A Fine Kettle of Schizophrenia Genetics

By: Nike Izmaylov '19
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Picture a modest doctor’s office at a routine visit. Picture someone suffering from schizophrenia asking about treatment options. Picture the doctor explaining that the disease can be nearly cured in as little as a few months with the help of a certain advanced gene therapy treatment.

Although that sounds like science fiction, and may likely remain in the fantasies of scientists and doctors for quite some time, researchers today are already laying the groundworks for being able to cure or lessen the impacts of illnesses such as schizophrenia. Several of these projects are on-going on Harvard campus today.

At the Schier lab, hundreds if not thousands of zebrafish swim about their tanks lined up against in neat rows in a slightly too-warm room. In the room over, newborns swim frantically around their petri dishes. These fish may hold the key to unravelling some of the secrets of schizophrenia, at least on a genetic level. Prior studies have identified several hundred genes that appear more frequently in people with schizophrenia than in the general population, but the next challenge involves determining which genes have significant effect, if any, and the size of that effect.

Part of the difficulty involves creating an assay to diagnose fish with schizophrenia. Imaging the brain after death assists in assessing which genetic mutants have significant mental impacts, by snapshotting the activity of different key molecules at the time of death. To normalise these patterns across different brain states, the images of several zebrafish with the same mutation are merged together to form a colourful map of brain activity. The Schier lab is still in the process of screening and analysing the mutants but have begun to prepare for the next step.

Behavioural assays of relevant mutants For example, most people without schizophrenia become accustomed to surprise. If Alice, who does not have schizophrenia, were tapped on the shoulder once, she might be surprised at the sudden touch. Yet, if the same person then tapped her again, she would get used to it (if annoyed that someone keeps tapping her). However, Bob, who has schizophrenia, would be surprised every time. A similar proposed for zebrafish involves turning on bright lights: A wild-type zebrafish becomes used to the lights flicking on and off and ceases to swim frantically about, while a zebrafish with schizophrenia will swim frantically every time.

Assuming these early experiments are successful, the research will focus on trying to rescue the zebrafish from these behaviours. Those rescues will constitute the basis of any genetic “cure” for schizophrenia.

Even if the genetics of schizophrenia can be unravelled, it’s possible that its overall impact is much smaller than anticipated. Gene therapy then might be wasteful or only help a tiny portion of the population. However, if genetic susceptibility to schizophrenia plays a major role in its development and continuation, cutting out those genes through mechanisms like CRISPR-Cas9 could lessen the probability of developing schizophrenia in the first place. For those already suffering from the illness, this gene therapy could lessen symptoms or possibly cure it entirely. That’s many years of research off, however. What we have so far is a fine kettle of zebrafish.