How do neurons in the human brain establish connections with other neurons in circuits, and work together to control behavior? How do these neurons and circuits change over time in development and disease states? Our knowledge of brain structure and function in nonhuman animals is highly advanced, but we are woefully ignorant of the vastly larger and more sophisticated human brain and how its assembly goes awry in disorders such as autism and schizophrenia.
Our laboratory seeks to understand the rules that govern the molecular and cellular steps underlying the assembly of the human nervous system and the molecular mechanisms that lead to neurological and psychiatric disease. Towards this, we developed bottom-up approaches to generate and assemble, from multi-cellular, self-organizing components, human neural circuits in vitro and, following engraftment, in vivo into animals. We have carved a research program that combines neuroscience, stem cell and molecular biology approaches to construct and deconstruct previously inaccessible stages of human neural development and function in health and disease.
Our group introduced the use of instructive signals for deriving self-organizing 3D cellular structures named regionalized neural organoids or spheroids (Nature Methods 2015; Neuron 2017; Nature Protocols 2018; Nature Neuroscience 2019; overview in Nature 2018). We demonstrated that these cultures, such as the ones resembling the cerebral cortex, can be reliably derived across dozens of stem cell lines and experiments, contain synaptically connected neurons and non-reactive astrocytes (Nature Methods 2019), and can be used to gain mechanistic insights into genetic and environmental brain disorders (Nature 2017; Nature Medicine 2019; Nature Medicine 2020). Moreover, when maintained as long-term cultures of over 800 days, we discovered an intrinsic program of maturation that progresses towards postnatal stages (Neuron 2017; Science 2020; Nature Neuroscience 2021).
The lab also pioneered a modular system to integrate 3D neural organoids and study human neuronal migration and neural circuit formation in functional preparations that we named assembloids (Nature 2017; Science 2019; Cell 2022; featured in Nature 2021). For instance, we demonstrated the assembly of the functional cortico-striatal (Nature Biotechnology 2020; Nature Protocols 2022) and cortico-motor (Cell 2020) circuits from human stem cells that are capable of outputs. We systematically applied these advanced cellular models to gain novel insights into human physiology, evolution and brain disease mechanisms (Nature 2021; Cell Stem Cell 2022).
We believe science is a community effort, and accordingly, we have been advancing the field by broadly and openly sharing our technologies with numerous laboratories around the world and organizing research conferences and training courses in the area of cellular models of the human brain, including as part of the Stanford Brain Organogenesis Program.
The lab also pioneered a modular system to integrate 3D neural organoids and study human neuronal migration and neural circuit formation in functional preparations that we named assembloids (Nature 2017; Science 2019; Cell 2022; featured in Nature 2021). For instance, we demonstrated the assembly of the functional cortico-striatal (Nature Biotechnology 2020; Nature Protocols 2022) and cortico-motor (Cell 2020) circuits from human stem cells that are capable of outputs. We systematically applied these advanced cellular models to gain novel insights into human physiology, evolution and brain disease mechanisms (Nature 2021; Cell Stem Cell 2022).
We believe science is a community effort, and accordingly, we have been advancing the field by broadly and openly sharing our technologies with numerous laboratories around the world and organizing research conferences and training courses in the area of cellular models of the human brain, including as part of the Stanford Brain Organogenesis Program.
