Investigating Stakeholder Perspectives to Inform Ethical Use of Organoids in Pediatric Rare Disease Research

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SUMMARY Organoids are three-dimensional in vitro structures generated by programming stem cells into organ specific cell types. These cells self-organize in ways that mimic the structure and function of intact organs, which allows organoids to act as cellular models for organs in healthy and disease systems. When generated from patient stem cells, they contain the patient’s DNA and can recapitulate organ-specific disease phenotypes. Organoids can therefore be used for experimentation such as genetic modification and personalized therapeutic trials without subjecting patients to physical and medical risks. The parent award, Systematic Identification and Phenotypic Characterization of Causal Genetic Variants in Rare Disease-Associated Birth Defects, generates patient-derived brain organoid models of abnormal brain morphology from pediatric patients. These brain organoids are functionally profiled through single-cell and spatial transcriptomics and may be genetically modified to functionally characterize candidate causal genetic variants. These organoid studies hold great promise in identifying causal genetic variants and in characterizing their functional consequences. However, because organoids are derived from patient tissues they are not seen as morally neutral, with brain organoids perceived as having special moral value due to the brain’s central role in the concept of self and humanity. While the use of organoids in biomedical research is advancing quickly, the study of the bioethics of organoid use is in its infancy. Therefore, the moral and legal status of organoids has yet to be defined and policies and regulations specific to organoid use have yet to be developed. This supplement aims to provide an evidence-base and recommendations for policy around organoid use in research by exploring perceptions of organoids and their use in pediatric rare disease research in key stakeholders. The study will conduct in-depth interviews with 1) adolescent and young adult patients with diagnosed or suspected rare conditions, 2) parents of child with diagnosed or suspected rare conditions, 3) researchers actively working with organoids, and 4) bioethicists with expertise in pediatrics, research ethics, and/or emerging technologies. The patient and parent interviews will explore perceptions of organoids and imagined connection with various organoid types derived from patient tissues. They will also explore patient and parent perceived hopes and concerns for organoid use in research and desired limitations and protections. This data will be integrated into interview guides for researchers and bioethicists who will be asked not only their own perceived benefits and risks of organoid research, but to consider the findings from patient and parent interviews to suggest potential solutions that both preserve potential for organoid research and provide needed protections. The analysis will be reported and used to generate evidence-based recommendations for policies around organoid use in research.