Scientists discover how dozens of genes may contribute to autism

November 24, 2023

The Washington Post

By Mark Johnson

October 5, 2023

Brain-cell cultures are suspended in a dish at the lab of Sergiu Pasca, a Stanford University professor of psychiatry and behavioral sciences. (Timothy Archibald)

Using a host of high-tech tools to simulate brain development in a lab dish, Stanford University researchers have discovered several dozen genes that interfere with crucial steps in the process and may lead to autism, a spectrum of disorders that affects about one inevery 36 Americans, impairing their ability to communicate and interact with others.

The results of a decade of work, the findings published in the journal Nature may one day pave the way for scientists to design treatments that allow these phases of brain development to proceed unimpaired.

The study delves into a 20-year-old theory that suggests one cause of autism may be a disruption of the delicate balance between two types of nerve cells found in the brain’s cerebral cortex, the area responsible for higher-level processes such as thought, emotion, decision-making and language.

Some nerve cells in this region of the brain excite other nerve cells, encouraging them to fire; other cells, called interneurons, do the opposite. Too much excitation can impair focus in the brain and cause epilepsy, a seizure disorder that is more common in people with autism than in the general population. Scientists therefore believe a proper balance requires more of the inhibiting interneurons.

Study leader Sergiu Pasca, a Stanford University professor of psychiatry and behavioral sciences. (Sergiu P. Pasca)

In the developing fetus, these nerve cells start out deep in the brain in a region called the subpallium, then migrate slowly to the cerebral cortex. The process begins mid-gestation and ends in the infant’s second year of life, said Sergiu Pasca, a Stanford University professor of psychiatry and behavioral sciences who led the study.

Pasca’s team, which included researchers from the University of California at San Francisco and the Icahn School of Medicine at Mount Sinai, tested 425 genes that have been linked to neurodevelopmental disorders to determine which ones interfere with the generation and migration of interneurons. Genes linked to autism were among those identified in the study.

“What’s really cool about this paper is that autism is a collection of different behaviors, but we don’t have [an] understanding of how those behaviors are connected to differences in the brain,” said James McPartland, a professor of child psychiatry and psychology at the Yale School of Medicine, who was not involved in the study.

The new work advances research into autism by “beginning to create a fundamental understanding of the building blocks of brain development,” he said.

A new way to screen for autism genes

For ethical reasons, it is not possible to view developmentalprocesses as they take place inside a fetal brain.

Often, scientists can instead learn the role an individual gene plays by observing what happens when that gene is knocked out of cells in a lab dish. But knocking out 425 genes one by one is time-consuming.

Clumps of cells in a lab dish, with the neurons shown in green. (Sergiu P. Pasca)

For their study, Pasca and his colleagues used a technique they developed six years ago that allowed them to test all 425 genes at once. They engineered the cells so that only those nerve cells that inhibit others from firing would cast a green glow. They also used the gene-editing system CRISPR to create different cells, each missing one of the 425 genes.

The scientists created clumps of cells that model the structures and functions of the brain’s subpallium and cerebral cortex. Then they placed the two different clumps beside each other in a lab dish.

“We discovered that if you put them together in close proximity, they’ll fuse immediately,” Pasca said. “And the cells know exactly what to do … and they invade the cortex exactly as they would in people.”

This was all the more remarkable because in living brains, the region of the subpallium that makes interneurons is not right next to the cerebral cortex, but is inches away, Pasca said.

Pasca and his colleagues allowed time for interneurons to form and migrate to the cerebral cortex. Then they examined the genetic profiles of the various cells. This allowed them to hunt for the genes that caused two defects: the failure to generate interneurons and the failure of interneurons to journey into the cerebral cortex.

They found 13 genes whose absence prevented interneurons from forming. They identified another 33 genes that, when missing, prevented interneurons from traveling to the cerebral cortex. All told, 46 genes — 11 percent of the 425 linked to neurodevelopmental disorders — appeared to affect the nerve cells that inhibit their neighbors, leading to an imbalance.

The scientists learned that one of the genes crucial to the migration of interneurons, LNPK, has been linked to seizure disorders. This would support the idea that seizures result from too much excitation of neurons and too little inhibition.

Using the fused clumps of cells, the researchers “performed by far the largest screen for autism and [neurodevelopmental disorder] genes,” Guo-li Ming, a professor in the departments of neuroscience and psychiatry at the University of Pennsylvania, wrote in an email commenting on the study.

Ming, who was not involved in the project, described it as a “tour-de-force” that may one day lead researchers to develop treatments for autism and other disorders — therapies based on the genetic profile of an individual patient.

The autism services cliff

Experts stressed that autism is not one disease, but a group of disorders. The neuron imbalance is only one of multiple possible causes.

Many people with autism, for example, have defects of the microglia, cells that regulate brain development, injury repair and maintenance of the networks that process information.

And genes alone cannot account for autism, saidYale’s McPartland. “It’s complicated, and it’s fascinating. You can have [autism in] identical twins and they almost always will both have autism. But not always.”

Jennifer Singh, an autism expert and associate professor in the school of history and sociology at Georgia Institute of Technology, said too much money has been poured into searching for the genetic underpinnings of autism spectrum disorder. Singh pointed to a 2018 report by a federal advisory committee, which found that 60 percent of the funding for autism research addressed the biology and risk factors, but only 2 percent dealt with “life span issues” for people living with the spectrum of disorders.

“This hyper focus and massive investment obscures the real issues people with autism and their families face,” Singh wrote in an email. She cited the “autism services cliff,” which occurs when people with autism can no longer attend public school. “Services that would be useful for autistic adults do not exist or are no longer available,” she said.

Pasca said that it’s important to study “the natural history of the disease. But we also need to understand the biological basis if we want to develop effective [treatments].”


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