Fall 2018
Phenotypic CRISPR Screening, main image gene editing illustration
How Phenotypic CRISPR Screening is Revolutionising Drug Discovery
By Dr Steffen Lawo and Dr Carlos le Sage
Fall 2018

Research in drug discovery and biotechnology increasingly exploits gene editing at industrial scale in order to identify and validate new biological targets for precision medicines. The discovery of CRISPR-Cas9 systems has fuelled a rapid expansion of gene editing adoption with particular interest in the increasingly prevalent area of functional genomic screening.

As these technologies have matured and evolved, so have the applications to which they are deployed. While early efforts were heavily enriched for studies in cancer biology, the advent of more complex phenotypic analyses, coupled to CRISPR-based discovery efforts, have substantially broadened the impact of these tools to provide discovery opportunities in myriad disease areas with greater power for hit ID and fewer off-target effects than other screening tools.

Broadly speaking, functional genomic screening requires three elements: an ability to perturb gene function, an assay by which to measure phenotypic response and a mechanism to couple these two observations together.

In the case of CRISPR, the most common perturbations are provided by the canonical knockout based approach (CRISPRko) or by transcriptional control using the catalytically-inactivated and repurposed CRISPR modalities of CRISRPi (interference) and CRISPRa (activation). For gene knock-outs, the benefits are in the high penetrance of the perturbation, where the frequency of homozygous deletion can drive the response close to maximum in the cell system and allows excellent reproducibility between samples and replicates.

Recent observations have indicated that some model systems might be unduly influenced by gene copy-number artefacts with this approach (2), but while this might be a concern for some cancer target ID applications, it is likely that in many cases the benefits of the clean and robust CRISPRko gene editing tool outweighs this consideration.....

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