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1. Research areas in which currently approved hESC lines sufficiently meet the needs of the research community as well as research areas for which new hESC lines are needed?
• hESC lines have been pivotal in a broad array of basic biological research studies including the use of genetically engineered lines, e.g. reporter lines, and expanding the genetic diversity as well as disease relevance with new hESC lines will provide for future advances.
• hESCs are being used for cell replacement therapies in many organ systems and are being tested in clinical trials for the treatment of Parkinson’s disease, age-related macular degeneration, epilepsy, and Type 1 diabetes, and access to additional genetically diverse hESC lines will provide new opportunities for therapies by reducing immune recognition as well as potentially beneficial biological responses, e.g lines carrying a favorable disease response genetic variant.
• New hESC lines are needed to study disease in which there are no other human models such as fertility research because the beginning of human development is inaccessible or embryonic lethal mutations where iPSC and other models are not possible.
2. Research areas for which hESCs are the gold standard and could not be pursued if hESCs were unavailable?
• hESC lines provide the “ground truth” of the earliest steps in human development because they are derived directly from the pre-implantation human embryo
• hESCs provide the only natural benchmark for defining human stem cells.
• hESCs are required to inform our understanding of how human organs develop, often in species-specific ways that are not recapitulated by animal models.
• Human ESCs remain the gold standard for human pluripotency and cannot be fully replaced by induced pluripotent stem cells (iPSCs). Although data shows that iPSCs are highly comparable and exhibit similar properties to hESCs in many respects, potentially important differences remain.
• The large number of genetically engineered hESC tools that are used in research and therapies would need to be rebuilt with other cell lines. The choice of the replacement cell line is not obvious, as many iPSCs have genomic or epigenomic variations.
• Pregnancy and fetal development are critical stages of life that have a large impact on the subsequent health of both mother and offspring. However, many aspects of both healthy development and pathology during this period remain poorly understood due to the logistical difficulties in obtaining samples.
3. Research areas in which the robustness of emerging biotechnologies such as induced pluripotent stem cells, adult stem cells, etc., can replace the use of hESCs:
• hESCs cannot be replaced by current alternative technologies and are needed as a reference standard and a benchmark for future work and the development of these alternatives. Lack of this benchmark may slow technological advancement or create insufficient technologies.
• hiPSCs have substantially expanded the field, but they are reprogrammed derivatives of adult somatic cells and do not fully replicate all epigenetic and developmental features of hESCs
• hIPSCs are more prone to harbor deleterious mutations, either from the somatic cell source or in the reprogramming process with the stress of prolonged passaging.
• Adult stem cells have limited utility as potential replacements for hESCs. Adult stem cells are not pluripotent (cannot differentiate into all cell types) and so their utility is restricted to the organ system from which they were derived (e.g. cord blood stem cells and blood). Adult stem cells cannot be maintained indefinitely in culture (not continuously self-renewing), requiring constant sourcing from individuals. Adult stem cells do not recapitulate features of the earliest steps in human development.
• An effective strategy should strengthen complementary technologies such as iPSCs, organoid systems, and genomic stability monitoring, while maintaining access to hESCs that serve as essential biological reference standards.
4. Research areas in which additional investments should be made to bolster validated models to replace use of hESCs:
• Comprehensive epigenomics, multiomics, metabolic, and functional comparisons to fully define the differences between hESCs and hiPSCs or other potential alternative technologies
• Methods to engineer hiPSCs to an hESC-like state would be needed but we do not have sufficient knowledge to do so.
• Rebuilding of infrastructure (e.g. banking and characterization) and tools (e.g. gene edited cells) would be needed to provide accessibility to high quality research reagents and enable researchers to carry out their research and therapeutic products.
• Public resources have been invested in the past thirty years to establish hESCs as a well-characterized biomedical research tool that expands our ability to understand human development and disease and to devise cell therapies to mitigate disease. Limiting access to hESCs would represent a waste of the public resources invested over the past several decades.