A team of Hopkins researchers is striving to change the course of schizophrenia research by giving scientists an unprecedented opportunity to observe DISC1-defective cells directly from patients.
The team, including Cheng-Hsuan Chiang and Guo-li Ming of the School of Medicine, has managed to produce healthy and viable pluripotent stem cell lines for use in future studies of the DISC-1 protein without the need to take brain samples from patients.
Previous genetic and pedigree analyses have identified a mutation in the gene encoding the protein DISC-1 as a risk factor for schizophrenia and other mental disorders, such as bipolar disorder and affective disorders.
These findings opened up a wide avenue of potential research into the molecular mechanisms involved in schizophrenia and related disorders.
Unfortunately, any molecular research in human patients with schizophrenia is obviously limited by the unethical practice of extracting brain samples from relatively healthy living patients.
Mouse models are of course an ideal alternative, but schizophrenia is a complex disorder, and many of its symptoms are not readily identifiable other than by self-report in human subjects.
Nevertheless, research has continued, though perhaps at a slower pace than if live human cells with DISC-1 dysfunctions were readily available for examination.
The stem cells Chiang, Ming and colleagues have created are derivatives of skin cells of schizophrenic patients with known DISC-1 mutations and of control patients with neither schizophrenia nor DISC-1 mutations.
Importantly, the team’s cell lines are integration-free, meaning that no potentially confounding viral vector was needed to reprogram patients’ cells back into pluripotent forms.
According to Russell Margolis, professor of psychiatry and neurology, and director of the Hopkins Schizophrenia Program and an author of the current paper, “Integration-free means that the genes used to change the skins cells (fibroblasts) into stem cells are not inserted into the genome of the cells. They are put into the cell, do their work, and eventually are eliminated from the cell.
“This decreases the chance of artifactual changes. The integration-free method facilitates understanding the biology of the cell and, in this case, the mutation in DISC-1, with less concern that abnormalities that may be detected are from the method of making the cells.”
Previously, the use of viral vectors was a major stumbling block for in vitro studies of induced pluripotent stem cells (iPSCs) from schizophrenic patients,
due to the presence of disruptive oncogenes present in those vectors.
Although other groups have tried and have even managed to produce integration-free cell lines before, the samples created are often not viable for long term use because of the inefficiency of integration-free processes.
Potential uses for these newly developed iPSCs are myriad. The iPSCs can potentially be made to differentiate into neurons so that researchers can study whole cell in vitro cultures for a better look at the cellular and molecular underpinnings of DISC1-mutated schizophrenia; by comparing DISC1-disrupted cells with similarly derived cells of normal patients, researchers may be able to identify macro-level morphological changes or disruptions in schizophrenia.
“One of our goals,” Margolis wrote in an e-mail to The News-Letter, “is to use these cells to help understand pathways involved in the pathogenesis of schizophrenia and other forms of major mental illness. Another goal is to use the cells to develop assays that can be used to screen for molecules with potential therapeutic relevance.”
Once the mechanisms of DISC1-mediated schizophrenia are better understood, scientists may be able to use these new iPSCs to assess the effects and efficacy of newly developed treatments for schizophrenia.
In particular, Margolis is interested in how the level of DISC-1 expression is affected by the mutation in the gene. “If there is less DISC-1 protein than normal made in the cells with the mutations, it may be possible to understand some of the effects on cell biology of this loss,” he wrote.
Other researchers, like Guo-li Ming, associate professor of neurology and senior author of the current findings, want to understand the affect of the mutated DISC-1 on neural development. “These [experiments could] be done by differentiating these iPSCs into neuronal lineages,” Ming wrote in an e-mail to The News-Letter.
Of course, whatever is done with these cell lines in the future, the benefits are sure to be numerous; not only may Chiang and Ming’s findings usher in a new era in schizophrenia research, but their stem cell derivation techniques may also prove useful for generalization to research on other diseases.
