Steve McCarroll, Broad Institute

Unscrambling Schizophrenia

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Unscrambling Schizophrenia


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Steve McCarroll

Steve McCarroll will always remember what sparked his interest in studying psychiatric disease. “I had a classmate in graduate school who developed schizophrenia,” said McCarroll, who today is the director of genetics at the Stanley Center for Psychiatric Research at the Broad Institute. “Over the course of two to three years, he went from being an exciting classmate, full of hope about the future, to someone who could barely perform even a simple job.”

McCarroll now devotes much of his energy to improving our understanding of schizophrenia and, through that research, to improving treatments for the disease. He developed a system, Drop-Seq, to study how genes are expressed in the hundreds of types of cells in the brain, and his lab’s open-source technology is downloaded every five minutes by scientists around the world.

In 2014, McCarroll’s colleagues at the Broad Institute led the largest study to date of the genetic basis of schizophrenia—or any psychiatric disorder. Combing the genomes of 37,000 schizophrenia patients and 113,000 people without the disease, they found 108 sites in the genome linked to schizophrenia. The strongest of these was a region linked to immune function.

But why were immune genes affecting a disorder of the brain? McCarroll and a student in his lab identified an immune gene that the brain repurposed into another role—sculpting the nervous system during key times in development—and determined that schizophrenia risk arises from over-active forms of this gene. McCarroll’s team also went on to find that the interaction between two types of cells in the brain—neurons and microglia—may be a key contributor to schizophrenia and a target for potential therapies.

The work is challenging, McCarroll notes, because of the very nature of the brain. Unlike diseased organs that can be biopsied, diseases of the brain, protected behind the skull, cannot be studied in a petri dish or a hospital setting. While cancer research has seen dramatic progress over the last several decades, advances have been few for illnesses of the brain, until quite recently.

“You can’t pull out people’s brains and study them. That is why the genome has provided such a powerful way in. We can acquire people’s genomes noninvasively through samples,” McCarroll said, even as easily as taking a sample of cells from someone’s skin. “That has made it possible to find genes underlying illnesses that had not been discovered in decades of earlier research.”


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number of genomes scientists searched for clues about schizophrenia
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newly identified sites in the genome linked to schizophrenia—four times the number of previously known links
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Million
Americans suffer from schizophrenia

Though finding treatments for the disease could take years or even decades, McCarroll’s work could pave the way. Currently, schizophrenia affects one in 100 people around the world. The mental illness can cause debilitating delusions, difficulties in a person’s emotional response and a collapse of thought processes.

Schizophrenia patients have been without new forms of treatment since the 1950s, when scientists pioneered drugs to treat delusions—and that strategy, which attacks the proteins linked to regulating dopamine in the brain, was discovered by accident and does not work equally well for all patients.

Until large-scale genomic studies like the one overseen by McCarroll, there was little ability or incentive to pursue research into mental illness. As Broad Institute Director Eric Lander put it, “pharmaceutical companies who left this field because there was nothing concrete to work on are putting their toes back in the water.”


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