Some diseases like sickle cell anemia, an inherited blood disorder, can be traced to a single known genetic mutation. But other diseases like autism spectrum disorder (ASD), are so varied in their symptoms and severity that pinpointing the underlying cause is extremely complicated. People with autism typically have difficulties communicating with the world around them, unable to fully process both verbal and non-verbal language, and plagued by repetitive behaviors. Some rare forms of autism appear to be inherited but over 80% of cases are idiopathic, a fancy term for “we don’t know what causes it.”

Process for making organoid “mini-brains” from iPS cells derived from patient skin samples (image credit: Keval Tilva, wikipedia)

Last week, a research team at the Yale School of Medicine published data in Cell that appears to unveil some of the mystery behind autism. The scientists relied on induced pluripotent stem cells (iPS) derived from skin samples of people with severe forms of ASD. Rather than maturing the stem cells into a flat layer of brain cells, or neurons, on a plastic petri dish, the Yale team stirred the cells in a bioreactor. This technique allows the cells to mature in a small three-dimensional clump, which self organizes into so-called brain “organoids” or “mini-brains.” The structure of these mini-brains resembles the portions of the developing fetal human brain, the stage at which autism is thought to arise.

An analysis of the mini-brains found no underlying genetic mutations. Instead, the team identified genes involved with cell growth and neuron development that were turned on higher in the ASD vs. non-ASD mini-brains. A closer look at cell growth showed that inhibitory neurons, responsible for keeping nerve signals in check, were increased in number in the ASD mini-brains. Teasing out this discovery further pinpointed a protein, called FOXG1, which was responsible for the increased cell growth of the inhibitory neurons.

Fluorescent microscopy images of minibrain organoids derived from ASD patients (right) and unaffected family members (left). The red and green color indicate the increased presence of inhibitory neurons in the ASD minibrain (right). (Image credit: Mariani et al. Cell Volume 162, Issue 2, p375–390, Fig 4I.)

Here’s the interesting part if you’re still with me: of the four patient samples used in this study, higher levels of FOXG1 protein correlated with more severe ASD. And blocking the production of FOXG1 in the ASD mini-brains reduced the inhibitory neurons back to normal levels. Although this initial finding doesn’t directly link FOXG1 and autism, the results suggest a common disease mechanism: that autism may arise by over producing FOXG1 which in turn creates too many inhibitory neurons during brain development and somehow disrupts connections between neurons.

In an interview with The Scientist, CIRM-funded grantee Alysson Muotri of UCSD, who also studies autism using patient derived iPS cells, finds this possible commonality in ASD remarkable:

“These are patients with idiopathic autism that do not share any genetic causes, and yet the authors find phenotypes shared between their cells. That’s impressive. If someone had asked me, I would have said, ‘You won’t find anything in common, it’s probably going to be a mixed bag.’ But no . . . there seems to be key things that are dysregulated in all of them.”