A technique that grows “mini brains” has led to new insights into autism, according to a study out of Yale.
The technique—known as induced reprogramming—produces things known as brain organoids, and it turns previous autism research on its head. Before, research primarily focused on how genes might affect brain development.
“Instead of starting from genetics, we’ve started with the biology of the disorder itself to try to get a window into the genome,” said senior author Flora Vaccarino, the Harris Professor of Child Psychiatry and Professor of Neurobiology at the Yale School of Medicine, in a press release.
“Brains in a dish”
Brain organoids are tiny clusters of brain tissue that possess some features of a human brain in the first trimester of development, including lobes of cortex. “It’s not of course identical to the embryonic brain,but in a way it resembles that,” Vaccarino explained to redOrbit by phone. “The cells express similar genes and markers, they are electrically active when they become neurons, they form primitive layers (so they have reciprocal relationships to each other), [they] separate into layers similar to the progenitors—or to the neurons—so there are many similarities with what the embryonic brain actually does.”
These tissues are commonly created from human skin. First skin cells are dedifferentiated into pluripotent stem cells. “You introduce transcription factors—which are genes and proteins that will basically alter the state of the cell. You sort of make that cell go back into development and become pluripotent. It alters the epigenetic profile of that cell, so that cell is no longer a skin cell, but it becomes more of a stem cell,” Dr. Vaccarino told redOrbit by phone.
Then, the stem cells are made into brain cells. “Now you can use the same signaling system that is used in an embryo to direct the fate of cells that are pluripotent—that is, they can generate almost any cell—into neural cells,” explained Vaccarino.
Since the skin cells come directly from live humans, the later cells contain all of their DNA, including genes that lead to different conditions of the brain.
So these “miniature brains” grow in way akin to how the cell donor’s brain developed, allowing scientists to see how the networks of the brain develop and function in the presence of the unidentified genes, and allowing scientists to test novel (and potentially dangerous) drug compounds and medications.
Network imbalance
In the Yale study, researchers took skin cells from autistic patients with enlarged brains (a common characteristic in autistic individuals) and from their unaffected fathers, for a point of comparison. Then, they turned the skin cells into stem cells and then brain cells, and grew them into brain organoids.
They discovered that the genes controlling neuronal development of the organoids of autistic patients were expressed differently than the same genes in the paternal organoids. The networks created by the genes had an unexpected overproduction of inhibitory neurons—leading to quieter neural activity. The excitatory neurons were unaffected, leading to an imbalance in favor of inhibition.
Even more exciting than discovering a possible mechanism for autism, the researchers discovered how to prevent the imbalance from happening. A gene known as FOXG1 was being abnormally expressed in the organoids; the researchers suppressed it, correcting the balance between excitatory and inhibitory neurons. This suggests that clinical intervention may be possible.
According to Vaccarino, “This study speaks to the importance of using human cells and using them in an assay that could bring a better understanding of the pathophysiology of autism and with that, possibly better treatments.”
The research is published today in Cell.
(Image credit: Jessica Mariani)
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