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How CRISPR Transforms Modern Drug Discovery

Consensus seems universal and the news about it flows literally by the minute over gene editing as a future therapy, complete with patent sagas and ethical conundrums. But at the bench, CRISPR's impact is also proving disruptive, and revolutionary, soon to irrevocably change the mechanics of drug discovery and pre-clinical development in multiple ways. One particular set of  CRISPR applications should be on every drug hunter's radar: disease relevant cellular reporter models manipulated to reflect disease phenotypes.

While the transition away from in vitro and immortalized cell assay systems has been underway over the last decade, the pace increased with the advent of easily manipulated stem cells to create fit-for-purpose biochemical and high content, high throughput screens. The principal accelerator here has been CRISPR editing to provide organotypic and disease specific models, including direct application of patient-sourced cells and assembled organoids (disease and control) as platforms for drug SAR and efficacy testing.

As Andrew Bassett  from the Wellcome puts the matter: "such cells can be generated in sufficient numbers to be able to perform whole genome genetic screens to identify molecular and cellular mechanisms of disease and therapeutic targets, and also for high throughput drug screening to identify compounds that may be able to revert the disease phenotype. Differences between patient-derived and control cells can be used to identify potential therapeutic targets or agents." (Ref. 1). A compelling example in an underserved area of research lies in the development of CRISPR driven new assays for glioblastoma (Ref. 2).

Diving deeper reveals how powerful CRISPR manipulation can be in effectively affording knock-in, through activation (CRISPRa), or knock-out, through interference (CRISPRi), of traits/phenotypes subject to targeting and modulation by candidate drugs (Refs. 3-5 and graphic below taken from Ref. 4). The technology is also extensible to organoids, deriving further informational value from this more physiologically meaningful cell platform (Refs. 6,7).

Practical applications of CRISPR in cell reporter assays are also noteworthy for by-passing the inconsistencies (or effective impossibility) of either durable or transient transfection in attaching the reporter to a target regulatory element at specific loci of a gene. Representative implementations, with benchmark methodology, include tagging with luciferases and luminescent proteins for both high throughput and high content, imaging assays (Refs. 8-10).

Is CRISPR panacea for discovery and validation assays? The answer depends on the cell-based context, so the exercise left to the reader is to examine the full spectrum of modalities (Ref. 11) where the influence of CRISPR methodology is more likely to be felt.



  1. Editing the genome of hiPSC with CRISPR/Cas9: disease models, Bassett, Mamm. Genome 2017 (O/A),
  2. Accelerating glioblastoma drug discovery: convergence of patient-derived models, genome editing and phenotypic screening, O'Duibhir et al., Mol. Cell Neurosci. 2017 (O/A),
  3. Beyond editing: repurposing CRISPR–Cas9 for precision genome regulation and interrogation, Dominguez et al., Nat. Rev. Mol. Cell Biol. 2016 (O/A),
  4. Elucidating drug targets and mechanisms of action by genetic screens in mammalian cells, Kampmann, Chem. Comm. 2016 (not O/A),
  5. CRISPRi and CRISPRa screens in mammalian cells for precision biology and medicine, Kampmann, ACS Chem. Biol. 2017 (not O/A),
  6. Drug discovery via human-derived stem cell organoids, Liu et al., Front. Pharmacol. 2016 (O/A),
  7. Three-dimensional cell cultures in drug discovery and development, Fang and Eglen, SLAS Discovery 2017 (O/A),
  8. Development of a luciferase reporter Jurkat cell line under the control of endogenous interleukin-2 promoter, Liu et al., J. Immunol. Methods 2017 (not O/A),
  9. A novel tool for monitoring endogenous alpha-synuclein transcription by NanoLuciferase tag insertion at the 3′end using CRISPR-Cas9 genome editing technique, Basu et al., Sci. Repts. 2017 (O/A),
  10. CRISPR-mediated tagging of endogenous proteins with a luminescent peptide, Schwinn et al., ACS Chem. Biol. 2017 (not O/A),
  11. Cell-based assay design for high-content screening of drug candidates, Nierode et al., J. Microbiol. Biotechnol. 2016 (O/A),


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