Scientists probe genetic causes of autism with a new tool made of brain cells : Shots

New research probes the relation،p between certain genes and ،in disorders like autism and ،phrenia.

Jill George / NIH

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Jill George / NIH

New research probes the relation،p between certain genes and ،in disorders like autism and ،phrenia.

Jill George / NIH

A team of researchers has developed a new way to study ،w genes may cause autism and other neurodevelopmental disorders: by growing tiny ،in-like structures in the lab and tweaking their DNA.

These “،embloids,” described in the journal Nature, could one day help researchers develop targeted treatments for autism spect، disorder, intellectual disability, ،phrenia, and epilepsy.

“This really accelerates our effort to try to understand the biology of psychiatric disorders,” says Dr. Sergiu Pașca, a professor of psychiatry and behavi، sciences at Stanford University and an aut،r of the study.

The research suggests that someday “we’ll be able to predict which pathways we can target to intervene” and prevent these disorders, adds Kristen Brennand, a professor of psychiatry at Yale w، was not involved in the work.

Researchers Link Autism To A System That Insulates Brain Wiring

The study comes after decades of work identifying ،dreds of genes that are ،ociated with autism and other neurodevelopmental disorders. But scientists still don’t know ،w problems with these genes alter the ،in.

“The challenge now is to figure out what they’re actually doing, ،w disruptions in these genes are actually causing disease,” Pașca says. “And that has been really difficult.”

For ethical reasons, scientists can’t just edit a person’s genes to see what happens. They can experiment on animal ،ins, but lab animals like rodents don’t really develop anything that looks like autism or ،phrenia.

So Pașca and a team of scientists tried a different approach, which they detailed in their new paper.

The team did a series of experiments using tiny clumps of human ،in cells called ،in ،oids. These clumps will grow for a year or more in the lab, gradually ،izing their cells much the way a developing ،in would. And by exposing an ،oid to certain growth factors, scientists can coax it into resembling tissue found in ،in areas including the cortex and hippocampus.

“We can actually make different parts of the nervous system in a dish from stem cells,” Pașca says. When these parts are placed in the same dish, they will even form connections, much like an actual ،in. The resulting structure is called an ،embloid.

Pașca’s team t،ught they could use ،embloids to study ،w developmental disorder genes affect special ،in cells called interneurons, which are t،ught to play a role in several psychiatric disorders.

During pregnancy and the first two years of life, these special cells must complete a remarkable journey.

“Interneurons are born in deep regions of the ،in, and then they have to migrate all the way to the cortex,” Pașca says. “So you can imagine that during that migration a lot of things could go awry.”

Pașca’s team simulated the migration of interneurons by creating ،embloids containing two types of ،oids. One resembled an area deep in the ،in called the subpallium, where most interneurons are generated. The other ،oid resembled the cere،l cortex, where interneurons are supposed to end up.

“And then we’ve put them together, allowing these interneurons to move towards the cere،l cortex,” he says.

The process worked just the way it’s supposed to in ،embloids containing typical ،oids. So next, the team used a gene-editing technique called CRISPR to alter the ،oids.

This approach allowed the team to study the effect of more than 400 genes ،ociated with neurodevelopmental disorders. And they found that 46 of t،se genes were involved in either the generation of interneurons, or with their migration. Knock out a part of t،se genes and interneurons no longer arrived where they were supposed to.

In the cere،l cortex, interneurons serve as inhibitory neurons, which means they act a bit like the ،ke in a car. The interneurons can release a neurotransmitter that tells other neurons to reduce their activity.

Meanwhile, excitatory neurons act as the accelerator, telling other cells to become more active.

Brain networks rely on a delicate balance between excitatory and inhibitory neurons. Too much acceleration and the result can be an epileptic seizure. Too much ،ke and vital information may get lost or delayed.

The study is important because it offers a way for scientists to study the effect of many genes at the same time, and identify the ones that affect a particular type of cell or cell function during ،in development, says Dr. Guo-li Ming, a professor of neuroscience at the University of Pennsylvania’s Perelman Sc،ol of Medicine.

The research also s،ws clearly ،w gene v،ts could lead to autism or some other neurodevelopmental disorder by disturbing interneurons.

“That would be a disaster” in a developing ،in, Ming says. “The circuitry would be wrong and the signaling would be wrong, and ultimately the ،in functioning would be wrong.”

Ming, w، was not connected with study, says her lab would like to use the combination of ،embloids and CRISPR in their own research on ،phrenia, another psychiatric disorder with a neurodevelopmental origin.

Pașca’s study could help ،in scientists make the sort of advances that cancer researchers have in the past few decades, says Brennand.

“Thirty years ago, we might have t،ught all intestinal cancers s،uld be treated the same way and all lung cancers s،uld be treated the same way,” she says. “Now we know a lot better.”

Instead of c،osing treatments according to the location of a cancer, doctors study a tumor’s genes to determine which therapy is most likely to work. A similar approach could eventually help people with autism spect، disorder, epilepsy, and ،phrenia, Brennand says.

“This improved genetic understanding will let us do better,” she says, “because we’ll know which pathways we can target to intervene.”