(November 14, 2018) The genetic terms for schizophrenia are extremely complex and heterogeneous, with hundreds of genes and thousands of variants implicated in disease development. Known environmental components, such as inflammation, also contribute to development, compounding difficulties in determining underlying causation.
However, new techniques in molecular biology, which are evolving at a blistering pace, may be the answer for making sense of these complicated genetic relationships and better understanding how specific types of DNA mutations contribute to the neurobiology of schizophrenia. 
Dr. Kristen Brennand, PhD, from Icahn School of Medicine at Mount Sinai won the 2018 Maltz Prize for Innovative and Promising Schizophrenia Research at the Brain and Behavior Research Foundation International Mental Health Research Symposium last month for her work in using molecular biology techniques to investigate schizophrenia. She utilizes two innovative molecular biology techniques, induced pluripotent stem cells and CRISPR technology, short for ‘clusters of regularly interspaced short palindromic repeats,’ to model schizophrenia at the cellular level. These cellular models can then be used to discover and test novel drugs for the debilitating disease.
Induced pluripotent stem cells
Induced pluripotent stem cell technology allows researchers to take any cell from an individual, such as a skin cell, and reverse program it into a stem cell, the progenitor cells that give rise to all the cells in the human body. These cells are then manipulated in a laboratory for personalized disease modeling and drug development.
In application, this process presents the opportunity for a wide variety of genetic and molecular biology experiments. For example, cells from individual patients with schizophrenia, collected via a mouth swab or other non-invasive technique, can be developed into induced pluripotent stem cells and then made into neurons, the messenger cells in our brains, with the exact same DNA as the patient.
Dr. Brennand and colleagues have used induced pluripotent stem cells to create cellular models for schizophrenia and bipolar disorder that are consistent with what is known about the actual brains in individuals with these illnesses. This gives researches the unprecedented ability to observe these cells as they develop and create cellular networks of connectivity. In other words, they can effectively simulate human brain activity in a laboratory setting.
CRISPR technology
CRISPR technology is a novel gene editing technique that has revolutionized molecular biology. CRISPR is a stretch of DNA composed of short, repeating sequences that when coupled with a cellular enzyme called Cas9, acts as a DNA scissor. The CRISPR-Cas9 system can cut specific segments of our genome and replace the cut segment with a new version of a gene.
Dr. Brennand and colleagues have used the CRISPR technology to generate a variety of cells that mimic genetic differences known to be found in individuals with schizophrenia. Using induced pluripotent stem cells and CRISPR in the lab, genetic variants of schizophrenia can be observed in tandem. The combination of these technologies allows for the development of a genetic cellular equivalent of the vast range of genes known to be involved in schizophrenia.
Drug development
Developing drugs to treat a complex disease like schizophrenia is extremely difficult. Potential drugs have many different mechanisms of action and cellular targets and work to improve symptoms in multifaceted ways. In addition, due to the genetic variability of schizophrenia, each of these potential drugs may work differently in different individuals. Therefore, until recently, large-scale drug screens were not feasible.
Induced pluripotent stem cells and CRISPR technology show promise for mitigating these challenges. Although the methods are still being refined, results are encouraging and may lead to the development of new drugs to treat schizophrenia in the future.
Elizabeth Sinclair
Director of Research
References
· Hoffman, G. E. (2018, August). New considerations for hiPSC-based models of neuropsychiatric disorders. Molecular Psychiatry.
· Readhead, B. et al. (2018, October). Expression-based drug screening of neural progenitor cells from individuals with schizophrenia. Nature Communications.