Revising,Correcting, and Transferring Genes

Abstract

The distinction between germline and somatic gene editing is fundamental to the ethics of human gene editing. Multiple conferences of scientists, ethicists, and policymakers, and multiple professional bodies, have called for moratoria on germline gene editing, and editing of human germline cells is considered to be an ethical “red line” that either never should be crossed, or should only be crossed with great caution and care. However, as research on germline gene editing has progressed, it has become clear that not all germline interventions are alike, and that these differences make a significant moral difference, when it comes to ethical questions about research, regulation, clinical application, and medical justification. In this paper, I argue that, rather than lumping all germline interventions together, we should distinguish between revising, correcting, and transferring genes, and I assess the consequences of this move for the ethics of gene editing.     

CRISPR/Cas9 genome editing – new and old ethical issues arising from a revolutionary technology

Although germline editing has been the subject of debate ever since the 1980s, it tended to be based rather on speculative assumptions until April 2015, when CRISPR/Cas9 technology was used to modify human embryos for the first time. This article combines knowledge about the technical and scientific state of the art, economic considerations, the legal framework and aspects of clinical reality. A scenario will be elaborated as a means of identifying key ethical implications of CRISPR/Cas9 genome editing in humans and possible ways of dealing with them. Unlike most other discussions of CRISPR/Cas9 germline editing, which are generally based on deontological arguments, the focus in this case will be on a consequentialistic argument against certain applications of germline and somatic editing that takes not only the potential benefits and risks but also socioeconomic issues into consideration. The practical need for an indication catalogue, guidelines for clinical trials, and for funding of basic research will be pointed out. It will be argued that this need for regulatory action and discussion does not stem primarily from the fact that CRISPR/Cas9 germline editing is revolutionary in terms of its ethical implications and potential for human therapy, although this is the prevailing view in the current discussion. Understanding the value and interest dependency of arguments put forward by different stakeholders and learning from past debates related to similar technologies might prove a fruitful method of reaching judgments and decisions that come closer to a consensus upon which society as a whole can agree - which after all should be the true goal of an ethical debate and of bioethics.     

Human Genome Editing and Ethical Considerations

Editing human germline genes may act as boon in some genetic and other disorders. Recent editing of the genome of the human embryo with the CRISPR/Cas9 editing tool generated a debate amongst top scientists of the world for the ethical considerations regarding its effect on the future generations. It needs to be seen as to what transformation human gene editing brings to humankind in the times to come.     

Raising the Virtuous Bar: The Underlying Issues of Genetic Moral Enhancement

From the perspective of virtue ethics, is it possible and permissible to enhance moral behavior through gene modification? In preparation to answer this question, we must ask five questions: (1) What may we assume regarding genetic inheritance and human nature? (2) Can specific genes predispose behavior related to the moral virtues? (3) What kind of genetic enhancement would be useful for moral enhancement? (4) Should there be a distinction between somatic and germline gene modification? (5) Is genetic modification best approach to moral enhancement? This article concedes that genetic engineering has the capacity to enhance the human disposition to moral behavior, but gene editing cannot create virtue because virtues are stable, habituated dispositions, acquired over time. That being said, gene editing for purposes of enhancing moral behavior is permissible.     

Editing the Reactive Genome: Towards a Postgenomic Ethics of Germline Editing

The reported birth of genetically modified twins in late 2018 has given new fuel to debates about the ethics of germline genome editing (GGE). There is a broad consensus among stakeholders that clinical uses of GGE should be temporarily banned as the technology is not yet deemed safe for use in humans. However, the idea of a complete ban is dismissed by many based on the expectation that more research will eventually allow scientists to make the technology safe without having to put humans at risk first. In this article, I will analyse this assumption and argue that it is undermined by recent developments in the postgenomic life sciences. In particular, I will argue that in a postgenomic view of germline editing a complete ban on specific uses of the technology is warranted, because the research needed to assess the safety of these interventions would not be morally defensible.     

Trust in Science: CRISPR–Cas9 and the Ban on Human Germline Editing

In 2015 scientists called for a partial ban on genome editing in human germline cells. This call was a response to the rapid development of the CRISPR–Cas9 system, a molecular tool that allows researchers to modify genomic DNA in living organisms with high precision and ease of use. Importantly, the ban was meant to be a trust-building exercise that promises a ‘prudent’ way forward. The goal of this paper is to analyse whether the ban can deliver on this promise. To do so the focus will be put on the precedent on which the current ban is modelled, namely the Asilomar ban on recombinant DNA technology. The analysis of this case will show (a) that the Asilomar ban was successful because of a specific two-step containment strategy it employed and (b) that this two-step approach is also key to making the current ban work. It will be argued, however, that the Asilomar strategy cannot be transferred to human genome editing and that the current ban therefore fails to deliver on its promise. The paper will close with a reflection on the reasons for this failure and on what can be learned from it about the regulation of novel molecular tools.     

Yesterday’s Child: How Gene Editing for Enhancement Will Produce Obsolescence—and Why It Matters

Despite the advent of CRISPR, safe and effective gene editing for human enhancement remains well beyond our current technological capabilities. For the discussion about enhancing human beings to be worth having, then, we must assume that gene-editing technology will improve rapidly. However, rapid progress in the development and application of any technology comes at a price: obsolescence. If the genetic enhancements we can provide children get better and better each year, then the enhancements granted to children born in any given year will rapidly go out of date. Sooner or later, every modified child will find him- or herself to be “yesterday’s child.” The impacts of such obsolescence on our individual, social, and philosophical self-understanding constitute an underexplored set of considerations relevant to the ethics of genome editing.     

Flashing the Yellow Traffic Light: Choices Forced Upon Us by Gene Editing Technologies

The 2018 birth of two designer babies in China has sparked an immediate global controversy over the ethics of gene editing. For the longer range future, however, we must assess how CRISPR/Cas9, like so many other new bio-technologies, is forcing choice—moral choice—on a large scale. Gene editing for purposes of medical therapy, human enhancement, engineering of future children, and even creating a posthuman species, confront our society with the inescapable necessity of making moral choices. The task for churches in partnership with universities is not to decide in advance what is right or wrong. Rather, it is to prepare our people to make responsible choices.     

Some neurolinguistic implications of prearticulatory editing in production

This paper argues that a complete model of language production must include a prearticulatory editing component. The function of this component is to monitor planned speech for deviations from the speaker's intention and repair any deviations that are found. It is claimed that adding such an editing component onto a production model fundamentally changes any account of aphasic symptoms using that model. As a case in point it is shown that E. M. Saffran's (1982, British Journal of Psychology, 73, 317-337) argument that agrammatic Broca's aphasia involves a deficit at the functional level of M. F. Garrett's (1975, in G. H. Bower (Ed.). The psychology of learning and motivation, New York: Academic Press) production model is no longer sound when prearticulatory editing processes are considered.     

Recollection rejection: how children edit their false memories.

A new methodology is presented for studying children's ability to suppress memory reports of false-but-gist-consistent events, one that measures children's use of a specific editing operation (recollection rejection) that suppresses false reports by accessing verbatim traces of true events. Children make memory reports under 2 instructional conditions, verbatim and gist, and the data are analyzed with fuzzy-trace theory's conjoint-recognition model. Application of the new methodology in studies of children's false memory for narrative events revealed that (a) false-memory editing increases dramatically between early and middle childhood, (b) even young children spontaneously edit their false memories, (c) measures of children's false-memory editing react appropriately to experimental manipulations, and (d) developmental reductions in the incidence of false-memory reports are primarily due to developmental improvements in verbatim memory ability (rather than to decreases in the formation of false memories). Implications for child forensic interviewing are discussed.     

Assessing the Predictive Accuracy of hMLH1 and hMSH2 Mutation Probability Models

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by a susceptibility to colorectal and extra-colonic cancers. Several guidelines exist for the identification of families suspected of having HNPCC, however these guidelines lack adequate sensitivity and specificity. In an attempt to improve accuracy for the detection of individuals with HNPCC, the Wijnen pre-test probability model (1998) and Myriad Genetics Laboratory prevalence table (2004) were developed. Here we evaluate the Wijnen model and Myriad table at predicting the presence of a mutation in individuals undergoing genetic testing for HNPCC. Forty-nine patients who had undergone genetic testing for germline mutations in hMLH1 and/or hMSH2 were part of our analysis. Our results revealed that the revised Bethesda guidelines performed with the highest sensitivity for germline mutations (94.4%), however the specificity was low (12.9%). Using a 10.0% mutation probability threshold, the Wijnen model and Myriad table had sensitivities of 55.6 and 60.0%, respectively and specificities of 54.8 and 23.8%, respectively. The Wijnen model and Myriad table were poor predictors of mutation prevalence, which is shown by the areas underneath their corresponding receiver operator characteristic curves (0.616 and 0.400, respectively). The results of this study demonsrate that neither the Wijnen model nor the Myriad table are sensitive or specific enough to be used as the only indication when to offer genetic testing for HNPCC.     

Traditional Roles in a Non-Traditional Setting: Genetic Counseling in Precision Oncology

Next generation sequencing technology is increasingly utilized in oncology with the goal of targeting therapeutics to improve response and reduce side effects. Interpretation of tumor mutations requires sequencing of paired germline DNA, raising questions about incidental germline findings. We describe our experiences as part of a research team implementing a protocol for whole genome sequencing (WGS) of tumors and paired germline DNA known as the Michigan Oncology Sequencing project (MI-ONCOSEQ) that includes options for receiving incidental germline findings. Genetic counselors (GCs) discuss options for return of results with patients during the informed consent process and document family histories. GCs also review germline findings and actively participate in the multi-disciplinary Precision Medicine Tumor Board (PMTB), providing clinical context for interpretation of germline results and making recommendations about disclosure of germline findings. GCs have encountered ethical and counseling challenges with participants, described here. Although GCs have not been traditionally involved in molecular testing of tumors, our experiences with MI-ONCOSEQ demonstrate that GCs have important applicable skills to contribute to multi-disciplinary care teams implementing precision oncology. Broader use of WGS in oncology treatment decision making and American College of Medical Genetics and Genomics (ACMG) recommendations for active interrogation of germline tissue in tumor-normal dyads suggests that GCs will have future opportunities in this area outside of research settings.     

The Editing Density of Moving Images Influences Viewers’ Time Perception: The Mediating Role of Eye Movements

The present study examined whether cinematographic editing density affects viewers’ perception of time. As a second aim, based on embodied models that conceive time perception as strictly connected to the movement, we tested the hypothesis that the editing density of moving images also affects viewers’ eye movements and that these later mediate the effect of editing density on viewers’ temporal judgments. Seventy participants watched nine video clips edited by manipulating the number of cuts (slow- and fast-paced editing against a master shot, unedited condition). For each editing density, multiple video clips were created, representing three different kinds of routine actions. The participants’ eye movements were recorded while watching the video, and the participants were asked to report duration judgments and subjective passage of time judgments after watching each clip. The results showed that participants subjectively perceived that time flew more while watching fast-paced edited videos than slow-paced or unedited videos; by contrast, concerning duration judgments, participants overestimated the duration of fast-paced videos compared to the master-shot videos. Both the slow- and the fast-paced editing generated shorter fixations than the master shot, and the fast-paced editing led to shorter fixations than the slow-paced editing. Finally, compared to the unedited condition, editing led to an overestimation of durations through increased eye mobility. These findings suggest that the editing density of moving images by increasing the number of cuts effectively altered viewers’ experience of time and add further evidence to prior research showing that performed eye movement is associated with temporal judgments.     

ARE WE CLOSER TO FREE MARKET EUGENICS? THE CRISPR CONTROVERSY

Might the 2018 birth of two designer babies in China write the opening paragraph for the next chapter in the history of eugenics? The worldwide scientific community has tacitly put a moratorium on human clinical application of CRISPR gene editing, waiting until unknown risks can become known. But this ethical agreement has been breached, and calls are now being heard for more rigorous regulations. Perhaps religious and spiritual leaders can join the bioethical chant: the yellow light of caution is flashing.     

TOWARD VERIFYING THE ASSUMPTIONS OF LABORATORY-INDUCED SLIPS OF THE TONGUE: THE OUTPUT-ERROR AND EDITING ISSUES

During the second half of the past decade, psycholinguistic models of speech production have been modified to include a “prearticulatory editing” component, the supposed function of which is to verify the linguistic integrity of impending phoneme strings destined for articulation. Empirical support for psycholinguistic editing comes primarily from studies by the present authors on laboratory-induced verbal slips. All of these studies have depended upon two crucial claims: that laboratory slips are errors of output, and that error-rate differentials are evidence of editing. Recently, however, it has been recognized that neither of these assumptions has been convincingly demonstrated, and consequently the editing models instigated by the earlier studies are being reassessed. The present study tested these two assumptions directly. The output-error assumption was supported by finding larger Galvanic Skin Resistance (GSR) responses for verbal slips than for correct vocalizations. The editing assumption was supported by finding that presumably edited vocal responses (identified by GSR) require more processing time (i.e., vocal response latency) than unedited responses. The reasoning from the empirical observations to conclusions about these assumptions is discussed in detail. Secondarily, a hypothesized social acceptability editing criterion was supported by the observation that neutral verbal slips outnumber taboo counterparts.     

记忆加工策略对ECM的影响

该研究采用ECM实验范式,操纵记忆加工策略验证联想网络模型或情绪渗透模型。电影片段诱发被试高兴或悲伤的情绪状态后,被试在有意识记和无意识记加工策略下学习情绪词,然后进行自由回忆。结果：情绪电影片段成功诱发被试高兴或悲伤情绪;被试在采用无意识记和有意识记加工策略学习情绪词时均出现ECM,无意识记加工策略下效应量的大小显著高于有意识记加工策略下效应量的大小,实验结果支持情绪渗透模型。     

The psychology of film: perceiving beyond the cut

First-order editing violations in film refer either to small displacements of the camera position or to small changes of the image size. Second-order editing violations follow from a reversal of the camera position (reversed-angle shot), leading to a change of the left–right position of the main actors (or objects) and a complete change of the background. With third-order editing violations, the linear sequence of actions in the narrative story is not obeyed. The present experiment focuses on the eye movements following a new shot with or without a reversed-angle camera position. The findings minimize the importance of editing rules which require perceptually smooth transitions between shots; there is also no evidence that changes in the left–right orientation of objects in the scene disturb the visual processing of successive shots. The observed eye movements are due either to the redirecting of attention to the most informative part on the scene or to attention shifts by motion transients in the shot. There is almost no evidence for confusion and/or for activities to restore the spatial arrangement following the reversal of the left–right positions.     

Multicategorical spline model for item response theory

Additional information contained in incorrect responses calls for a multicategorical rather than a binary analysis of multiple choice data. A nonparametric divided-by-total model for joint maximum likelihood estimation of probability-of-choice functions (for particular responses) and of latent ability is proposed. The model approximates probability functions by rational splines. Some illustrative examples of real test data analysis and the results of a Monte Carlo study are presented.The research in this paper was supported by the National Sciences and Engineering Research Council of Canada Grants OGP0105521 and APA 320 awarded to the first and the second author, respectively. The authors are indebted to R. Melzack and A. Baker for making available the data analyzed in this paper. We would also like to thank J. McKenna and B. Cont for their assistance in editing this paper.     

自拍照编辑与女大学生主观幸福感的关系:积极反馈与自我概念的中介作用

该研究基于自我差异理论与自我验证理论探究自拍照编辑与女大学生主观幸福感的关系,以及积极反馈与自我概念的中介作用。采用自拍照编辑问卷、线上自拍照积极反馈问卷、一般自我概念量表、主观幸福感量表对550名女大学生进行调查研究,结果发现：（1）自拍照编辑的频率、积极反馈、自我概念、主观幸福感两两之间均呈显著正相关;（2）自拍照编辑的频率通过三条中介路径影响女大学生主观幸福感：通过积极反馈的中介作用;通过自我概念的中介作用;通过积极反馈及自我概念的链式中介作用;（3）积极反馈与自我概念在自拍照编辑的频率与女大学生主观幸福感的关系中起完全中介作用。研究结果进一步揭示自拍照编辑对主观幸福感影响的作用机制,为女大学生健康使用社交网站及社交网站的功能完善提供依据。