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Human screens are currently limited to two-dimensional cell cultures, which lack the ability to score tissue-dependent gene function. Esk\n            <jats:italic>et al.<\/jats:italic>\n            combined CRISPR-Cas9 screening with barcoded cellular lineage tracing to enable loss-of-function screening in three-dimensional human cerebral organoid tissue. By testing microcephaly candidate genes, the endoplasmic reticulum was found to control extracellular matrix protein secretion regulating tissue integrity and brain size. 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