RECODE-ing the Logic of Ectodermal Organoid Patterning via Combinatorial Morphogen Treatments and Longitudinal Monitoring

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Brain organoids are living models of the human brain derived from stem cells. Organoids are also promising tools for understanding how the brain develops and studying neurological disorders. They may also be used for discovering new drugs and developing therapies. However, organoids are difficult to produce at large scales. This project aims to improve production of complex brain organoids by creating a map of differentiation and engineering a “location tracker” of an organoid's current state. Based on these tools, strategies to route differentiation to a desired organoid type will be developed. The approaches developed in this project can be used for broadening participation in STEM, allowing student to perform remote experiments following organoid differentiation. This RECODE project is based on the premise that quantitative knowledge of differentiation trajectories combined with active sensing will support the reproducible, generalizable, and self-correcting production of brain organoids. To systematically record organoid cell types and composition during differentiation, gene expression in single cells across a range of organoid protocols will be measured, enabled by multiple types of cellular barcodes. These trajectories will be compared to the development of diverse brain regions in vivo. Improved life support systems, enabled by automation and microfluidics, will be developed to support scalability. Non-sacrificial molecular and imaging based methods will be utilized to longitudinally track organoid states during differentiation and to supply missing trophic and patterning factors. The results of this project will support novel strategies for robust and reproducible organoid generation for disease models and regenerative medicine. Finally, by enabling remote experimentation the methods developed in this study support inclusion of diverse communities in the scientific process.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.