A Multistakeholder Perspective on Advancing Individualized Therapeutics.

Precision medicine has evolved from the application of pharmacogenetic biomarkers to the prospective development of targeted therapies in patients with specific molecular/genetic subtypes of disease to truly "N-of-1" medicines targeted to very small numbers of patients - in some cases, a single identified patient. This latter iteration of precision medicine presents unprecedented opportunities for patients with severe, life-threatening, or life-limiting diseases. At the same time, these modalities present complex scientific, clinical, and regulatory challenges. To realize the promise of individualized medicines, a multistakeholder approach to streamlining medical diagnoses, advancing the technologies that enable development of these therapeutic modalities, and re-envisioning collaborative environments for access and evidence generation is of critical importance. Herein, we highlight some of these challenges and opportunities.

Neuroethical implications of focused ultrasound for neuropsychiatric illness.

BACKGROUND: MR-guided focused ultrasound is a promising intervention for treatment-resistant mental illness, and merits contextualized ethical exploration in relation to more extensive ethical literature regarding other psychosurgical and neuromodulation treatment options for this patient population. To our knowledge, this topic has not yet been explored in the published literature. OBJECTIVE: The purpose of this paper is to review and discuss in detail the neuroethical implications of MR-guided focused ultrasound for neuropsychiatric illness as an emerging treatment modality. METHODS: Due to the lack of published literature on the topic, the approach involved a detailed survey and review of technical and medical literature relevant to focused ultrasound and established ethical issues related to alternative treatment options for patients with treatment-resistant, severe and persistent mental illness. The manuscript is structured according to thematic and topical findings. RESULTS: This technology has potential benefits for patients suffering with severe mental illness, compared with established alternatives. The balance of technical, neuroscientific and clinical considerations should inform ethical deliberations. The nascent literature base, nuances in legal classification and permissibility depending upon jurisdiction, influences of past ethical issues associated with alternative treatments, tone and framing in media articles, and complexity of clinical trials all influence ethical assessment and evaluations of multiple stakeholders. Recommendations for future research are provided based on these factors. CONCLUSION: Salient ethical inquiry should be further explored by researchers, clinicians, and ethicists in a nuanced manner methodologically, one which is informed by past and present ethical issues related to alternative treatment options, broader psychiatric treatment frameworks, pragmatic implementation challenges, intercultural considerations, and patients' ethical concerns.

Acceptance of genetic editing and of whole genome sequencing of human embryos by patients with infertility before and after the onset of the COVID-19 pandemic.

RESEARCH QUESTION: Has acceptance of heritable genome editing (HGE) and whole genome sequencing for preimplantation genetic testing (PGT-WGS) of human embryos changed after the onset of COVID-19 among infertility patients? DESIGN: A written survey conducted between April and June 2018 and July and December 2021 among patients at a university-affiliated infertility practice. The questionnaire ascertained the acceptance of HGE for specific therapeutic or genetic 'enhancement' indications and of PGT-WGS to prevent adult disease. RESULTS: In 2021 and 2018, 172 patients and 469 patients (response rates: 90% and 91%, respectively) completed the questionnaire. In 2021, significantly more participants reported a positive attitude towards HGE, for therapeutic and enhancement indications. In 2021 compared with 2018, respondents were more likely to use HGE to have healthy children with their own gametes (85% versus 77%), to reduce disease risk for adult-onset polygenic disorders (78% versus 67%), to increase life expectancy (55% versus 40%), intelligence (34% versus 26%) and creativity (33% versus 24%). Fifteen per cent of the 2021 group reported a more positive attitude towards HGE because of COVID-19 and less than 1% a more negative attitude. In contrast, support for PGT-WGS was similar in 2021 and 2018. CONCLUSIONS: A significantly increased acceptance of HGE was observed, but not of PGT-WGS, after the onset of COVID-19. Although the pandemic may have contributed to this change, the exact reasons remain unknown and warrant further investigation. Whether increased acceptability of HGE may indicate an increase in acceptability of emerging biomedical technologies in general needs further investigation.

New monkey embryo models-it's getting complicated.

Li et al.1 report on the generation of cynomolgus monkey models of blastocyst-stage embryos (called "blastoids") using naive cynomolgus embryonic stem cells. These blastoids recapitulate gastrulation in vitro and induce early pregnancy responses when transferred into cynomolgus monkey surrogates, prompting consideration of the policy implications for human blastoid research.

Stem cell ethics and policy: What's old is new again.

Stem cells are increasingly being used to model human development and disease in the form of self-organizing embryo models, brain organoids, and neurological chimeras. These new research directions are resurrecting old embryo debates around moral status and personhood. Hyun considers how these old questions are tackled in these new contexts.

Moral Status and the Oversight of Research Involving Chimeric Animals.

The use of nonhuman animals in research has long been a source of bioethical and scientific debate. We consider the oversight and use of nonhuman animals in chimeric research. We conducted interviews with twelve members of embryonic stem cell research oversight committees, nine members of institutional animal care and use committees, and fourteen scientists involved in human-nonhuman-animal chimeric research in different areas of the United States. Interviews addressed animal welfare and conceptual issues associated with moral status and humanization of nonhuman animals that contain human cells. Our findings suggest that concepts of enhanced moral status and consciousness are not very useful in human-nonhuman-animal chimeric research in part because their meanings are not easily defined, which presents challenges to applying the concepts in research. Instead, scientists and oversight committee members we interviewed seemed to rely on standard assessments of changes in animal welfare when focusing on the ethics of human-animal chimeric research.

Clarifying the Ethics and Oversight of Chimeric Research.

This article is the lead piece in a special report that presents the results of a bioethical investigation into chimeric research, which involves the insertion of human cells into nonhuman animals and nonhuman animal embryos, including into their brains. Rapid scientific developments in this field may advance knowledge and could lead to new therapies for humans. They also reveal the conceptual, ethical, and procedural limitations of existing ethics guidance for human-nonhuman chimeric research. Led by bioethics researchers working closely with an interdisciplinary work group, the investigation focused on generating conceptual clarity and identifying improvements to governance approaches, with the goal of helping scholars, funders, scientists, institutional leaders, and oversight bodies (embryonic stem cell research oversight [ESCRO] committees and institutional animal care and use committees [IACUCs]) deliver principled and trustworthy oversight of this area of science. The article, which focuses on human-nonhuman animal chimeric research that is stem cell based, identifies key ethical issues in and offers ten recommendations regarding the ethics and oversight of this research. Turning from bioethics' previous focus on human-centered questions about the ethics of "humanization" and this research's potential impact on concepts like human dignity, this article emphasizes the importance of nonhuman animal welfare concerns in chimeric research and argues for less-siloed governance and oversight and more-comprehensive public communication.

The need for a standard for informed consent for collection of human fetal material.

The ISSCR has developed the Informed Consent Standards for Human Fetal Tissue Donation and Research to promote uniformity and transparency in tissue donation and collection. This standard is designed to assist those working with and overseeing the regulation of such tissue and reassure the wider community and public.

Rescuing human fetal tissue research in the United States: A call for additional regulatory reform.

Research using human fetal tissue has saved millions of lives through vaccines and other advances, but was markedly restricted by federal regulations in 2019. Although the restrictions were partially reversed in 2021, additional regulatory changes are needed to prevent further damage to essential research programs while preserving protection for human subjects.

ISSCR Guidelines for Stem Cell Research and Clinical Translation: The 2021 update.

The International Society for Stem Cell Research has updated its Guidelines for Stem Cell Research and Clinical Translation in order to address advances in stem cell science and other relevant fields, together with the associated ethical, social, and policy issues that have arisen since the last update in 2016. While growing to encompass the evolving science, clinical applications of stem cells, and the increasingly complex implications of stem cell research for society, the basic principles underlying the Guidelines remain unchanged, and they will continue to serve as the standard for the field and as a resource for scientists, regulators, funders, physicians, and members of the public, including patients. A summary of the key updates and issues is presented here.

ISSCR guidelines for the transfer of human pluripotent stem cells and their direct derivatives into animal hosts.

The newly revised 2021 ISSCR Guidelines for Stem Cell Research and Clinical Translation includes scientific and ethical guidance for the transfer of human pluripotent stem cells and their direct derivatives into animal models. In this white paper, the ISSCR subcommittee that drafted these guidelines for research involving the use of nonhuman embryos and postnatal animals explains and summarizes their recommendations.

Rethinking organoid technology through bioengineering.

In recent years considerable progress has been made in the development of faithful procedures for the differentiation of human pluripotent stem cells (hPSCs). An important step in this direction has also been the derivation of organoids. This technology generally relies on traditional three-dimensional culture techniques that exploit cell-autonomous self-organization responses of hPSCs with minimal control over the external inputs supplied to the system. The convergence of stem cell biology and bioengineering offers the possibility to provide these stimuli in a controlled fashion, resulting in the development of naturally inspired approaches to overcome major limitations of this nascent technology. Based on the current developments, we emphasize the achievements and ongoing challenges of bringing together hPSC organoid differentiation, bioengineering and ethics. This Review underlines the need for providing engineering solutions to gain control of self-organization and functionality of hPSC-derived organoids. We expect that this knowledge will guide the community to generate higher-grade hPSC-derived organoids for further applications in developmental biology, drug screening, disease modelling and personalized medicine.

Ethical issues related to brain organoid research.

This review provides a snapshot of the current ethical issues related to research with human brain organoids. The issues fall into the following main themes: research oversight; human biomaterials procurement and donor consent; translational delivery; animal research; and organoid consciousness and moral status. Each of these areas poses challenges for researchers, bioethicists, regulators, research institutions, and tissue banks. However, progress can be made if these parties build on past experiences with stem cell research, ethics, and policy, but adapted accordingly to new aspects of brain organoid research.

Toward Guidelines for Research on Human Embryo Models Formed from Stem Cells.

Over the past few years, a number of research groups have reported striking progress on the generation of in vitro models from mouse and human stem cells that replicate aspects of early embryonic development. Not only do these models reproduce some key cell fate decisions but, especially in the mouse system, they also mimic the spatiotemporal arrangements of embryonic and extraembryonic tissues that are required for developmental patterning and implantation in the uterus. If such models could be developed for the early human embryo, they would have great potential benefits for understanding early human development, for biomedical science, and for reducing the use of animals and human embryos in research. However, guidelines for the ethical conduct of this line of work are at present not well defined. In this Forum article, we discuss some key aspects of this emerging area of research and provide some recommendations for its ethical oversight.

Ethical considerations for human-animal neurological chimera research: mouse models and beyond.

Research that uses stem cell-based chimeras promises to advance our understanding of human developmental biology, as well as new medical interventions, such as generating transplantable human organs in livestock. However, along with these exciting research possibilities come moral concerns about the moral humanization of animals, especially when it comes to the potential effects of human cells in the brains of experimental animals. Recent work involving neurologically chimeric mice may suggest that such worries are reasonable. However, this overlooks the crucial social and neurological conditions for enabling the development of conscious self-awareness, the absence of which leaves us only with animal welfare to monitor and consider.