of results from genetic testing in the context of orofacial (...) clefts.Methods Using an online survey, we evaluated the experiences of 252 HCPs and 197 parents across participating cleft clinics in Ghana and Nigeria toward the return of SFs across several domains.Results Only 1.6% of the HCPs felt they had an expert understanding of when and how to incorporate genomic medicine into practice, while 50.0% agreed that all SFs should be returned to patients. About 95.4% of parents were willing to receive all the information from genetic testing (including SFs), while the majority cited physicians as their primary information source (64%).Conclusions Overall, parents and providers were aware that genetic testing could help in the clinical management of diseases. However, they cited a lack of knowledge about genomic medicine, uncertain clinical utility, and lack of available learning resources as barriers. The knowledge gained from this study will assist with developing guidelines and policies to guide providers on the return of SFs in sub-Saharan Africa and across the continent. (shrink)

The replicon hypothesis, first proposed in 1963 by Jacob and Brenner(1), states that DNA replication is controlled at sites called origins. Replication origins have been well studied in prokaryotes. However, the study of eukaryotic chromosomal origins has lagged behind, because until recently there has been no method for reliably determining the identity and location of origins from eukaryotic chromosomes. Here, we review a technique we developed with the yeast Saccharomyces cerevisiae that allows both the mapping of replication origins and an (...) assessment of their activity. Two‐dimensional agarose gel electrophoresis and Southern hybridization with total genomic DNA are used to determine whether a particular restriction fragment acquires the branched structure diagnostic of replication initiation. The technique has been used to localize origins in yeast chromosomes and assess their initiation efficiency. In some cases, origin activation is dependent upon the surrounding context. The technique is also being applied to a variety of eukaryotic organisms. (shrink)

_Gender issues arise in relation to the human genome across a number of dimensions: the level of attention given to the nuclear genome as opposed to the mitochondrial; the level of basic scientific research; decision-making in the clinic related to both reproductive decision-making on the one hand, and diagnostic and predictive testing on the other; and wider societal implications. Feminist bioethics offers a useful perspective for addressing these issues._.

On October 1, 1988, thirty-five years after co-discovering the structure of the DNA molecule, Dr. James Watson launched an unprecedented experiment in American science policy. In response to a reporter's question at a press conference, he unilaterally set aside 3 to 5 percent of the budget of the newly launched Human Genome Project to support studies of the ethical, legal, and social implications of new advances in human genetics. The Human Genome Project (HGP), by providing geneticists with the molecular maps (...) of the human chromosomes that they use to identify specific human genes, will speed the proliferation of a class of DNA-based diagnostic and risk-assessment tests that already create professional ethical and health-policy challenges for clinicians. “The problems are with us now, independent of the genome program, but they will be associated with it,” Watson said. “We should devote real money to discussing these issues.” By 1994, the “ELSI program” (short for “Ethical, Legal, and Social Implications”) had spent almost $20 million in pursuit of its mission, and gained both praise and criticism for its accomplishments. (shrink)

Passage through the cell cycle requires the successive activation of different cyclin‐dependent protein kinases (CDKs). These enzymes are controlled by transient associations with cyclin regulatory subunits, binding of inhibitory polypeptides and reversible phosphorylation reactions. To promote progression towards DNA replication, CDK/cyclin complexes phosphorylate proteins required for the activation of genes involved in DNA synthesis, as well as components of the DNA replication machinery. Subsequently, a different set of CDK/cyclin complexes triggers the phosphorylation of numerous proteins to promote the profound structural (...) reorganizations that accompany the entry of cells into mitosis. At present, much research is focused on elucidating the links between CDK/cyclin complexes and signal transduction pathways controlling cell growth, differentiation and death. In future, a better understanding of the cell cycle machinery and its deregulation during oncogenesis may provide novel opportunities for the diagnostic and therapeutic management of cancer and other proliferation‐related diseases. (shrink)

The book examines the evolution and current state of corporate social responsibility (CSR), using a five-stage maturity model: defensive, charitable, promotional, strategic and transformative CSR. The first four stages are dubbed CSR 1.0 and characterise most current CSR practice, while the fifth stage is named CSR 2.0 (also transformative or systemic CSR) and describes emergent and future CSR practices. Reasons are given why CSR 1.0 approaches have failed to have any significant impact on the most serious global social, environmental and (...) ethical challenges. The emergent CSR 2.0 will then be explored in detail by elaborating on five principles underlying the new approach, including: creativity, scalability, responsiveness, glocality and circularity. A four-part DNA Model is also introduced, covering value creation, good governance, societal contribution and ecological integrity, which provides the basis for defining and measuring CSR 2.0. Finally, a 70-question CSR 2.0 self-assessment diagnostic tool developed by the author is presented, with sample data to show how the tool can be used for future research and practitioner application. (shrink)

High‐precision tumor targeting with conventional therapeutics is based on the concept of the ideal drug as a “magic bullet”; this became possible after techniques were developed for production of monoclonal antibodies (mAbs). Innovative DNA technologies have revolutionized this area and enhanced clinical efficiency of mAbs. The experience of applying small‐size recombinant antibodies (monovalent binding fragments and their derivatives) to cancer targeting showed that even high‐affinity monovalent interactions provide fast blood clearance but only modest retention time on the target antigen. Conversion (...) of recombinant antibodies into multivalent format increases their functional affinity, decreases dissociation rates for cell‐surface and optimizes biodistribution. In addition, it allows the creation of bispecific antibody molecules that can target two different antigens simultaneously and do not exist in nature. Different multimerization strategies used now in antibody engineering make it possible to optimize biodistribution and tumor targeting of recombinant antibody constructs for cancer diagnostics and therapy. BioEssays 30:904–918, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Background Massively parallel sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), may reveal unsolicited findings (UFs) unrelated to the diagnostic aim. Such techniques are frequently used for diagnostic purposes in pediatric cases of developmental delay (DD). Yet policy guidelines for informed consent and return of UFs are not well equipped to address specific moral challenges that may arise in these children’s situations. Discussion In previous empirical studies conducted by our research group, we found that it (...) is sometimes uncertain how children with a DD will develop and whether they could come to possess capacities for autonomous decision-making in the future. Parents sometimes felt this brought them into a Catch-22 like situation when confronted with choices about UFs before undergoing WES in trio-analysis (both the parents’ and child’s DNA are sequenced). An important reason for choosing to consent to WES was to gain more insight into how their child might develop. However, to make responsible choices about receiving or declining knowledge of UFs, some idea of their child’s future development of autonomous capacities is needed. This undesirable Catch-22 situation was created by the specific policy configuration in which parents were required to make choices about UFs before being sequencing (trio-analysis). We argue that this finding is relevant for reconfiguring current policies for return of UFs for WES/WGS and propose guidelines that encompass two features. First, the informed consent process ought to be staged. Second, differing guidelines are required for withholding/disclosing a UF in cases of DD appropriate to the level of confidence there is about the child’s future developmental of autonomous capacities. Conclusion When combined with a dynamic consent procedure, these two features of our guidelines could help overcome significant moral challenges that present themselves in the situations of children undergoing genomic sequencing for clarifying a DD. (shrink)

Human individuals often exhibit important differences in their sensitivity to ionising radiation. Extensive literature links radiation sensitivity with impaired DNA repair which is due to a lack of correct functioning in many proteins involved in DNA‐repair pathways and/or in DNA‐damage checkpoint responses. Given that ionising radiation is an important and widespread diagnostic and therapeutic tool, it is important to investigate further those factors and mechanisms that underlie individual radiosensitivity. Recently, evidence is accumulating that telomere function may well be involved in (...) cellular and organism responses to ionising radiation, broadening still further the currently complex and challenging scenario. BioEssays. BioEssays 28: 1172–1180, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:The Human Genome Project and BioethicsEric T. Juengst, Ph.D. (bio)The fifteen-year "human genome project" at the National Institutes of Health and the Department of Energy officially began on October 1, 1990. With it began a new dimension in federally supported scientific research: concurrent funding for work to anticipate the social consequences of the project's research and to develop policies to guide the use of the knowledge it produces. As (...) a result, the National Center for Human Genome Research (NCHGR) at NIH will support the largest public investment in bioethical analysis to date.NCHGR was established to work with other federal, private, and international organizations on the scientific effort to characterize the form and content of the human genome. The research will yield information—high-resolution genetic linkage and physical maps of all the human chromosomes as well as human DNA sequence data—that will be a resource for studies of gene structure and function. It will greatly increase our understanding of the genetic aspects of human health and disease. That increased understanding will eventually provide insights into the prevention and treatment of the 3,000 known inherited disorders, and of conditions caused by our (gene-governed) physiological reactions to pathogens, toxins, and mutagens of external origin.It has been clear since the conception of the human genome project, however, that professional and public deliberations concerning the responsible use of genetic information must be a part of the process. The most immediate consequence of genome research will be the development of new diagnostic and predictive tests, well in advance of corresponding therapeutic or curative advances. The implications of acquiring and using that knowledge about individuals raise policy questions at many levels within society. The primary purpose of the Ethical, Legal and Social Implications Program at the NCHGR is to anticipate and address these questions early in the life of the scientific project, to help optimize the [End Page 71] benefits to human welfare and opportunity from the new knowledge, and to guard against its misuses.The program has identified three sets of questions as particularly important to pursue as the genome initiative proceeds:1.Issues involved in the integration of new genetic tests into medical practice. Human genome research is expected to increase greatly the number of gene-based diagnostic and prognostic tests available to health professionals. The bioethical policy problems involved in integrating those tests effectively into medical practice include developing standards for:— accuracy and quality control of genetic tests;— medical indications for testing and design of testing protocols;— professional responsibilities of clinicians who perform tests;— confidentiality of information obtained from testing;— access to and use of test results by third parties, such as health insurers; and— reimbursement for testing and test-related counseling.These are problems for both those charged with regulating the use of new genetic tests and for those establishing the standards of practice within the health professions. Thus, in addition to soliciting and funding scholarly research proposals on both the factual and normative questions raised by these problems, the program is commissioning a major new study by the National Academy of Sciences/Institute of Medicine aimed at providing professional guidelines for the integration of genetic services into mainstream medical practice.2. Issues involved in educating and counseling individuals about genetic test results. The primary risk that health professionals will face in using genetic tests is the misinterpretation of their findings and the resulting potential for psychological trauma, stigmatization, and discrimination. Sometimes, out of ignorance, patients, families, and social institutions already stigmatize genetic disorders and treat those with them unfairly. This risk broadens as the genetic elements of more health problems are uncovered and gene-based tests for susceptibilities and carrier states are developed.To protect against these risks, NCHGR is soliciting and supporting projects aimed at improving professional and public understanding of these tests and their implications. For example, a philosopher is leading a team of geneticists and physicians in a scholarly effort to clarify [End Page 72] concepts of genetic susceptibility and draw out the social meaning of their different interpretations. Other projects involve social scientific studies of genetic risk perceptions, stigmatization, and discrimination. The conclusions of these studies, and... (shrink)

RNAs have emerged as a major target for diagnostics and therapeutics approaches. Regulatory nonprotein‐coding RNAs (ncRNAs) in particular display remarkable versatility. They can fold into complex structures and interact with proteins, DNA, and other RNAs, thus modulating activity, localization, or interactome of multi‐protein complexes. Thus, ncRNAs confer regulatory plasticity and represent a new layer of regulatory control. Interestingly, long noncoding RNAs (lncRNAs) tend to acquire complex secondary and tertiary structures and their function—in many cases—is dependent on structural conservation rather (...) than primary sequence conservation.Whereas for many proteins, structure and its associated function are closely connected, for lncRNAs, the structural domains that determine functionality and its interactome are still not well understood. Numerous approaches for analyzing the structural configuration of lncRNAs have been developed recently. Here, will provide an overview of major experimental approaches used in the field, and discuss the potential benefit of using combinatorial strategies to analyze lncRNA modes of action based on structural information. (shrink)

Though in existence for over thirty-five years, due to the increasing panoply of possible tests. Newborn screening programs are drawing public attention. Many jurisdictions have mandatory newborn screening programs for treatable disorders. Disorders are detected through tests on blood spots drawn from a newborn’s heel soon after birth and verified through a diagnostic test with follow-up. Unbeknownst to most parents, these blood spot cards are also stored thereafter. Indeed, while dried blood spots are primarily used for screening for health problems, (...) experience demonstrates that they can be made useful in various contexts unrelated to screening.Newborn dried blood spots have taken on a new life as a result of developments in genetics and the increasing ability of bioinformatics to link DNA information with clinical data. Additionally, storage and secondary uses have been documented to occur without parental consent. (shrink)

Though in existence for over thirty-five years, due to the increasing panoply of possible tests. Newborn screening programs are drawing public attention. Many jurisdictions have mandatory newborn screening programs for treatable disorders. Disorders are detected through tests on blood spots drawn from a newborn’s heel soon after birth and verified through a diagnostic test with follow-up. Unbeknownst to most parents, these blood spot cards are also stored thereafter. Indeed, while dried blood spots are primarily used for screening for health problems, (...) experience demonstrates that they can be made useful in various contexts unrelated to screening.Newborn dried blood spots have taken on a new life as a result of developments in genetics and the increasing ability of bioinformatics to link DNA information with clinical data. Additionally, storage and secondary uses have been documented to occur without parental consent. (shrink)

In light of scientific advances such as genomics, predictive diagnostics, genetically engineered agriculture, nuclear transfer cloning, and the manipulation of stem cells, the idea that genes carry predetermined molecular programs or blueprints is pervasive. Yet new scientific discoveries—such as rna transcripts of single genes that can lead to the production of different compounds from the same pieces of dna—challenge the concept of the gene alone as the dominant factor in biological development. Increasingly aware of the tension between certain empirical (...) results and interpretations of those results based on the orthodox view of genetic determinism, a growing number of scientists urge a rethinking of what a gene is and how it works. In this collection, a group of internationally renowned scientists present some prominent alternative approaches to understanding the role of dna in the construction and function of biological organisms. Contributors discuss alternatives to the programmatic view of dna, including the developmental systems approach, methodical culturalism, the molecular process concept of the gene, the hermeneutic theory of description, and process structuralist biology. None of the approaches cast doubt on the notion that dna is tremendously important to biological life on earth; rather, contributors examine different ideas of how dna should be represented, evaluated, and explained. Just as ideas about genetic codes have reached far beyond the realm of science, the reconceptualizations of genetic theory in this volume have broad implications for ethics, philosophy, and the social sciences. Contributors. Thomas Bürglin, Brian C. Goodwin, James Griesemer, Paul Griffiths, Jesper Hoffmeyer, Evelyn Fox Keller, Gerd B. Müller, Eva M. Neumann-Held, Stuart A. Newman, Susan Oyama, Christoph Rehmann-Sutter, Sahotra Sarkar, Jackie Leach Scully, Gerry Webster, Ulrich Wolf. (shrink)

The discovery of the molecular structure of deoxyribonucleic acid and the science of molecular biology have profoundly changed medicine’s diagnostic capability and promise to transform the therapeutic realm. When some genetic disorders are diagnosed, physicians can intervene for prevention or treatment. While the basic structure of DNA is the same for all human beings, no two individuals, other than identical twins, have the same DNA sequence. This discovery has had important repercussions in the criminal justice system, where DNA can serve (...) as an identification tool.At the crossroads of these different uses of DNA, there are great concerns about potential misuses of genetic information. Preventing disease, curing illness, and convicting criminals are all seen as worthwhile uses of the technology, but concerns of potential misuse in medicine or in the criminal justice system are not unfounded. A 1998 American Medical Association study showed that 68 percent of patients had fears that their genetic test results would be used against them by their employers or insurers. Others, pointing to racial profiling, have suggested that we may now face genetic profiling. (shrink)

The Streptococcus pyogenes CRISPR‐Cas system has gained widespread application as a genome editing and gene regulation tool as simultaneous cellular delivery of the Cas9 protein and guide RNAs enables recognition of specific DNA sequences. The recent discovery that Cas9 can also bind and cleave RNA in an RNA‐programmable manner indicates the potential utility of this system as a universal nucleic acid‐recognition technology. RNA‐targeted Cas9 (RCas9) could allow identification and manipulation of RNA substrates in live cells, empowering the study of cellular (...) gene expression, and could ultimately spawn patient‐ and disease‐specific diagnostic and therapeutic tools. Here we describe the development of RCas9 and compare it to previous methods for RNA targeting, including engineered RNA‐binding proteins and other types of CRISPR‐Cas systems. We discuss potential uses ranging from live imaging of transcriptional dynamics to patient‐specific therapies and applications in synthetic biology. (shrink)

In 1996, President Clinton offered a promissory vision for human genetics when he said: “I think it won't be too many years before parents will be able to go home from the hospital with their newborn babies with a genetic map in their hands that will tell them, here's what your child's future will likely be like.”The rapid evolution of genetic sequencing technologies has advanced that vision. In October 2006, the cost of sequencing an entire human genome was $10.4 million; (...) by 2014 the cost had decreased a thousand fold. The term next generation sequencing describes a variety of laboratory methods that allow efficient determination of the precise order of nucleotides in a DNA sequence. The papers in this issue of the Journal of Law, Medicine & Ethics focus on “clinical NGS,” which refers to rapid DNA sequencing using second-, third- and fourth-generation sequencing technologies to perform genome-wide sequencing of multiple genes or alleles for clinical prognostic, diagnostic, and therapeutic purposes. (shrink)

Extracellular nucleic acids are found in different biological fluids in the organism and in the environment: DNA is a ubiquitous component of the organic matter pool in the soil and in all marine and freshwater habitats. Data from recent studies strongly suggest that extracellular DNA and RNA play important biological roles in microbial communities and in higher organisms. DNA is an important component of bacterial biofilms and is involved in horizontal gene transfer. In recent years, the circulating extracellular nucleic acids (...) were shown to be associated with some diseases. Attempts are being made to develop noninvasive methods of early tumor diagnostics based on analysis of circulating DNA and RNA. Recent observations demonstrated the possibility of nucleic acids exchange between eukaryotic cells and extracellular space suggesting their participation in so far unidentified biological processes. BioEssays 29:654–667, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The discovery of the molecular structure of deoxyribonucleic acid and the science of molecular biology have profoundly changed medicine’s diagnostic capability and promise to transform the therapeutic realm. When some genetic disorders are diagnosed, physicians can intervene for prevention or treatment. While the basic structure of DNA is the same for all human beings, no two individuals, other than identical twins, have the same DNA sequence. This discovery has had important repercussions in the criminal justice system, where DNA can serve (...) as an identification tool.At the crossroads of these different uses of DNA, there are great concerns about potential misuses of genetic information. Preventing disease, curing illness, and convicting criminals are all seen as worthwhile uses of the technology, but concerns of potential misuse in medicine or in the criminal justice system are not unfounded. A 1998 American Medical Association study showed that 68 percent of patients had fears that their genetic test results would be used against them by their employers or insurers. Others, pointing to racial profiling, have suggested that we may now face genetic profiling. (shrink)

The Human Genome Project (HGP) represents a massive merging of science and technology in the name of all humanity. While the disease aspects of HGP-generated data have received the greatest publicity and are the strongest rationale for the project, it should be remembered that the HGP has, as its goal the sequencing of all 100,000 human genes and the accurate depiction of the ancestral and functional relationships among these genes. The HGP will thus be constructing the molecular taxonomic norm for (...) humanity. Currently the HGP genomic baseline is almost exclusively skewed toward North Atlantic European lineages through the extensive use of the Centre d’Études du Polymorphisme Humaine (CEPH) data set. More recently, the HGP has shifted to the use of volunteer donors since adequate informed consent had not been secured from the CEPH families. No evidence exists that either the CEPH families or the current volunteers are the most appropriate demographic or evolutionary lineages for the functional genomic studies that will guide production of new DNA based drugs, targeted therapeutics and gene-based diagnostics. The lack of scientific representativeness of the HGP is a serious impediment to its broad applicability. Yet this can be remedied, and five alternative sampling strategies are presented. In response to the current exclusionary design of the HGP, there is noteworthy caution and skepticism in the African American community concerning genetic studies. The Manifesto on Genomic Studies Among African Americans reflects both a desire to be systematically included in federally funded genomic studies and a desire to maintain some control over the interpretation and application of research results. Representative sampling in the HGP is seen as an international human rights issue with domestic ethical implications. (shrink)

A new diagnostic modeling system for automatically synthesizing a deep‐structure model of a student's misconceptions or bugs in his basic mathematical skills provides a mechanism for explaining why a student is making a mistake as opposed to simply identifying the mistake. This report is divided into four sections: The first provides examples of the problems that must be handled by a diagnostic model. It then introduces procedural networks as a general framework for representing the knowledge underlying a skill. The challenge (...) in designing this representation is to find one that facilitates the discovery of misconceptions or bugs existing in a particular student's encoding of this knowledge. The second section discusses some of the pedagogical issues that have emerged from the use of diagnostic models within an instructional system. This discussion is framed in the context of a computer‐based tutoring/gaming system developed to teach students and student teachers how to diagnose bugs strategically as well as how to provide a better understanding of the underlying structure of arithmetic skills. The third section describes our uses of an executable network as a tool for automatically diagnosing student behavior, for automatically generating “diagnostic” tests, and for judging the diagnostic quality of a given exam. Included in this section is a discussion of the success of this system in diagnosing 1300 school students from a data base of 20.000 test items. The last section discusses future research directions. (shrink)

Ockham’s razor is the idea that simpler hypotheses are to be preferred over more complex ones. In the context of medical diagnosis, this is taken to mean that when a patient has multiple symptoms, a single diagnosis should be sought that accounts for all the clinical features, rather than attributing a different diagnosis to each. This paper examines whether diagnostic parsimony can be justified by reference to probability theory. I argue that while attempts to offer universal justifications of diagnostic parsimony (...) fail, a more constrained use of this diagnostic principle can be supported. (shrink)

This Christian sermon uses a DNA lab experience as a basis for theological reflection on ourselves and our offering. Who are we to God? What determines the self that we offer? Can the alphabet of DNA shed light for us on the Word of God in our lives? This first attempt to introduce the language and laboratory environment of genetic testing (represented by DNA fingerprinting) within a parish preaching context juxtaposes liturgical, scientific, and biblical language and settings for fresh insights.

This paper explores how the diagnosis of mental disorder may affect the diagnosed subject’s self-concept by supplying an account that emphasizes the influence of autobiographical and social narratives on self-understanding. It focuses primarily on the diagnoses made according to the criteria provided by the Diagnostic Statistical Manual of Mental Disorders (DSM), and suggests that the DSM diagnosis may function as a source of narrative that affects the subject’s self-concept. Engaging in this analysis by appealing to autobiographies and memoirs written by (...) people diagnosed with mental disorder, the paper concludes that a DSM diagnosis is a double-edged sword for self- concept. On the one hand, it sets the subject’s experience in an established classificatory system which can facilitate self-understanding by providing insight into subject’s condition and guiding her personal growth, as well as treatment and recovery. In this sense, the DSM diagnosis may have positive repercussions on self-development. On the other hand, however, given the DSM’s symptom-based approach and its adoption of the Biomedical Disease model, a diagnosis may force the subject to make sense of her condition divorced from other elements in her life that may be affecting her mental- health. It may lead her frame her experience only as an irreversible imbalance. This form of self-understanding may set limits on the subject’s hopes of recovery and may create impediments to her flourishing. (shrink)

DNA methylation can be considered a component of epigenetic memory with a critical role during embryo development, and which undergoes dramatic reprogramming after fertilization. Though it has been a focus of research for many years, the reprogramming mechanism is still not fully understood. Recent results suggest that absence of maintenance at DNA replication is a major factor, and that there is an unexpected role for TET3-mediated oxidation of 5mC to 5hmC in guarding against de novo methylation. Base-resolution and genome-wide profiling (...) methods are enabling more comprehensive assessments of the extent to which ART might impair DNA methylation reprogramming, and which sequence elements are most vulnerable. Indeed, as we also review here, studies showing the effect of culture media, ovarian stimulation or embryo transfer on the methylation pattern of embryos emphasize the need to face ART-associated defects and search for strategies to mitigate adverse effects on the health of ART-derived children. DNA methylation, critical for embryo development, suffers significant changes after fertilization, including demethylation, remethylation and TET3-mediated oxidation of 5 mC to 5 hmC. In addition to infertility and environmental insults, ART could impact DNA methylation and ART related consequences in the offspring have been reported. (shrink)

Diagnostic frameworks are essential to many scientific and technological activities and clinical practice. This study examines the main fundamental aspects of such frameworks. The three components required for all diagnoses are identified and examined, i.e. their normative dimension, temporal nature and structure, and teleological perspective.The normative dimension of a diagnosis is based on (1) epistemic values when associated with Hempel's inductive risk concerning the balance between false‐positive and false‐negative outcomes, leading to probabilistic judgements; and (2) non‐epistemic values when related to (...) ideas such as well‐being, normality, illness, etc, as idealized norms or ideal points of reference.It should be noted that medical diagnoses match the three necessary components, while some essential diagnostic frameworks – the taxonomies of Gordon and NANDA – in nursing lack some components. The main lack is normative as the most popular frameworks in nursing diagnosis seem to be descriptions of observed reality rather than normative and value‐based judgements in which both epistemic and non‐epistemic values may coexist. (shrink)

The pedagogical function of science teaching may benefit from an analysis of the historical-epistemic dimension, without neglecting the socio-political context in which a given research was carried out. In the case of DNA structure, the background of its discovery is particularly complex. Starting from the analysis of some papers, the view on the circumstances that led to their drafting broadens. We try to answer the fundamental question for any educator: why teach all that? Ethics issues are related to the general (...) organisation of research, increasingly focused on speed and competition. Even teaching is affected by these dynamics, not only in higher education, but also at secondary level; students should be made aware of this trend. The history of science could therefore favour a more general awareness. _SUNTO_ La funzione pedagogica dell’insegnamento scientifico può trarre vantaggio da un’analisi della dimensione storico-epistemica, senza trascurare il contesto socio-politico nel quale una determinata ricerca è stata condotta. Nel caso della struttura del DNA, i retroscena della sua scoperta sono particolarmente complessi. Dopo l’analisi di alcuni articoli, si allarga gradualmente la vista sulle circostanze che hanno condotto alla loro stesura. Si cerca di rispondere a una domanda fondamentale per ogni educatore: perché insegnare tutto ciò? Le questioni etiche riguardano l’organizzazione generale della ricerca, sempre più tesa alla velocità e alla competizione. Persino l’insegnamento è influenzato da dinamiche simili, non solo in ambito accademico, ma anche a livello secondario; gli studenti dovrebbero essere a conoscenza di questa tendenza. La storia della scienza può dunque favorire una maggiore consapevolezza. (shrink)

This paper focuses on the question of whether DNA patents help or hinder scientific discovery and innovation. While DNA patents create a wide variety of possible benefits and harms for science and technology, the evidence we have at this point in time supports the conclusion that they will probably promote rather than hamper scientific discovery and innovation. However, since DNA patenting is a relatively recent phenomena and the biotechnology industry is in its infancy, we should continue to gather evidence about (...) the effects of DNA patenting on scientific innovation and discovery as well the economic, social, and legal conditions relating to intellectual property in biotechnology. We should give the free market, the courts, researchers, and patent offices a chance to settle issues related to innovation and discovery, before we seek legislative remedies, since new laws proposed at this point would lack adequate foresight and could do more harm than good. However, we should be open to new laws or regulations on DNA patents if they are required to in order to deal with some of the biases and limitations of the free market. (shrink)

DNA topoisomerases, capable of manipulating DNA topology, are ubiquitous and indispensable for cellular survival due to the numerous roles they play during DNA metabolism. As we review here, current structural approaches have revealed unprecedented insights into the complex DNA‐topoisomerase interaction and strand passage mechanism, helping to advance our understanding of their activities in vivo. This has been complemented by single‐molecule techniques, which have facilitated the detailed dissection of the various topoisomerase reactions. Recent work has also revealed the importance of topoisomerase (...) interactions with accessory proteins and other DNA‐associated proteins, supporting the idea that they often function as part of multi‐enzyme assemblies in vivo. In addition, novel topoisomerases have been identified and explored, such as topo VIII and Mini‐A. These new findings are advancing our understanding of DNA‐related processes and the vital functions topos fulfil, demonstrating their indispensability in virtually every aspect of DNA metabolism. (shrink)

Diagnosing the Diagnostic and Statistical Manual of Mental Disorders (Karnac, 2014) evaluates the latest edition of the D.S.M.The publication of D.S.M-5 in 2013 brought many changes. Diagnosing the Diagnostic and Statistical Manual of Mental Disorders asks whether the D.S.M.-5 classifies the right people in the right way. It is aimed at patients, mental health professionals, and academics with an interest in mental health. Issues addressed include: How is the D.S.M. affected by financial links with the pharmaceutical industry? To what extent (...) were and should patients involved in revising the classification? How are diagnoses added to the D.S.M.? Does medicalization threaten the idea that anyone is normal? What happens when changes to diagnostic criteria mean that people lose their diagnoses? How important will the D.S.M. be in the future? (shrink)