An ethical framework for human embryology with embryo models.

A human embryo's legal definition and its entitlement to protection vary greatly worldwide. Recently, human pluripotent stem cells have been used to form in vitro models of early embryos that have challenged legal definitions and raised questions regarding their usage. In this light, we propose a refined legal definition of an embryo, suggest "tipping points" for when human embryo models could eventually be afforded similar protection to that of embryos, and then revisit basic ethical principles that might help to draft a roadmap for the gradual, justified usage of embryo models in a manner that aims to maximize benefits to society.

Synthetic Genomes.

DNA synthesis technology has progressed to the point that it is now practical to synthesize entire genomes. Quite a variety of methods have been developed, first to synthesize single genes but ultimately to massively edit or write from scratch entire genomes. Synthetic genomes can essentially be clones of native sequences, but this approach does not teach us much new biology. The ability to endow genomes with novel properties offers special promise for addressing questions not easily approachable with conventional gene-at-a-time methods. These include questions about evolution and about how genomes are fundamentally wired informationally, metabolically, and genetically. The techniques and technologies relating to how to design, build, and deliver big DNA at the genome scale are reviewed here. A fuller understanding of these principles may someday lead to the ability to truly design genomes from scratch.

Somatic Gene Therapy: Ethics and Access.

Manipulation of a patient's genome for therapeutic ends is being attempted through numerous methods, some of which have resulted in disease-modifying interventions. The much anticipated promise of somatic gene therapy is starting to pay off; however, there remain many scientific unknowns, including concerns about safety and durability. A significant ethical concern is that of access to these novel interventions, an issue that is normally framed in terms of the high costs of approved products. I describe how access issues permeate gene therapy long before there is any commercial product and how even upstream decisions-such as choices of indication to pursue, viral vector, and where to site a trial-have significant implications for access to resultant products in both the developmental and commercial stages.

Toward Realizing the Promise of AI in Precision Health Across the Spectrum of Care.

Significant progress has been made in augmenting clinical decision-making using artificial intelligence (AI) in the context of secondary and tertiary care at large academic medical centers. For such innovations to have an impact across the spectrum of care, additional challenges must be addressed, including inconsistent use of preventative care and gaps in chronic care management. The integration of additional data, including genomics and data from wearables, could prove critical in addressing these gaps, but technical, legal, and ethical challenges arise. On the technical side, approaches for integrating complex and messy data are needed. Data and design imperfections like selection bias, missing data, and confounding must be addressed. In terms of legal and ethical challenges, while AI has the potential to aid in leveraging patient data to make clinical care decisions, we also risk exacerbating existing disparities. Organizations implementing AI solutions must carefully consider how they can improve care for all and reduce inequities.

Vulnerability in research ethics: A call for assessing vulnerability and implementing protections.

Ethics standards reference the need for special consideration of vulnerable populations, such as pregnant women, incarcerated individuals, and minors. The concept of vulnerability is poorly conceptualized in the medical sciences where it originated, and its application to the social sciences is even more challenging. Social science researchers may unwittingly fail to appreciate preexisting vulnerabilities and indeed may be responsible for inducing new research-related vulnerability. In this paper, we present the first comprehensive coding of country-level vulnerability designations. Specifically, we coded all 355 official documents governing social/behavioral human subjects research for the 107 countries with such regulations and identified 68 distinct vulnerability categories. The data reveal substantial regional variation, overemphasis of categories derived from medical sciences, neglect of critical categories such as displacement, and likely heterogeneity within and across groups. The article provides a conceptual framework that shifts the problem away from static, enumerated categories toward emphasis on research-induced vulnerability. Based on our conceptualization and coding, we present a framework for assessing vulnerability and implementing appropriate protections.

Ethics and responsibility in biohybrid robotics research.

The industrial revolution of the 19th century marked the onset of an era of machines and robots that transformed societies. Since the beginning of the 21st century, a new generation of robots envisions similar societal transformation. These robots are biohybrid: part living and part engineered. They may self-assemble and emerge from complex interactions between living cells. While this new era of living robots presents unprecedented opportunities for positive societal impact, it also poses a host of ethical challenges. A systematic, nuanced examination of these ethical issues is of paramount importance to guide the evolution of this nascent field. Multidisciplinary fields face the challenge that inertia around collective action to address ethical boundaries may result in unexpected consequences for researchers and societies alike. In this Perspective, we i) clarify the ethical challenges associated with biohybrid robotics, ii) discuss the need for and elements of a potential governance framework tailored to this technology; and iii) propose tangible steps toward ethical compliance and policy formation in the field of biohybrid robotics.

Return of Results in Genomic Research Using Large-Scale or Whole Genome Sequencing: Toward a New Normal.

Genome sequencing is increasingly used in research and integrated into clinical care. In the research domain, large-scale analyses, including whole genome sequencing with variant interpretation and curation, virtually guarantee identification of variants that are pathogenic or likely pathogenic and actionable. Multiple guidelines recommend that findings associated with actionable conditions be offered to research participants in order to demonstrate respect for autonomy, reciprocity, and participant interests in health and privacy. Some recommendations go further and support offering a wider range of findings, including those that are not immediately actionable. In addition, entities covered by the US Health Insurance Portability and Accountability Act (HIPAA) may be required to provide a participant's raw genomic data on request. Despite these widely endorsed guidelines and requirements, the implementation of return of genomic results and data by researchers remains uneven. This article analyzes the ethical and legal foundations for researcher duties to offer adult participants their interpreted results and raw data as the new normal in genomic research.

Open Data in the Era of the GDPR: Lessons from the Human Cell Atlas.

The Human Cell Atlas (HCA) is striving to build an open community that is inclusive of all researchers adhering to its principles and as open as possible with respect to data access and use. However, open data sharing can pose certain challenges. For instance, being a global initiative, the HCA must contend with a patchwork of local and regional privacy rules. A notable example is the implementation of the European Union General Data Protection Regulation (GDPR), which caused some concern in the biomedical and genomic data-sharing community. We examine how the HCA's large, international group of researchers is investing tremendous efforts into ensuring appropriate sharing of data. We describe the HCA's objectives and governance, how it defines open data sharing, and ethico-legal challenges encountered early in its development; in particular, we describe the challenges prompted by the GDPR. Finally, we broaden the discussion to address tools and strategies that can be used to address ethical data governance.

Studying the impact of translational genomic research: Lessons from eMERGE.

Two major goals of the Electronic Medical Record and Genomics (eMERGE) Network are to learn how best to return research results to patient/participants and the clinicians who care for them and also to assess the impact of placing these results in clinical care. Yet since its inception, the Network has confronted a host of challenges in achieving these goals, many of which had ethical, legal, or social implications (ELSIs) that required consideration. Here, we share impediments we encountered in recruiting participants, returning results, and assessing their impact, all of which affected our ability to achieve the goals of eMERGE, as well as the steps we took to attempt to address these obstacles. We divide the domains in which we experienced challenges into four broad categories: (1) study design, including recruitment of more diverse groups; (2) consent; (3) returning results to participants and their health care providers (HCPs); and (4) assessment of follow-up care of participants and measuring the impact of research on participants and their families. Since most phases of eMERGE have included children as well as adults, we also address the particular ELSI posed by including pediatric populations in this research. We make specific suggestions for improving translational genomic research to ensure that future projects can effectively return results and assess their impact on patient/participants and providers if the goals of genomic-informed medicine are to be achieved.

A Scientist's Oath.

Data on the perceptions of scientists suggest a moderate public distrust of scientist's motivations. Bettridge et al. suggest scientist's reluctance to engage the public on controversial ethical issues may be a contributing factor. The authors propose a Scientist's Oath to send a clear message to the public about our ideals.

Should research administrators be regulated as carefully as researchers?

This essay assesses the rationale for regulating research administrators as carefully as they regulate researchers. The reasons for such regulation are identical: protecting scientific integrity, ensuring responsible use of public funds, addressing the lack of effective recourse for victims, creating negative consequences for misbehaving actors, and addressing high incentives for misconduct. Whereas the reasons compelling us to regulate research administrators are obvious, counterarguments to administrative oversight are based on suggestions that the incidence and prevalence of cases of administrative misconduct are too low to warrant formal regulation. I briefly describe examples of the phenomenon drawn from publicly available records. My analysis suggests that the misconduct of research administrators is both serious and worthy of better oversight. Improved oversight of research administration will help steward tax dollars appropriately and enhance the overall integrity of the scientific record and of the free pursuit of knowledge more generally.

Using the Veil of Ignorance to align AI systems with principles of justice.

The philosopher John Rawls proposed the Veil of Ignorance (VoI) as a thought experiment to identify fair principles for governing a society. Here, we apply the VoI to an important governance domain: artificial intelligence (AI). In five incentive-compatible studies (N = 2, 508), including two preregistered protocols, participants choose principles to govern an Artificial Intelligence (AI) assistant from behind the veil: that is, without knowledge of their own relative position in the group. Compared to participants who have this information, we find a consistent preference for a principle that instructs the AI assistant to prioritize the worst-off. Neither risk attitudes nor political preferences adequately explain these choices. Instead, they appear to be driven by elevated concerns about fairness: Without prompting, participants who reason behind the VoI more frequently explain their choice in terms of fairness, compared to those in the Control condition. Moreover, we find initial support for the ability of the VoI to elicit more robust preferences: In the studies presented here, the VoI increases the likelihood of participants continuing to endorse their initial choice in a subsequent round where they know how they will be affected by the AI intervention and have a self-interested motivation to change their mind. These results emerge in both a descriptive and an immersive game. Our findings suggest that the VoI may be a suitable mechanism for selecting distributive principles to govern AI.

Brain organoids, consciousness, ethics and moral status.

Advances in the field of human stem cells are often a source of public and ethical controversy. Researchers must frequently balance diverse societal perspectives on questions of morality with the pursuit of medical therapeutics and innovation. Recent developments in brain organoids make this challenge even more acute. Brain organoids are a new class of brain surrogate generated from human pluripotent stem cells (hPSCs). They have gained traction as a model for studying the intricacies of the human brain by using advancements in stem cell biology to recapitulate aspects of the developing human brain in vitro. However, recent observation of neural oscillations spontaneously emerging from these organoids raises the question of whether brain organoids are or could become conscious. At the same time, brain organoids offer a potentially unique opportunity to scientifically understand consciousness. To address these issues, experimental biologists, philosophers, and ethicists united to discuss the possibility of consciousness in human brain organoids and the consequent ethical and moral implications.

"When does human life begin?" teaching human embryology in the context of the American abortion debate.

The Dobbs decision of the United States Supreme Court and the actions of several state legislatures have made it risky, if not outright dangerous, to teach factual material concerning human embryology. At some state universities, for instance, if a professor's lecture is felt to teach or discuss abortion (as it might when teaching about tubal pregnancies, hydatidiform moles, or eneuploidy), that instructor risks imprisonment for up to 14 years (Gyori, 2023). Some states' new censorship rules have thus caused professors to drop modules on abortion from numerous science and humanities courses. In most states, instructors can still teach about human embryonic development and not risk putting their careers or livelihoods in jeopardy. However, even in many of these institutions, students can bring a professor to a disciplinary hearing by claiming that the instructor failed to provide ample trigger warnings on such issues. This essay attempts to provide some strategies wherein human embryology and the ethical issues surrounding it might be taught and students may be given resources to counter unscientific falsehoods about fertilization and human development. This essay provides evidence for teaching the following propositions. Mis-information about human biology and medicine is rampant on the internet, and there are skills that can be taught to students that will help them determine which sites should trusted. This is a skill that needs to be taught as part of science courses.

Use of Artificial Intelligence in Improving Outcomes in Heart Disease: A Scientific Statement From the American Heart Association.

A major focus of academia, industry, and global governmental agencies is to develop and apply artificial intelligence and other advanced analytical tools to transform health care delivery. The American Heart Association supports the creation of tools and services that would further the science and practice of precision medicine by enabling more precise approaches to cardiovascular and stroke research, prevention, and care of individuals and populations. Nevertheless, several challenges exist, and few artificial intelligence tools have been shown to improve cardiovascular and stroke care sufficiently to be widely adopted. This scientific statement outlines the current state of the art on the use of artificial intelligence algorithms and data science in the diagnosis, classification, and treatment of cardiovascular disease. It also sets out to advance this mission, focusing on how digital tools and, in particular, artificial intelligence may provide clinical and mechanistic insights, address bias in clinical studies, and facilitate education and implementation science to improve cardiovascular and stroke outcomes. Last, a key objective of this scientific statement is to further the field by identifying best practices, gaps, and challenges for interested stakeholders.

Thirty Years of Neuroscientific Investigation of Placebo and Nocebo: The Interesting, the Good, and the Bad.

Over the past 30 years there has been a surge of research on the placebo effect using a neuroscientific approach. The interesting aspects of this effort are related to the identification of several biological mechanisms of both the placebo and nocebo effects, the latter of which is defined as a negative placebo effect. Some important translational implications have emerged both in the setting of clinical trials and in routine medical practice. One of the principal contributions of neuroscience has been to draw the attention of the scientific and medical communities to the important role of psychobiological factors in therapeutic outcomes, be they drug related or not. Indeed, many biological mechanisms triggered by placebos and nocebos resemble those modulated by drugs, suggesting a possible interaction between psychological factors and drug action. Unfortunately, this new knowledge regarding placebos has the potential of being dangerously exploited by pseudoscience.

Ethical Guidance in Human Paleogenomics: New and Ongoing Perspectives.

Over the past two decades, the study of ancient genomes from Ancestral humans, or human paleogenomic research, has expanded rapidly in both scale and scope. Ethical discourse has subsequently emerged to address issues of social responsibility and scientific robusticity in conducting research. Here, we highlight and contextualize the primary sources of professional ethical guidance aimed at paleogenomic researchers. We describe the tension among existing guidelines, while addressing core issues such as consent, destructive research methods, and data access and management. Currently, there is a dissonance between guidelines that focus on scientific outcomes and those that hold scientists accountable to stakeholder communities,such as descendants. Thus, we provide additional tools to navigate the complexities of ancient DNA research while centering engagement with stakeholder communities in the scientific process.

A scoping review of guidelines for the use of race, ethnicity, and ancestry reveals widespread consensus but also points of ongoing disagreement.

The use of population descriptors such as race, ethnicity, and ancestry in science, medicine, and public health has a long, complicated, and at times dark history, particularly for genetics, given the field's perceived importance for understanding between-group differences. The historical and potential harms that come with irresponsible use of these categories suggests a clear need for definitive guidance about when and how they can be used appropriately. However, while many prior authors have provided such guidance, no established consensus exists, and the extant literature has not been examined for implied consensus and sources of disagreement. Here, we present the results of a scoping review of published normative recommendations regarding the use of population categories, particularly in genetics research. Following PRISMA guidelines, we extracted recommendations from n = 121 articles matching inclusion criteria. Articles were published consistently throughout the time period examined and in a broad range of journals, demonstrating an ongoing and interdisciplinary perceived need for guidance. Examined recommendations fall under one of eight themes identified during analysis. Seven are characterized by broad agreement across articles; one, "appropriate definitions of population categories and contexts for use," revealed substantial fundamental disagreement among articles. Additionally, while many articles focus on the inappropriate use of race, none fundamentally problematize ancestry. This work can be a resource to researchers looking for normative guidance on the use of population descriptors and can orient authors of future guidelines to this complex field, thereby contributing to the development of more effective future guidelines for genetics research.

"Choice of law" in precision medicine research.

Large-scale precision medicine research requires massive amounts of data representing people from all walks of life; thus, in the US, it is often multistate research. Significant legal and ethical quandaries arise as a result of the patchwork of laws states have enacted that may apply to research, are not preempted by federal law, and may impose requirements or provide participant rights and protections that differ from other states. Determining which state's laws apply, and under what circumstances, is not solved by the transition to a single-IRB model and researchers cannot simply choose one state's laws to apply uniformly. At a minimum, the current process of meeting each state's requirements could be made more reliable and efficient. To fundamentally change this status quo, however, requires action at multiple levels. Federally, well-known gaps in the Genetic Information Nondiscrimination Act should be closed, and a coherent system of compensation for research injury-including non-physical injuries-should be developed. States should clarify which of their laws are intended to apply to research and work collaboratively to harmonize them. At the level of individual research projects, numerous policies and procedures could be standardized through authoritative guidelines. Examples include clarifying the scope of broad consent, understanding and upholding Certificates of Confidentiality, offering individual research results responsibly, and consistently disseminating aggregate results to participants and the public. Overall, development of a choice of law framework specific to the research context could significantly promote clarity and consistency.

Is It Ever Wise to Edit Wild-Type Alleles? Engineered CRISPR Alleles Versus Millions of Years of Human Evolution.

The tremendous burden of lipid metabolism diseases, coupled with recent developments in human somatic gene editing, has motivated researchers to propose population-wide somatic gene editing of PCSK9 (proprotein convertase subtilisin/kexin type 9) within the livers of otherwise healthy humans. The best-characterized molecular function of PCSK9 is its ability to regulate plasma LDL (low-density lipoprotein) levels through promoting LDL receptor degradation. Individuals with loss-of-function PCSK9 variants have lower levels of plasma LDL and reduced cardiovascular disease. Gain-of-function variants of PCSK9 are strongly associated with familial hypercholesterolemia. A new therapeutic strategy delivers CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats; CRISPR-associated protein 9) specifically to liver cells to edit the wild-type alleles of PCSK9 with the goal of producing a loss-of-function allele. This direct somatic gene editing approach is being pursued despite the availability of US Food and Drug Administration-approved PCSK9 inhibitors that lower plasma LDL levels. Here, we discuss other characterized functions of PCSK9 including its role in infection and host immunity. We explore important factors that may have contributed to the evolutionary selection of PCSK9 in several vertebrates, including humans. Until such time that more fully understand the multiple biological roles of PCSK9, the ethics of permanently editing the gene locus in healthy, wild-type populations remains highly questionable.