April 14, 2011

Schizophrenia Study Uses Patient’s Own Stem Cells

After more than a century of studying schizophrenia, the root cause of the disorder is still unknown. But induced pluripotent stem cells (iPSCs) generated from schizophrenic patients have brought researchers a step closer to understanding the biological underpinnings of the disease.

A team of scientists at Penn State University, the Salk Institute for Biological Studies, and other institutions expect the new method can be used to study other mysterious disease such as autism and bipolar disorder, and researchers hope that it will open the door to personalized medicine and customized treatments.

In the co-authored study, posted on the journal Nature's online website on Wednesday, Gong Chen, an associate professor of biology at Penn State, explained that the team first took samples of skin cells from schizophrenia patients. They then used molecular techniques to reprogram the skin cells to become the primitive, undifferentiated iPSCs.

"A pluripotent stem cell is a kind of blank slate," explained Chen. "During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell."

From this blank slate, the stem cells were then cultured to become brain cells, enabling them to be used for Petri-dish experiments into studying how schizophrenia is tailored to an individual.

"Using this method, we can figure out how a particular drug will affect that particular patient's brain cells without needing the patient to try the drug and potentially suffer the side effects," said Chen.

"The patient can be his or her own guinea pig for the design of his or her own treatment, without having to be experimented on directly," he said.

The scientists used commonly-prescribed anti-psychotic medications to see whether this boosted communication between neighboring cells. They found that the only one that worked was Loxapine, although it also had unexpected effects on hundreds of genes.

"This is the first time that a complex mental disease has been modeled in live human cells," said lead author Fred Gage, Ph.D., a professor in the Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. "This model not only affords us the opportunity to look at live neurons from schizophrenia patients and healthy individuals to understand more about the disease mechanism, but also to screen for drugs that may be effective in reversing it."

Kristen Brennand, a Salk researcher and one of the study's authors, added that the model system "allows us to study how antipsychotic drugs work in live, genetically identical neurons from patients with known clinical outcomes, and we can start correlating pharmacological effects with symptoms."

Chen described the new method as "patient specific," offering a step toward personalized medicine for sufferers of schizophrenia and potentially other diseases.

"What's so exciting about this approach is that we can examine patient-derived neurons that are perhaps equivalent to a particular patient's own neural cells," Chen said.

"Obviously, we don't want to remove someone's brain cells to experiment on, so recreating the patient's brain cells in a Petri dish is the next best thing for research purposes," he said.

Schizophrenia is a complex condition that is believed to have environmental as well as hereditary factors. It is characterized by paranoid delusions and hallucinatory voices. Around one percent of the population worldwide are believed to be afflicted by the disorder -- the equivalent of nearly 3 million people in the US alone.

"Nobody knows how much the environment contributes to the disease," said Brennand. "By growing neurons in a dish, we can take the environment out of the equation and start focusing on the underlying biological problems."

In another part of the study, Brennand used an altered rabies virus, developed by professors Edward Callaway and John Young of the Salk Institute, to highlight connections between neurons. The viral tracer made it clear that the schizophrenic neurons connected less frequently with each other and had fewer projections growing out from their cell bodies.

In addition, gene-expression profiles identified almost 600 genes whose activity was misregulated in these neurons; 25 percent of those genes had been implicated in schizophrenia before.

Gage added that, for many years, mental illness has been thought of as a strictly social or environmental disease. "Many people believed that if affected individuals just worked through their problems, they could overcome them," he said. "But we are showing real biological dysfunctions in neurons that are independent of the environment."


Image Caption: In this microscopic image, nuclei originated from human cells are stained red and stem-cell-derived newborn neurons are stained green. Credit: Gong Chen laboratory, Penn State University


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