Light is the be-all and the end-all in new biological screens

Many biological questions are answered by systematically 'screening' experimental conditions, such as different genetic make-ups of organisms, environmental parameters or drug candidates. Light is at the heart of a new method that radically reduces complexity in and simplifies design of biological high-throughput screens.

HFSP Young Investigator Grant holder Harald Janovjak and colleagues
authored on Tue, 03 November 2015

Automated studies with high-throughput, also called ‘screens’, are essential for the identification and characterization of drug candidates and genetic modifications that influence biological processes. In particular, screens using living cells and behaving animals preserve the native functional context and interactions of genes and drug targets. In turn, these methods are currently challenged by the need to add or withdraw chemicals or proteins that stimulate and/or read-out the biological state of the cell or animal. Complex robotic design, high cost and additional sources of error are common consequences. We found inspiration to overcome these limitations in research conducted outside of the field of biology. In chemical engineering, research and manufacturing processes were developed in which chemical reagents, such catalysts or initiators, are replaced with physical signals, such as light or ultrasound. Although replacement achieved improvement in cost, robustness and sustainability, screens that harness this power of light or ultrasound have yet to be demonstrated in biological research.

Figure: Artist’s interpretation of the ‘all-optical’ screening method. The combination of a blue light-activated oncogene and a green light-emitting reporter enabled the identification of small-molecule inhibitors against the oncogene.

In our recent paper, we showed that a physical stimulus (light) can indeed act as both the activator and read-out in a biological screen where drugs are tested for action against human oncogenes. To develop this novel screening method we re-purposed optogenetics, a technique originally developed in neuroscience that enables the optical ‘remote control’ of the activity of proteins and cells. As in the examples from chemical engineering, our ‘all-optical’ method obviated the use of assay chemicals (e.g. chemicals or proteins for cell activation, or chemicals for cell read-out) and limited the number of required operational steps (e.g. solution exchange or other invasive actions using robotics). Light activation was not only available at negligible cost but also provided unparalleled specificity and reproducibility. For instance, by illuminating only selected cells in a large group of cells in an individual experiment we created internal references that can be used to normalize results and to obtain independent measurements under identical conditions. This work was the first expansion of optogenetic methods into the field of drug discovery and we foresee the extension and adaptation of this approach to other drug targets to be straightforward because of the increasing number of available optical reporters, including those that we aim to develop in the context of our HFSP Young Investigator Grant.

Reference

Light-assisted small molecule screening against protein kinases. A. Ingles-Prieto, E. Reichhart, M.K. Muellner, M. Nowak, S.M. Nijman, M. Grusch & H. Janovjak. Nat Chem Biol. 2015 Oct 12. [Epub ahead of print] doi: 10.1038/nchembio.1933.

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