The 'serious' factor in germline modification.

Current advances in assisted reproductive technologies aim to promote the health and well-being of future children. They offer the possibility to select embryos with the greatest potential of being born healthy (eg, preimplantation genetic testing) and may someday correct faulty genes responsible for heritable diseases in the embryo (eg, human germline genome modification (HGGM)). Most laws and policy statements surrounding HGGM refer to the notion of 'serious' as a core criterion in determining what genetic diseases should be targeted by these technologies. Yet, this notion remains vague and poorly defined, rendering its application challenging and decision making subjective and arbitrary. By way of background, we begin by briefly presenting two conceptual approaches to 'health' and 'disease': objectivism (ie, based on biological facts) and constructivism (ie, based on human values). The basic challenge under both is sorting out whether and to what extent social and environmental factors have a role in helping to define what qualifies as a 'serious' disease beyond the medical criteria. We then focus on how a human rights framework (eg, right to science and right to the highest attainable health) could integrate the concepts of objectivism and constructivism so as to provide guidance for a more actionable consideration of 'serious'. Ultimately, it could be argued that a human rights framework, by way of its legally binding nature and its globally accepted norms and values, provides a more universal foundation for discussions of the ethical, legal and social implications of emerging or disruptive technologies.

Moral reasons to edit the human genome: picking up from the Nuffield report.

In July 2018, the Nuffield Council of Bioethics released its long-awaited report on heritable genome editing (HGE). The Nuffield report was notable for finding that HGE could be morally permissible, even in cases of human enhancement. In this paper, we summarise the findings of the Nuffield Council report, critically examine the guiding principles they endorse and suggest ways in which the guiding principles could be strengthened. While we support the approach taken by the Nuffield Council, we argue that detailed consideration of the moral implications of genome editing yields much stronger conclusions than they draw. Rather than being merely 'morally permissible', many instances of genome editing will be moral imperatives.

Zinc finger nucleases: looking toward translation.

Genetic engineering has emerged as a powerful mechanism for understanding biological systems and a potential approach for redressing congenital disease. Alongside, the emergence of these technologies in recent decades has risen the complementary analysis of the ethical implications of genetic engineering techniques and applications. Although viral-mediated approaches have dominated initial efforts in gene transfer (GT) methods, an emerging technology involving engineered restriction enzymes known as zinc finger nucleases (ZFNs) has become a powerful new methodology for gene editing. Given the advantages provided by ZFNs for more specific and diverse approaches in gene editing for basic science and clinical applications, we discuss how ZFN research can address some of the ethical and scientific questions that have been posed for other GT techniques. This is of particular importance, given the momentum currently behind ZFNs in moving into phase I clinical trials. This study provides a historical account of the origins of ZFN technology, an analysis of current techniques and applications, and an examination of the ethical issues applicable to translational ZFN genetic engineering in early phase clinical trials.

Exome sequencing: dual role as a discovery and diagnostic tool.

Recent developments in high-throughput sequence capture methods and next-generation sequencing technologies have now made exome sequencing a viable approach to elucidate the genetic basis of Mendelian disorders with hitherto unknown etiology. In addition, exome sequencing is increasingly being employed as a diagnostic tool for specific genetic diseases, particularly in the context of those disorders characterized by significant genetic and phenotypic heterogeneity, for example, Charcot-Marie-Tooth disease and congenital disorders of glycosylation. Such disorders are challenging to interrogate with conventional polymerase chain reaction-Sanger sequencing methods, because of the inherent difficulty in prioritizing candidate genes for diagnostic testing. Here, we explore the value of exome sequencing as a diagnostic tool and discuss whether exome sequencing can come to serve a dual role in diagnosis and discovery. We summarize the current status of exome sequencing, the technical challenges facing it, and its adaptation to diagnostics, and make recommendations for the use of exome sequencing as a routine diagnostic tool. Finally, we discuss pertinent ethical concerns, such as the use of exome sequencing data, originally generated in a diagnostic context, in research investigations.