From Stem Cells to Organoids to Assembloids and Toward Building Human Circuits in Living Systems to Develop Therapeutics

Sponsored by The Ewald W. Busse, MD, ScD Lectureship Endowment Fund Dr. Sergiu P. Pfasca is the Kenneth T. Norris Jr. Professor at Stanford University and the Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program. His lab seeks to understand the rules that govern the molecular and cellular steps underlying the assembly of the human brain and the molecular mechanisms that lead to disease. They are developing bottom-up approaches to generate and assemble, from multi-cellular components, human neural circuits in vitro and following engraftment, in vivo (Nature, 2022). Following clinical training, he developed some of the early models of disease using stem cell-derived neurons. Dr. Pasca's lab pioneered the use of instructive signals for deriving self-organizing 3D cell ensembles called spheroids or regionalized neural organoids. These resemble nervous system domains, contains synaptically connected neurons and astrocytes and can be derived reliably across lines and experiments (Nature Meth, 2015; Neuron, 2017; Nature Prot, 2018; Nature Meth, 2019). When maintained for up to 2 years, they recapitulate a maturation program that progresses into postnatal stages(Science, 2020; Nature Neuro, 2021). We applied these methods in combination with ex vivo preparations to model myelination (Nature Neuro, 2019), discover evolutionary changes in evolution (Nature, 2021), identify cell-specific vulnerability in hypoxia (Nature Med, 2019), map chromatin dynamics (Cell, 2021) or to discover mechanisms of disease (Nature Med, 2020). He also pioneered a modular system to integrate organoids in preparations we named assembloids (Nature, 2018; Science, 2019), which can be used to capture migration (Nature 2017) and circuit formation and to model disease (Cell, 2020; Nature Biotech, 2020; Nature Prot, 2022; Cell Stem Cell, 2022; Nature, 2023) and to develop novel therapeutic approaches (Nature, 2024). Dr. Pasca believes science is a community effort, and accordingly, he has been advancing the field by openly sharing their technologies with numerous laboratories around the world and organizing the primary research conference and the training courses and leading a field-wide nomenclature effort (Nature, 2022).