RECODE: Rules-based Morphogenesis of Brain Organoids through Synthetic Gene Circuits

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Brain disorders cost the US an estimated $800 billion each year. In general, the human brain cannot be experimented on directly. However, patient-sourced stem cells can be used to create organoids, which partially resemble the tissue of origin. Brain-derived organoids have proven to be helpful in understanding brain development and disease, but currently do not fully replicate the complexity and connectivity of the human brain. In this project, brain organoids will be engineered to more reliably develop into an interconnected network resembling the brain. The project tightly integrates research with education. It provides direct support for scientific outreach programs to Metro Nashville Public Schools and recruitment of high school students to participate in the research project. These efforts will help develop the next generation of scientists and STEM-career workers.Brain organoid generation exploits the ability of human pluripotent stem cells (hPSCs) to integrate global and local morphogenetic cues to self-assemble and differentiate. Building brain organoids requires addition of external cues that activate or suppress specific signaling pathways. The hPSCs interpret this signaling cocktail through networks that establish internal gradients of morphogen agonists and antagonists. Signaling centers coordinate embryo development. Without them, organoid production can lead to inconsistencies in size, shape, and cellular organization. These features must be faithfully replicated in brain organoids. The goal of this project is to establish the molecular logic and design rules required to generate cerebral cortical organoids. The objective is to create a self-contained system with reproducible and defined architecture, size, and cellular composition. Rewiring cellular networks will direct cells to autonomously respond to their microenvironment. These cells will reproducibly template early corticogenesis while balancing progenitor cell proliferation and differentiation during later stages. The principles uncovered will guide the utilization of brain organoids for understanding development and disease, and for screening potential therapeutics. Understanding the design rules that govern higher-order structure formation in the brain may potentially be applied to other types of tissues. This further opens the possibility of engineering tissue replacements for transplantation.This project is being jointly supported by the Engineering Biology and Health Cluster in ENG/CBET and the Systems and Synthetic Biology Cluster in BIO/MCB.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.