Genomics


Figure 1


Editing the genome with molecular scissors


of screening techniques have revealed a large amount of significant and relevant data, the gene editing technologies underpinning these approaches have only taken us so far. Many early gene knockdown screens were based


on RNA interference (RNAi) techniques, a means of silencing genes by deactivating messenger RNA (mRNA). Among the most widely used knock- down screens were those based on small interfering RNA (siRNA). However, while this technique pro- vides an abundance of information on biological pathways, it is frequently hampered by poor gene knockdown rates. In contrast, CRISPR-Cas9 allows the modula-


tion of specific endogenous genes to cause com- plete gene silencing, leaving no residual activity to complicate analysis. While pooled CRISPR libraries have made genome-wide knockout more efficient, they require an additional deep sequenc- ing deconvolution step for the reliable identifica- tion of hits. The development of arrayed CRISPR screening approaches is set to provide complete gene knockout without the complexity and cost associated with big data analysis2. These scalable


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screening methods may now be able to accelerate the search for candidate genes that could have been missed using earlier approaches. “Genomic CRISPR screening has the potential to


demonstrate which pathways are involved in the manifestation of particular diseases or conditions,” says Gregory Alberts, Global Subject Matter Expert at Lonza. “Once the particular genes associated with responsive pathways are identified, there could be numerous candidates, such as potential drug targets, which can then be assessed for the appropriate responses to drug intervention.” Alberts believes that these high-throughput screens


are well placed to contribute to the major paradigm shift currently taking place in medicine: the move away from treating disease symptoms and towards the targeting of their underlying mechanisms. “By determining which gene expression or signal


transduction pathways are turned on or off in spe- cific cancers, for example, you can potentially tar- get the individual components of these pathways.” In this way, pathway analysis may offer opportuni- ties to attack diseases using a whole range of new approaches.


Drug Discovery World Spring 2018


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