New high throughput screening technique generates behavioural fingerprints based on the responses of fish larvae to potential drugs
A novel screening method that probes the behaviour of zebrafish in response to thousands of different small molecules could help speed up the drug development process, according to US researchers. The approach could prove particularly valuable in the search for treatments for psychiatric disorders.
Zebrafish have become widely used as model organisms in drug discovery. Inspired by parallel work with zebrafish in genetic screening, Alexander Schier at Harvard University and his team have developed a high throughput technique in which a single zebrafish larva is pipetted into each well of a 96-well plate, along with a drug or potential drug, and monitored using computer software. In this way, they can generate a behavioural ’barcode’ or ’fingerprint’ for each compound they test.
’We do a lot of experiments in gene expression profiling, so we thought well, maybe we can use the same approach of clustering that’s used in gene expression profiling, but for behavioural profiling,’ explains Schier. ’That was the conceptual breakthrough for us - when we realised we have this huge dataset, we have these fingerprints, and we can actually group them using clustering algorithms that have been used in gene expression profiling.’
Using this method, Schier’s team has screened nearly 4,000 unique structures and recorded behavioural profiles for more than 60,000 larvae in just a couple of years, demonstrating the immense potential of the screen. By analysing how the compounds affected the sleeping or waking patterns of the fish they were able to group compounds into possible indications for drugs. One particular molecule, for instance - MRS-1220 - clustered with antidepressant compounds. Schier thinks the technique could be used to complement cell culture and rodent studies by helping to characterise large groups of drugs very rapidly.
Su Guo, a pharmaceutical chemist studying zebrafish behaviour at the University of California, San Francisco, is intrigued by Schier’s approach. ’It’s a rather novel and unprecedented idea to use zebrafish behaviour as an in vivo read-out for drug screening,’ says Guo. Since behaviour is so complex, however, she thinks the real challenge is still ahead - to figure out exactly what the chemicals are doing at molecular and cellular levels.
But Schier says his technique provides exactly the kind of behavioural information that is essential to developing psychiatric drugs. ’Behaviour is the emerging property of many neurons interacting and that can’t be studied in a dish - you cannot reduce behaviour to a bunch of cells in culture,’ he says. ’You can study aspects of it, like vesicle release, or channel opening, but then what this does in the context of a whole animal, that is extremely hard or, so far, impossible to mimic in culture.’
J Rihel et al, Science, 2010, DOI: 10.1126/science.1183090