Zebrafish Behavior Screens Could Hold Potential for Drug Discovery

Researchers from the University of British Columbia and Harvard University have co-developed a system that captures on video and barcodes the behavioral responses of zebrafish to chemical compounds on a large scale. The approach could dramatically speed up the discovery of new psychiatric drugs.

The discovery in the 1950s of drugs that act in the nervous system has been important both for the understanding of neurobiology and the treatment of neurological diseases. Since then, very few new classes of drugs have been developed.

Current drug discovery approaches are typically target based, meaning they attempt to identify compounds that modify the activity of a specific protein target. These approaches benefit from being systematic and high throughput, but ussually lack the ability to discover drugs that modify nervous system function in new ways.

The new system, detailed in today's edition of Nature Chemical Biology, was developed by UBC statisticians Jennifer Bryan and Rick White and Harvard's Randall Peterson and David Kokel. It can track the behavioral effects of up to 14,000 chemicals at a time and has already identified new chemicals that affect behaviour in fish.

"The capacity of this approach is quite distinctive," says Bryan, an associate professor in the Department of Statistics and the Michael Smith Laboratories. "Most pharmacological studies of behaviour have been relatively small scale, involving a few small molecules at most."

"New psychoactive drugs represent new windows into how the brain works," says Randall Peterson of Harvard. "We hope that behavioral screens with zebrafish will lead to many new compounds that help us understand and ultimately treat nervous system disorders."

Zebrafish models have increasingly been used to assess drug toxicity and safety, largely because the fish are transparent, genetically tractable, and have organ systems that are very similar to those of humans. Zebrafish embryos are permeable to drugs.

Capable of screening approximately 5,000 zebrafish embryos per day, the new platform monitors the motion of embryos in response to two strong light pulses after exposure to chemicals, and compares that to untreated controls. In total, the study evaluated the behavioral effects of compounds on more than a quarter million embryos.

"The UBC team was able to help devise ways to turn these behavioral observations into more manageable barcodes that capture how the behavior in a treated group differs from that in an untreated, control," says Bryan, co-author of the study. "This makes it possible to generate visualizations of the massive screening datasets generated by this powerful tool, and to group compounds based on the similarity of their associated barcodes."

The new tool may also make it possible to generate genetic models of nervous system disorders and screen for chemical modifiers of the associated behavioral defects.

The study's other contributors are: Christian Laggner and Brian Shoichet (Department of Pharmaceutical Chemistry, University of California, San Francisco) Chung Yan J Cheung, Rita Mateus, David Healey, Sonia Kim, Andreas Werdich and Calum MacRae (Department of Medicine, Harvard Medical School) and Stephen Haggarty (Broad Institute, Cambridge, Massachusetts).

Watch the video capture from the study: www.nature.com/nchembio/journal/vaop/ncurrent/suppinfo/nchembio.307_S1…