Figure 1: People with schizophrenia have differences in neural anatomy when compared to neurotypical individuals – studies have shown, for example, that the lateral ventricles of schizophrenic patients are enlarged. With the help of organoids, scientists will be able to look at the developing brain to study the formation of these anatomical abnormalities, helping to broaden our understanding of the disease. Picture source: Wikimedia Commons
Anahita Kodali —
Understanding how the human brain develops and functions is critical to the study of many neurodevelopmental disorders. Until recently, the best way for researchers to study neurodevelopment was by utilizing rodent models; however, after the 1st trimester of pregnancy, rodent models become inadequate because rodent neurodevelopment becomes significantly different than human neurodevelopment. As a consequence, researchers have long had a very poor understanding of how the mind functioned from the 2nd trimester to birth [1].
Now, psychiatrist Sergiu Paşqa and his team of researchers at Stanford University have developed a new way to study neural development. The team created make-shift “organoids” composed of lab-grown cells that are designed to mimic the brain’s tissue composition and function. These organoids are so advanced that specific regions of the brain can be modeled and studied over time and used to understand development. For example, Paşqa’s team used organoids to model development of the forebrain – the portion of the brain where thinking, planning, language processing, and reasoning occur [2].
The team started with pluripotent stem cells (cells that have the ability to differentiate into cells of the body’s three main tissue layers: the ectoderm, endoderm, and mesoderm) and put them into 3D cultures. These cells were arranged such that once they differentiated, they would mimic the structure of the dorsal and ventral forebrain. The scientists used specific drugs and proteins to induce the pluripotent stem cells to form neural progenitor cells, which subsequently developed into neuronal cell types like neurons and glia and ultimately became functional organoids. While the organoids formed, Paşqa’s team used a technique called ATAC-seq (a way scientists can determine which regions of DNA are accessible for transcription at any time during development) in order to study gene activation in different cells and stages of growth. This ultimately allowed them to create a gene map of the developing brain, which they used to find genes linked to schizophrenia and autism [3].
While Paşqa is focused on schizophrenia and autism, the organoids and the gene mapping technique that the team utilized can be powerful tools for scientists to gain better insight into how the fetal brain develops. In addition, this approach to analyzing gene expression can be taken further to the study of other neurological and neurodevelopmental disorders.
References:
[1] Makin, S. (24 January, 2020). “Organoids” Reveal How Human Forebrain Develops. Scientific American. Retrieved from https://www.scientificamerican.com/article/organoids-reveal-how-human-forebrain-develops/
[2] Queensland Brain Institute. The forebrain. (15 October, 2018) Retrieved from https://qbi.uq.edu.au/brain/brain-anatomy/forebrain
[3] Trevino, A. E., Sinnott-Armstrong, N., Andersen, J., Yoon, S.-J., Huber, N., Pritchard, J. K., … Pașca, S. P. (2020). Chromatin accessibility dynamics in a model of human forebrain development. Science, 367 (6476). doi: 10.1126/science.aay1645