Assembling Three‐Dimensional Models of the Human Brain to Study Development and Disease

A critical challenge in understanding the programs underlying the development, assembly and dysfunction of the human brain is the lack of direct access to intact, functioning human brain tissue for direct investigation and manipulation. In my talk, I will describe efforts in my laboratory to build functional cellular models and capture previously inaccessible aspects of human brain function and dysfunction. To achieve this, we have been developing methods for deriving in vitro , from pluripotent stem cells, self‐organizing 3D tissue structures called brain region‐specific spheroids or organoids that resembles specific regions of the human brain. We have shown that these brain‐region specific organoids, such as the ones resembling the cerebral cortex, recapitulate many features of in utero neural development, can be derived with high reliability across dozens of cell lines and can be maintained for years to capture advanced stages of neural and glial maturation and function. Moreover, we demonstrated that regionalized brain organoids can be put together to form fused structures called brain assembloids, which can be subsequently applied to investigate cell migration, long‐distance connections and the formation of neural circuits. Lastly, I will illustrate how our modular, stem‐cell derived 3D platform can be used to model disease and to study the cellular and molecular consequences of mutations associated with neuropsychiatric disorders.