Modeling Schizophrenia: An In Vitro Model of a Tough Disease

This column has always been about the world of molecular mental health research. In the April issue of Psychiatric Times, I discussed how adult stem cells were being used to aid in research on a neurological disorder (spinal muscular atrophy). I revisit the technology in this column, now aimed at one of molecular neuropsychiatry’s most intractable, frustrating lines of research: the molecular/cellular basis of schizophrenia.

I use the word “frustrating” because a biological explanation for the disease seems heartbreakingly just out of reach. Schizophrenia has a powerful genetic component (heritability percentage is in the low 80s), something I’ve known for years, something that could make it low-hanging research fruit. There is also a large clinical base on which to do studies: schizophrenia afflicts millions of people (the estimated prevalence rate is about 1% of the global population). Despite these seeming advantages, a molecular mechanism capable of describing all aspects of schizophrenia has almost completely eluded researchers.

There’s a simple reason for this. A deep understanding of schizophrenia at such an intimate level has been hampered by a single technical bottleneck: the lack of a robust in vitro disease model.

That may all be about to change. The results from a study that used cells derived from a deceased patient’s skin tissue has recently been published.¹ Findings from the study may provide just such a model. It is not yet full-fledged schizophrenia-in-a-dish, but the findings portend a powerful future for the field. I’d like to tell you what happened. I’ll start with a brief review of hiPSCs (human inducible pluripotent stem cells), then move to the data.

Pluripotent stem cells

August 2006 is a landmark in the field of regenerative medicine. An article published that month from a group in Kyoto, Japan, described how to take garden-variety mouse skin cells and turn them into pluripotent stem cells.² It was reported that stem cells have an ability to transform themselves into different cell types, depending on the tissue, essentially at the scientist’s whim.

Researchers had been trying to harness this power for a long time, and for good reason. Such technologies could be useful for screening the effects of drugs, valuable as replacement therapies for damaged tissues, and relevant to this article on creating disease models. The cells are formally termed “iPSCs.” I received a further shock when a year later, the same research group did the same trick with human cells.³

Four separate gene sequences are loaded onto genetically reengineered retroviruses (members of the genus lentivirus, which includes HIV). These viruses are allowed to infect a host skin cell, and because they are retroviruses, they immediately integrate into the host cell’s DNA. For reasons not fully understood, this integrated gene combination goes right to work reprogramming the skin, transforming it into a batch of versatile iPSCs. One of the most interesting of the 4 retroviral-stitched sequences is called Myc, which before this work was mostly known for causing cancer.

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