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Cerebral Organoids: Using stem cell derived 3D cultures to understand human brain development and neurological disorders

Periodic Reporting for period 3 - MiniBrain (Cerebral Organoids: Using stem cell derived 3D cultures to understand human brain development and neurological disorders)

Reporting period: 2020-01-01 to 2021-06-30

The human brain is the most complex but also the most fascinating organ of all. Its 87 billion neurons arise during development following a precisely orchestrated plan. Any defect in this process can lead to profound cognitive deficiencies and severe life-long impairment. Currently, essentially all we know about human brain development is deduced from animal experiments. While it is safe to assume that the basic principles of neurogenesis are widely conserved, recent experiments have revealed a growing number of specific features that are unique to the human brain and cannot be studied in animals. The overall goal of this project is to use three-dimensional cell culture in order to elucidate how those processes are regulated and how their impairment can lead to neuro-developmental disorders. We use a tissue culture system called cerebral organoids that we have developed in 2013 and that can recapitulate brain development at a remarkable level of detail (Lancaster et al., 2013). Our goal is to recapitulate various human diseases in those organoids and to develop methodology for large-scale parallel analysis of genes that could potentially be responsible for those diseases.
During the first reporting period, we were already able to improve the culture system by combining it with bio-engineered scaffold material, allowing for even better reconstitution of key developmental pathways (Lancaster et al., 2017). In addition, we could reconstruct even long-range interactions between distant parts of the human brain in the organoid system (Bagley et al., 2017). This allowed us to reconstitute the long-range migration of human interneurons from the lower to the upper part of the brain. And finally, we could recapitulate brain cancer, the deadliest of all brain diseases (Bian et al., 2018).
During the second funding period, we will build on those initial achievements to reconstitute even more complex developmental events and to identify the genes that are responsible for their correct execution in the human fetus.