During the first reporting period, we were already able to improve the culture system by combining it with bio-engineered scaffold material, allowing for even better reconstitution of key developmental pathways (Lancaster et al., 2017). In addition, we could reconstruct even long-range interactions between distant parts of the human brain in the organoid system (Bagley et al., 2017). This allowed us to reconstitute the long-range migration of human interneurons from the lower to the upper part of the brain. We recapitulated brain cancer, the deadliest of all brain diseases (Bian et al., 2018). We further discovered that metabolic reprograming in neural stem cells irreversibly converts them into tumor stem cells initiating malignant overgrowth (Bonnay et al., 2020). In addition, we used cerebral organoids to model the teratogenic effects of pathogenic viruses (Krenn, et al., 2021). Furthermore, we were able to ascertain that Tuberous Sclerosis, a rare neurodevelopmental genetic disorder, arises developmentally rather than only genetically (Eichmueller et al., 2022). We expect to apply our knowledge on human-specific principles in brain development and pathology to other known diseases for which no therapies exist to-date.
We developed a genetic loss-of-function screening (CRISPR-LICHT) using the cerebral organoid model which allows us to screen for genes with suspected involvement in a specific human brain disorder. Not only were we able to identify microcephaly genes with this method, but we also pinpointed a specific mechanism involved in controlling the size of the brain. This mechanism affects the integrity of the tissue, and thus the brain size and was identified as one cause of microcephaly (Esk, Lindenhofer et al., 2020). A direct application of the CRISPR-LICHT is nearing completion, and a manuscript is under preparation (Chong et al., in preparation).
Finally, we developed a novel cerebral organoid technology that enables the introduction of a cortical patterning axis in human brain organoids (Bosone, et al., in revision).
