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Landmark Gene Discovery Cracks Open ‘Black Box’ Of Schizophrenia

Sydney and her mother Lori look into the bedroom mirror where Sydney experienced her first symptoms of schizophrenia. Now 20, Sydney has had no symptoms for almost two years now. (Jesse Costa/WBUR)

Sydney and her mother Lori look into the bedroom mirror where Sydney experienced her first symptoms of schizophrenia. Now 20, Sydney has had no symptoms for almost two years now. (Jesse Costa/WBUR)

One November day in her senior year of high school, Sydney accidentally broke the full-length mirror leaning up against the wall of her bedroom.

She felt a gust of superstitious dread: “Oh my God, I have to put this mirror together or I’m going to have bad luck.” Then, it escalated oddly into religious terror: “The devil’s coming to get me!”

Something inside her seemed to snap, she said. She sensed demons invading through the broken glass.

Not long afterward, President Obama spoke to Sydney inside her head: “OK, this is how the world is now,” he told her. “Everyone is so in love with each other, we can hear each other in our heads.”

The menacing voices of demons started to torment her, especially at night. She became convinced that she was going out with the pop star Justin Bieber, that he was chatting with her on her phone and sending her hidden messages in his Twitter feed. She thought he set up paparazzi in her backyard on Boston’s North Shore, that he was sending planes over her house to let her know he cared.

“Is this really happening?” She would ask the voices in her head. “Is this?” Yes, they told her. Yes.

What was really happening? How does a sunny girl who’d never had psychiatric problems before, who grew up loving dance and Disney princesses, a good student who was rich in family and friends, how does that girl suddenly lose her hold on reality?

Schizophrenia affects about 1 in every 100 people, and one thing is clear: Genetics plays a role. Sydney’s uncle had schizophrenia, and scientists have identified more than 100 genes that can raise the risk for it.

Now, researchers based at the Broad Institute in Cambridge and Harvard Medical School have pinpointed the gene that is the biggest risk factor for schizophrenia discovered so far, and figured out how it does its damage: It makes the brain prune away too many of the connections between neurons.

“[I]t may be like you have an over-energetic gardener who prunes back so much that the bushes die off…”

– Bruce Cuthbert, of the National Institute of Mental Health

That finding, just published in the journal Nature, may also explain why schizophrenia tends to hit at such an odd age, in the late teens and early 20s. That pruning of connections is a normal process that ramps up during adolescence, but this genetic culprit may make it go overboard.

Pruning may sound bad, said Bruce Cuthbert, the acting director of the National Institute of Mental Health, but actually, it’s helpful: “It’s like clearing away the underbrush so your brain can function more efficiently.”

But, he said, “in people with this overactive version of the gene, it may be like you have an over-energetic gardener, who prunes back so much that the bushes die off because they don’t have enough branches.”

Cuthbert called the paper a “genetic breakthrough” and “a crucial turning point in the fight against mental illness.” Eric Lander, director of the Broad Institute, said it means we’re finally starting to understand what causes schizophrenia at the level of brain biology.

“For the first time,” Lander said, “we’re opening up the black box and looking inside and seeing, how does the disease really arise? That makes this, in my opinion, perhaps the most important paper in schizophrenia since the disease itself was ever defined,” over a century ago.

This scientific excitement does not mean, however, that the findings will lead to new treatments for schizophrenia any time soon, Lander and others said. It takes years for such basic science to translate into treatments — if it ever does.

But the new paper does suggest some promising new targets for drug development, some already being worked on for other diseases, said Harvard Medical School’s Steve McCarroll, who led the research team. Continue reading