Medical News Today 17 July 2015 by Markus MacGill
Skin cells from the patients with autism were converted to induced pluripotent stem cells.
The researchers say this method allows them to overcome the difficulties of understanding diseases like autism and schizophrenia that affect development of the brain related to the complexity of the diseases and the difficulty of studying developmental processes in human tissues.
“Instead of starting from genetics,” says senior author Dr. Flora Vaccarino, the Harris professor of child psychiatry and professor of neurobiology at the Yale School of Medicine in New Haven, CT, “we’ve started with the biology of the disorder itself to try to get a window into the genome.”
Previously, autism researchers have had to trawl through patient genomes for gene mutations that may explain the disorder and then taken animal or histological models to study those genes and effects on brain development.
A number of rare disease genes have been identified in this way but over 80% of autism cases still have no clear genetic cause, the researchers state.
Dr. Vaccarino says:
“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 researchers focused on people with autism who have an enlarged brain, representing about a fifth of cases. This helped to zone out the complex and wide-ranging clinical characteristics that frustrate the search for common underlying factors.
After isolating skin cells from these individuals, as well as their unaffected fathers for comparison, the researchers converted them into induced pluripotent stem cells (iPSCs) that were then grown into miniature brains, referred to as brain organoids.
Just a few millimeters in diameter, the organoids nonetheless mimic the basics of early human brain development during the first few months of gestation.
When the researchers analyzed the miniature brains derived from patients, they uncovered altered expression networks for genes controlling neuronal development.
An imbalance in neuron type was created by organoids showing an unexpected overproduction of neurons that inhibit neural activity, while those that excited the partners they were wired to were unaffected.
By suppressing a single gene whose expression was abnormally increased in patient organoids, the authors were able to correct this bias. This success suggests that it may be possible to intervene clinically to restore neuronal balance.
Further insights into disease mechanisms will follow when various scientific groups extend human brain organoids to later stages of development.
The present authors will now use their data to focus on the elusive mutations or epigenetic changes responsible for the gene expression alterations and neuronal imbalance seen in the study.