A critical view on using "life not worth living" in the bioethics of assisted reproduction.

This paper critically engages with how life not worth living (LNWL) and cognate concepts are used in the field of beginning-of-life bioethics as the basis of arguments for morally requiring the application of preimplantation genetic diagnosis (PGD) and/or germline genome editing (GGE). It is argued that an objective conceptualization of LNWL is largely too unreliable in beginning-of-life cases for deriving decisive normative reasons that would constitute a moral duty on the part of intending parents. Subjective frameworks are found to be more suitable to determine LNWL, but they are not accessible in beginning-of-life cases because there is no subject yet. Conceptual and sociopolitical problems are additionally pointed out regarding the common usage of clear case exemplars. The paper concludes that a moral requirement for the usage of PGD and GGE cannot be derived from the conceptual base of LNWL, as strong reasons that can be reliably determined are required to limit reproductive freedom on moral grounds. Educated predictions on prospective well-being might still be useful regarding the determination of moral permissibility of PGD and/or GGE. It is suggested that due to the high significance of subjective experience in the normativity of beginning-of-life bioethics, the discipline is called to more actively realize the inclusion of people with disabilities. This regards for instance research design, citation practices, and language choices to increase the accessibility of societal debates on the reproductive ethics of genetic technologies.

The interplay of ethics and genetic technologies in balancing the social valuation of the human genome in UNESCO declarations.

This study investigates changes in the social valuation of the human genome over the more than 30 years since the establishment of the Human Genome Project. It offers a descriptive sociological analysis of the three waves of this valuation, mainly by considering three key UNESCO declarations and a relevant report. These waves represent a shifting balance between collectivism and individualism, starting with a broadly constructed valuation of the human genome as common human heritage and moving toward a valuation of dynamic applications within various social and medical contexts (e.g., personalized genomic medicine and genome editing). We seek to broaden the analytical perspective by examining how the declarations' ethical foci are framed within the context of rapidly evolving genetic technologies and their social applications. We conclude by discussing continuity and change in value balancing vis-à-vis changing genomic technologies.

What we know about effective public engagement on CRISPR and beyond.

Advances in gene editing technologies for human, plant, and animal applications have led to calls from bench and social scientists, as well as a wide variety of societal stakeholders, for broad public engagement in the decision-making about these new technologies. Unfortunately, there is limited understanding among the groups calling for public engagement on CRISPR and other emerging technologies about 1) the goals of this engagement, 2) the modes of engagement and what we know from systematic social scientific evaluations about their effectiveness, and 3) how to connect the products of these engagement exercises to societal decision or policy making. Addressing all three areas, we systematize common goals, principles, and modalities of public engagement. We evaluate empirically the likely successes of various modalities. Finally, we outline three pathways forward that deserve close attention from the scientific community as we navigate the world of Life 2.0.

Evaluation of Homology-Independent CRISPR-Cas9 Off-Target Assessment Methods.

The ability to alter genomes specifically by CRISPR-Cas gene editing has revolutionized biological research, biotechnology, and medicine. Broad therapeutic application of this technology, however, will require thorough preclinical assessment of off-target editing by homology-based prediction coupled with reliable methods for detecting off-target editing. Several off-target site nomination assays exist, but careful comparison is needed to ascertain their relative strengths and weaknesses. In this study, HEK293T cells were treated with Streptococcus pyogenes Cas9 and eight guide RNAs with varying levels of predicted promiscuity in order to compare the performance of three homology-independent off-target nomination methods: the cell-based assay, GUIDE-seq, and the biochemical assays CIRCLE-seq and SITE-seq. The three methods were benchmarked by sequencing 75,000 homology-nominated sites using hybrid capture followed by high-throughput sequencing, providing the most comprehensive assessment of such methods to date. The three methods performed similarly in nominating sequence-confirmed off-target sites, but with large differences in the total number of sites nominated. When combined with homology-dependent nomination methods and confirmation by sequencing, all three off-target nomination methods provide a comprehensive assessment of off-target activity. GUIDE-seq's low false-positive rate and the high correlation of its signal with observed editing highlight its suitability for nominating off-target sites for ex vivo CRISPR-Cas therapies.

Budgets versus Bans: How U.S. Law Restricts Germline Gene Editing.

In late 2019, He Jiankui, the Chinese scientist who created the world's first gene-edited babies, and two embryologists were sentenced to prison and fined. Thirteen months earlier, when the world first learned about the experiment, He and his colleagues drew swift and nearly uniform international condemnation for prematurely moving to human trials, for the risks they took with the children's health, and for He's secrecy. The organizing committee for the second genome editing summit said the experiment failed to conform with international norms." In the United States, the legal picture is complex. No doubt the specific experiment He performed would have run afoul of long-standing research regulations due to its problems with informed consent and ethical review. But other laws also affect this kind of work, in particular, a budget rider that for the past four years has been included in federal appropriations legislation.

Germline Genome Editing Research: What Are Gamete Donors (Not) Informed About in Consent Forms?

The potential for using germline genome editing (GGE) in humans has garnered a lot of attention, both for its scientific possibilities as well as for the ethical, legal, and social challenges it ignites. The ethical debate has focused primarily on the suggestions of using GGE to establish a pregnancy (i.e., to offer it in a clinical setting), which is, to date, illegal in many jurisdictions. The use of GGE in research (where a pregnancy would not be established) has received much less attention, despite the fact that it raises serious ethical and social issues as well. Herein, we report on the analysis of informed consent forms for egg and sperm donation used in a widely publicized study where genome editing was used to correct a disease-causing genetic mutation in human embryos. Importantly, embryos were created using eggs and sperm obtained specifically for these experiments. The analysis indicates deficiencies in how the forms addressed various issues, including limited and potentially misleading information about the sensitive nature of the study, the lack of an explicit mention of genomic sequencing, as well as the poor readability of the forms. Furthermore, the arguably high compensation of U.S.$5,000 for egg donors raises questions about undue inducement to participate in research. Moreover, since the procurement of eggs involves serious health risks, it may be questioned whether research requiring such a procedure should be pursued. If such experiments are continued, donors should be informed about all relevant aspects in order to make informed decisions about participating.

Focusing on Human Rights: a framework for CRISPR germline genome editing ethics and regulation.

The late 2018 announcement of the claimed births of CRISPR-edited babies has stimulated widespread condemnation and calls by some leading scientists for a moratorium on any further germline genome editing (GGE) for reproductive purposes. Concurrently, national and international bodies are calling for the development of robust guidelines and regulations that will identify permissible conditions under which such GGE efforts might eventually proceed. Crucially, these conditions go beyond rigorous safety standards to address some of the social and ethical concerns that arise with germline interventions. As these bodies convene to navigate this unique terrain, we suggest an important standard for generating ethically robust guidelines. Our approach builds from concerns about social exclusion and social justice with a focus on fundamental human rights. We believe that a deontological or rights-based approach, rather than a utilitarian approach, is needed to ensure that this socially disruptive technology minimizes further marginalization of people with disabilities and does not create a new form of social injustice. In pursuit of a deontological framework, we propose the implementation of an objective assessment tool: the Human Rights Impact Assessment (HRIA). Use of the HRIA establishes necessary constraints on applications of GGE in order to safeguard the most vulnerable members of society.

Islamic Perspectives on CRISPR/Cas9-Mediated Human Germline Gene Editing: A Preliminary Discussion.

The recent development of CRISPR/Cas9 technology has rekindled the ethical debate concerning human germline modification that has begun decades ago. This inexpensive technology shows tremendous promise in disease prevention strategies, while raising complex ethical concerns about safety and efficacy of the technology, human dignity, tampering with God's creation, and human genetic enhancement. Germline gene editing may result in heritable changes in the human genome, therefore the question of whether it should be allowed requires deep and careful discussion from various perspectives. This paper explores Islamic perspectives on the concerns raised and highlights the ethical principles in Islam that should be taken into consideration when assessing the permissibility of CRISPR/ Cas9-mediated human germline gene editing. As argued in this paper, human germline gene editing would be considered lawful for medical purpose under certain conditions. It should not be applied on humans until the safety and efficacy issues are resolved. Robust ethical guidelines and strict regulations are necessary to preserve human dignity and to prevent premature and misuse of the technology. Maqasid al-shariah's principles of preservation of human life, lineage, and dignity and 'preventing harm takes precedence over securing benefit' are among the guiding principles in assessing the permissibility of CRISPR/Cas9-mediated human germline editing from an Islamic perspective. Further discussions are important to address the controversies as well as to explore the related ethical principles.

Does human genome editing reinforce or violate human dignity?

Germline genome editing is often disapproved of at the international policy level because of its possible threats to human dignity. However, from a critical perspective the relationship between this emerging technology and human dignity is relatively understudied. We explore the main principles that are referred to when 'human dignity' is invoked in this context; namely, the link with eugenics, the idea of a common genetic heritage, the principle of equal birth and broader equality and justice concerns. Yet the concept is also used in favour of germline genome editing as it might improve the overall well-being of future generations. We conclude that dignity concerns do not justify a complete ban on safe heritable genome editing but should inform the implementation of side constraints to ensure that the value judgements about human traits that are inherent in this practice do not result in a diminished basic respect for those people affected by them.

How Should Gene Editing Be Managed by Risk Managers?

Gene editing, because it is a new technology, presents challenges to health care organizations' risk managers. At this time, little claims data exists upon which to make informed decisions about loss control and to draw upon when developing risk mitigation strategies. This article explores gene editing through the eyes of risk managers and underwriters and concludes that traditional risk management tools must be used to reduce risk until more is known about the frequency and severity of claims.

Why Include the Public in Genome Editing Governance Deliberation?

With the birth of genetically engineered twins in November 2018, international debate about human genome editing governance has moved from an emphasis on mutual engagement among multiple stakeholders to a self-regulatory model enacted through high-level expert groups with little or no public input. This article reconstructs this paradigm shift and suggests that inclusive public deliberation should still have a role in public decision making about genome editing.

What Should Clinicians Do to Engage the Public About Gene Editing?

Genome editing holds tremendous promise for preventing, ameliorating, or even curing disease, but a thorough discussion of its bioethical and social implications is necessary to protect humankind against harm, a central tenet of the original Hippocratic Oath. It is therefore essential that medical students, physicians, and all health care workers have a working understanding of what gene editing entails, the controversy surrounding its use, and its far-reaching clinical and ethical implications.

Human Germline Genome Editing: An Assessment.

This article assesses human germline genome editing (GGE). It argues that such editing is not inherently unethical, largely because of the fuzzy nature of "The Human Germline Genome" and its constant changes, often caused by humans. It further argues that GGE is unlikely to be very useful, at least in the near term to mid term. Other methods, such as preimplantation genetic testing and somatic cell gene therapy, are likely to be safer and more effective for dealing with avoiding single gene diseases. The main exceptions are rare couples wherein both have the same recessive condition or one has two copies of an allele causing a dominant condition. Although GGE should have advantages in dealing with multigenic or enhancement applications, our genomic knowledge is inadequate to support more than a few such applications for many years.

The Daunting Economics of Therapeutic Genome Editing.

There is no shortage of enthusiasm for the clinical potential of CRISPR-based genome editing: many life-changing cures appear to be just around the corner. However, as mature genetic therapies reach the market, it seems that million-dollar price tags are the new normal. Several factors contribute to the extreme pricing of next-generation medicines, including the need to recoup development costs, the undeniable value of these powerful therapies, and the inherent technical challenges of manufacture and delivery. CRISPR technology has been hailed as a great leveler and a democratizing force in biomedicine. But for this principle to hold true in clinical contexts, therapeutic genome editing must avoid several pitfalls that could substantially limit access to its transformative potential, especially in the developing world.

The clinical application of gene editing: ethical and social issues.

Gene-editing techniques have progressed rapidly in the past 5 years. There are already ongoing human somatic gene-editing clinical trials for multiple diseases. And there has been one purported scenario of human germline gene editing in late 2018. In this paper, we will review the current state of the technology, discuss the ethical and social issues that surround the various forms of gene editing, as well as review emerging stakeholder data from professionals, the 'general public' and individuals and families dealing with genetic diseases potentially treatable by gene editing.