The same cells, the same way

The researchers focused on organoids of the cerebral cortex — the part of the brain responsible for cognition, language, and sensation. The cerebral cortex plays a key role in neuropsychiatric diseases such as autism spectrum disorder and schizophrenia.

“We made organoids from multiple stem cell lines, from both male and female origins — so their genetic backgrounds were different,” said lead author Silvia Velasco, a research scientist at Harvard and the Broad Institute.

Human brain tissues grow very slowly. In this study, after six months the organoids had grown to three millimeters across. In the largest single-cell RNA sequencing experiment in brain organoids to date, the researchers grouped cells based on which genes were expressed at various stages. Using computational models for big data analysis, they compared each group to the cell types that develop in the embryonic cerebral cortex.

“Despite the different genetic backgrounds, we saw that the same cell types were made in the same way, in the correct order and, most importantly, in each organoid,” said Velasco. “We were really excited that this model gave us such consistency.”

A new way to investigate disease

Using the optimized method from this study, researchers could make organoids from stem cells derived from patients, or engineer cells containing mutations that are associated with specific diseases.

Arlotta’s lab is currently exploring autism, using CRISPR/Cas9 gene-editing techniques to develop brain organoids specific to the disorder.

“It is now possible to compare ‘control’ organoids with ones we create with mutations we know to be associated with the disease. This will give us a lot more certainty about which differences are meaningful, which cells are affected, and which molecular pathways go awry,” said Arlotta. “Having reproducible organoids will help us move much more swiftly toward concrete interventions, because they will direct us to the specific genetic features that give rise to the disease. In the future, I envisage we will be able to ask far more precise questions about what goes wrong in the context of psychiatric illness.”

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“In a short time, we have gained a remarkable amount of knowledge about the many different cell types in the human brain,” said co-author Aviv Regev, who is a core institute member and chair of the Faculty at the Broad Institute, as well as co-chair of the Human Cell Atlas project. “That knowledge has given us a foundation for creating models of this incredibly complex organ. Overcoming the problem of reproducibility opens the doors to studying the human brain in ways that would have been thought impossible just a few years ago.”

“Not only does this advance make it immediately possible to study brain diseases,” added Doug Melton, Xander University Professor at Harvard University and co-director of the Harvard Stem Cell Institute, “but the consistency and reproducibility is likely a first step in using organoids to begin to understand how brain functions develop — how sets of neurons ‘learn’ and ‘remember.’”

This work was supported by grants from the Stanley Center for Psychiatric Research, the Broad Institute of Harvard and MIT, the National Institutes of Health, the Klarman Cell Observatory, and the Howard Hughes Medical Institute.

Source article: Velasco S., et al. (2019). Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature (in press).

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