9.30.2005

Of Schizophrenic Mice and Men

He starts with a normal mouse, then changes a single gene to give it a “beautiful mind.” Though neuroscientist Akira Sawa will never know if the altered critters hear imaginary voices, he does know their brains look remarkably similar to those of the 1% of humans who have schizophrenia.  

Working at the Johns Hopkins University School of Medicine, Sawa has recently added a mutated gene—previously linked to schizophrenia—into the brains of mouse embryos. Remarkably, he found this stunted their development in the same way it does to many human schizophrenics. These modified mice could serve as models of the disease, to design and test new drugs. And further down the road, Sawa hopes to create more effective therapies using them in combination with ground-breaking stem-cell technology.  

Schizophrenia—a disease that causes hallucinations and emotional apathy—is usually diagnosed between age 15 and 30. Many researchers have thus assumed that it’s caused by environmental influences after birth, such as viral infections or psychological stresses. But in recent years, research on identical twins and autopsied brains of schizophrenics pointed to a genetic link.

Convinced of the genetic basis, Sawa looked for a gene or mutation that was reliably associated with the disease—a daunting task, as “more than 100 genes have been implicated in the disease but maybe 90 are junk.” He chose a gene called DISC-1 (Disrupted-in-Schizophrenia) for two reasons: “the other candidates were known genes with known functions…and only [DISC-1] has a clear disease-associated mutation.”  

To get mut-DISC1 into a developing mouse’s genome, Sawa’s latest study took advantage of the gene’s electrical properties. He placed a pregnant mouse in an electric field such that the negatively-charged mut-DISC1 was attracted to the positive end of the field, and thus forced into the embryo’s brain. Although Sawa said the technique only worked in one to five percent of cells, it was enough to dramatically change brain development.

In the mutated mice, the migration of neurons from the inside chambers of the brain to the outer layers of cortex was severely delayed. What’s more, an abnormal orientation of neurons in their brains matched that seen in the autopsied brains of human schizophrenics. Taken together, these results show that mut-DISC1 disrupts brain development and often leads to schizophrenia.

But mut-DISC1 isn’t a gene for schizophrenia. If “a mutation is in the same gene, but in a different place [within the gene],” Sawa said, “clinical manifestations can be very different.” In identical twins, for instance, sometimes only one gets the disease. “Even if they have the exact genome,” he said, “they may have different gene expression or one may catch a viral infection or…have different social stresses.”

The mouse models can be used right away to test new drugs; Sawa admitted he was funded by several pharmaceutical companies. But he’s more excited about a new treatment that uses human stem cells. Starting with a biopsy through a patient’s nose, neuronal stem cells could be harvested and then manipulated in the lab to replace the damaged ones. They “mimic neurodevelopmental features, even in an adult,” he said. “Here,” pointing to his nose, “they’re still young.” Though still three to five years away, Sawa has high hopes that using stem cell therapy in combination with the mouse models will ultimately “bridge bench to bed.”

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