Harvard researchers unveil new technology to investigate autism

Technology could also be used to study cancer, autoimmune disease, and other major diseases

BOSTON — Local researchers hope they’re one step closer to figuring out what may cause autism spectrum disorder.

The group from Harvard, MIT, and the Broad Institute of Harvard and MIT are focusing on genes, and say the new technology they’re using could help us understand other major diseases as well, including cancer, autoimmune disease, and many genetic diseases -- whose causes aren’t known right now.

Their work, which involved new technology they developed, was just published in the journal “Science.”

What causes autism?

For decades, researchers have been unable to pinpoint an exact cause for autism and many other intellectual and developmental disabilities, but believe it’s caused by a combination of genetic and environmental factors.

“In the last few years there’s been a surge in human genetic studies that offer hope for new research,” said Dr. Paola Arlotta, a Developmental Neurobiologist, the Senior Author of the study, and the Principal Investigator of the Arlotta Lab at Harvard University.

While geneticists are only able to track down a single genetic cause of autism about 20% of the time, they’ve identified *dozens of “risk genes” that may lead to a higher chance of developing autism. That’s where the researchers at Harvard, MIT, and the Broad institute picked up. They wanted to investigate what those high-risk genes do to brain cells.

“Many of these genes are not only present in the brain. They’re also present in other cells and other tissues in the body, and it’s very hard to predict simply by knowing the name of the gene or the position of the gene in the genome, what that specific genetic defect may do to the brain or how it may affect other cells in the body,” explained Dr. Arlotta.

The “Perturb-Seq” Method

Over the past five years, Dr. Arlotta and her colleagues have been working on the application of new technology they developed called the “Perturb-Seq” method. It’s a type of sequencing that allows researchers to see how gene expression changes in tens of thousands of individual cells. Using what’s known as “Crispr” technology, developed by other researchers, Dr. Arlotta’s team made precise edits to 35 risk genes in mouse brains and studied the consequences. They then delivered the mutant autism risk genes to brain cells, waited for the cells to react to the genetic changes, and then used RNA sequencing on each cell (a technology that allows researchers to read how genes change) to read how gene expression changes. In this study, they surveyed more than 40,000 individual brain cells.

“So the picture that the experiments are painting is a complex one where more than one cell type is likely affected and more than one mechanism may be at play. Now, this doesn’t mean that we can’t figure it out. I think it means we need to continue to develop technologies and be creative about how we bridge the genetics to allow us to understand what a genetic context does to the development and functionality of the brain,” said Dr. Arlotta.

Dr. Arlotta and her colleagues compared their results to data from post-mortem human brains. They found some of the key genes with altered expression in the post-mortem brains of people who had autism, were also affected in their sequencing model, leading them to believe they’re on the right track.

Applications to cancer, autoimmune conditions, and genetic diseases

Dr. David Sweetser, Chief of Medical Genetics and Metabolism at Mass General Hospital, says the method is very promising, and could also be applied to understanding other conditions, and their impact on other human organs, besides the brain.

“It is a technique that could be involved, for instance, in studying Cancer. We know that in Cancer there are many different genetic changes that happen within a Cancer. It’s not always clear which one of the mutations are driving the cancer to develop,” said Dr. Sweetser. “The applications are really only limited, if you will, by the imagination of the researchers.”