. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature. 2019 Jun 5; PubMed.


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  1. This is another groundbreaking paper from the Arlotta lab. This study tackles a fundamental challenge of brain organoid models, “heterogeneity and reproducibility.” Since generation of organoids solely depends on the self-assembly and patterning capacity of stem cells, it is inevitable to have a severe organoid-to-organoid variability if we make complex structures like a brain-in-a-dish. In this paper, Dr. Arlotta and her colleagues elegantly demonstrate that it is possible to get homogenous and reproducible brain organoids without sacrificing the complexity. This study will largely accelerate applications of brain organoid models in drug discovery and basic mechanistic studies.

    Only a patterned dorsal brain organoid seems to show desirable properties out of four different brain organoid models in this study. However, it is highly likely that different types of brain organoids with similar homogeneity will follow after this study, using the similar protocol, which, we believe, will be the most significant impact of this study. In the future, we hope that the Arlotta lab and others will address another challenging but important issue—the functional homogeneity of brain organoids, which is possibly regulated by spontaneous neuronal activities and excitatory/inhibitory neural networks.

    Many challenges still lie ahead in applying current brain organoid technology to study neurodegenerative diseases such as Alzheimer’s disease (AD). As shown in the new paper, the reproducible dorsal forebrain organoids exhibited a transcriptome pattern that was very similar to that of human fetal brains. Thus, fetal brain-like organoid models may be limited in recapitulating a mature/aged brain environment representative of the pathogenic cascade of AD and other neurodegenerative diseases.

    We have previously shown that the expression of the adult four-repeat tau isoform (along with three-repeat tau) is essential for recapitulating AD-associated tau pathology using our three-dimensional human neural cell culture model of AD (Choi et al., 2014). Although some progress has been made, it is still highly challenging to generate homogenous brain organoids with critical brain components such as microglia, oligodendrocytes with mature myelinated axons, and vascular structures with peripheral immune components, all of which are all important to generate a comprehensive AD-in-a-dish model. Despite many challenges ahead, we are optimistic, owing to recent fast-moving innovations in organoid biology, bioinformatics, nanotechnology, and mechanical engineering, which have been instrumental in building three-dimensional human brain models in a dish.

    Once again, we congratulate Dr. Arlotta and her colleagues for their very important scientific contribution to modeling a human brain in a dish.


    . A three-dimensional human neural cell culture model of Alzheimer's disease. Nature. 2014 Nov 13;515(7526):274-8. Epub 2014 Oct 12 PubMed.

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  1. Reproducible Brain Organoids Could Offer New Models for Research