Organoids: the third dimension of human brain development and disease

Stem cell technologies have opened up new avenues in the study of human biology and disease. Especially, the advent of human embryonic stem cells followed by reprograming technologies for generation of induced pluripotent stem cells have instigated studies for modeling human brain development and disease by providing a means to simulate a human tissue with otherwise limited or no accessibility to researchers. Brain development is a complex process achieved in a remarkably controlled spatial and temporal manner through coordinated cellular and molecular events. In vitro models aim to mimic these processes and recapitulate brain organogenesis. Initially, two-dimensional neural cultures presented an innovative landmark for investigating human neuronal and, more recently, glial biology as well as for modeling brain neurodevelopmental and neurodegenerative diseases. The establishment of three-dimensional cultures in the form of brain organoids was an equally important milestone in the field. Brain organoids mimic more closely the in vivo tissue composition and architecture and are more physiologically relevant than monolayer cultures. They therefore represent a more realistic cellular environment for modeling the cell biology and pathology of the nervous system. Here we highlight the journey to recapitulate human brain development and disease in-a-dish, starting from two-dimensional in vitro systems up to the third dimension provided by brain organoids. We discuss the potential of these approaches for modeling human brain development and evolution and their promise for understanding and treating brain disease.