Primate brains vary dramatically in size and organization, but the genetic and developmental basis for these differences has been difficult to study due to lack of experimental models. Pluripotent stem cells and brain organoids provide a potential opportunity for comparative and functional studies of evolutionary differences, particularly during the early stages of neurogenesis. However, many challenges remain, including isolating stem cell lines from additional great ape individuals and species to capture the breadth of ape genetic diversity, improving the reproducibility of organoid models to study evolved differences in cell composition and combining multiple brain regions to capture connectivity relationships. Here, we describe strategies for identifying evolved developmental differences between humans and non-human primates and for isolating the underlying cellular and genetic mechanisms using comparative analyses, chimeric organoid culture, and genome engineering. In particular, we focus on how organoid models could ultimately be applied beyond studies of progenitor cell evolution to decode the origin of recent changes in cellular organization, connectivity patterns, myelination, synaptic development, and physiology that have been implicated in human cognition.

Primate brains vary dramatically in size and organization, but the genetic and developmental basis for these differences has been difficult to study due to lack of experimental models. Pluripotent stem cells and brain organoids provide a potential opportunity for comparative and functional studies of evolutionary differences, particularly during the early stages of neurogenesis. However, many challenges remain, including isolating stem cell lines from additional great ape individuals and species to capture the breadth of ape genetic diversity, improving the reproducibility of organoid models to study evolved differences in cell composition and combining multiple brain regions to capture connectivity relationships. Here, we describe strategies for identifying evolved developmental differences between humans and non-human primates and for isolating the underlying cellular and genetic mechanisms using comparative analyses, chimeric organoid culture, and genome engineering. In particular, we focus on how organoid models could ultimately be applied beyond studies of progenitor cell evolution to decode the origin of recent changes in cellular organization, connectivity patterns, myelination, synaptic development, and physiology that have been implicated in human cognition.

Organ-on-a-chip systems combine microfluidics, cell biology, and tissue engineering to culture 3D organ-specific in vitro models that recapitulate the biology and physiology of their in vivo counterparts. Here, we have developed a multiplex platform that automates the culture of individual organoids in isolated microenvironments at user-defined media flow rates. Programmable workflows allow the use of multiple reagent reservoirs that may be applied to direct differentiation, study temporal variables, and grow cultures long term. Novel techniques in polydimethylsiloxane (PDMS) chip fabrication are described here that enable features on the upper and lower planes of a single PDMS substrate. RNA sequencing (RNA-seq) analysis of automated cerebral cortex organoid cultures shows benefits in reducing glycolytic and endoplasmic reticulum stress compared to conventional in vitro cell cultures.

Project-based learning (PBL) has long been recognized as an effective way to teach complex biology concepts. However, not all institutions have the resources to facilitate effective project-based coursework for students. We have developed a framework for facilitating PBL using remote-controlled internet-connected microscopes. Through this approach, one lab facility can host an experiment for many students around the world simultaneously. Experiments on this platform can be run on long timescales and with materials that are typically unavailable to high school classrooms. This allows students to perform novel research projects rather than just repeating standard classroom experiments. To investigate the impact of this program, we designed and ran six user studies with students worldwide. All experiments were hosted in Santa Cruz and San Francisco, California, with observations and decisions made remotely by the students using their personal computers and cellphones. In surveys gathered after the experiments, students reported increased excitement for science and a greater desire to pursue a career in STEM. This framework represents a novel, scalable, and effective PBL approach that has the potential to democratize biology and STEM education around the world.