Gene-Edited Brain Organoids Are Unlocking Secrets

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HUNDREDS OF GENES have been linked to autism spectrum disorder (ASD), a complicated range of conditions affecting the behavior, social development, and communication of tens of millions people worldwide. But teasing out exactly what effect those genes have and how they relate to ASD has been devilishly difficult. “Nobody can study an actual human brain as it develops,” says Paola Arlotta, a professor of stem cell and regenerative biology at Harvard University. But a new approach based on growing clumps of brain cells in the lab is now yielding promising results.

Arlotta and her colleagues at Harvard and the Broad Institute of Harvard and MIT have been working with organoids—three-dimensional clumps of brain tissue grown from stem cells—usually just a few millimeters across. When organoids are left to grow, they start to develop different types of brain cells, and begin to organize into primitive networks that mimic some, but not all, of the architecture of the human brain.

Organoids grown from stem cells donated by people with ASD have been used to study the condition in the past. But Arlotta and her team went a step further, as they describe in a paper published recently in the journal Nature. They created genetically modified organoids of the human cerebral cortex, each with a mutation in one of three genes thought to be linked to autism.

After growing the organoids, the first stage of the analysis involved sequencing the RNA of the neurons that had grown in the organoids and comparing it to that of cells from non-modified organoids developed from the same source of stem cells. (RNA is a messenger molecule that carries the instructions from the DNA to the parts of the cell that execute those instructions.) By combining RNA sequencing with information on the types of proteins being formed by the organoids, the researchers were able to determine what types of brain cells were being developed, and the maturity of those cells.

This mixture of cells—some more mature than they should be, some less—can cause big differences in brain development as the cells attempt to “wire” together into networks later on. “The trouble with neurons being more mature is that then they are out of step,” explains Deep Adhya, a research associate at the University of Cambridge who studies autism and brain development using stem cells. “If neuron development is out of step the brain will develop differently.”

This mixture of cells—some more mature than they should be, some less—can cause big differences in brain development as the cells attempt to “wire” together into networks later on. “The trouble with neurons being more mature is that then they are out of step,” explains Deep Adhya, a research associate at the University of Cambridge who studies autism and brain development using stem cells. “If neuron development is out of step the brain will develop differently.”

That’s one theory for the cognitive differences seen in people with autism. “There are indications that the balance between bottom-up sensory, and top-down modulation, may be shifted,” says Matthew Belmonte, who researches neurophysiology and behavior in autism at Bangalore’s Com DEALL Trust and Nottingham Trent University. In other words, some people with autism may find it difficult to filter the information coming in—which could be caused by underlying differences in brain structure like the ones Arlotta saw in the organoids.

After working on CHD8, Arlotta and her team grew two more types of organoids, this time focussing on two other genes that had been linked to the condition: ARID1B and SUV420H1. Although these genes do different things, they had what Arlotta calls a “convergent” effect on brain development—like CHD8, mutations in these genes also changed the timing of cell development in the organoids, and affected the balance between excitatory and inhibitory neurons.