"The biggest surprise to me was that we could rescue the autistic phenotype [in the human cells] to something close to normal," said Alysson Muotri of the University of California San Diego.
The researchers made the discovery by first transforming adult cells taken from patients with Rett Syndrome into induced pluripotent stem cells (iPS cells) using an established cocktail. iPS cells look and act very much like embryonic stem cells.
Those stem cells were able to form functional neurons in cell culture. However, neurons derived from Rett Syndrome patients exhibited some abnormalities when compared to those derived in the same way from healthy individuals.
The first thing the researchers noticed was that the cells were smaller than healthy neurons. They also had fewer synapses and displayed other signs of a failure to communicate properly, including altered calcium signaling and electrophysiological defects.
When the cells were treated with drugs that had shown promise for correcting autism symptoms in mice, those abnormalities were reversed. In fact, depending on the dose, Muotri said it appeared that the cellular defects could actually be "overcorrected."
The findings are especially notable because symptoms of Rett Syndrome typically don't set in until children are 6 to 18 months old, suggesting that the gene responsible isn't essential for early wiring of the nervous system, Muotri explained. The fact that newborn neurons derived in the laboratory already show signs of the disease suggests that there may still be underlying aberrations at the earliest stages of development, and that may have important clinical implications.
"Our data provide evidence of an unexplored developmental window, before disease onset, in Rett syndrome where potential therapies could be successfully employed," the researchers write.
Muotri says there is a need to search for better, more specific drugs than the ones applied in the study. That will require the development of methods to create iPS cells from human cells in large quantities, allowing for high-throughput screens for drug candidates.
His team is now working to derive iPS cells and neurons from children with sporadic autism, in which the causes are completely unknown. He suspects that at least some of their cells will show something similar to what has been observed in the case of Rett syndrome.
More generally, Muotri says he hopes that as this study and others shed more light on the biology of autism and other neuropsychiatric diseases, it will help to lift the stigma that is sometimes associated with them.
"There is a real, basic biology behind these diseases," he said. "We can see it in a culture dish."
Mapping human biology: Human Cell Atlas leads a new era in precision medicine