Recently, there has been a transition from traditional siRNA-based drug discovery to CRISPR-based methods. Using CRISPR Cas9 to enable drug discovery could radically improve people’s lives worldwide. Timothy Dahlem, Director of Biology at Recursion Pharmaceuticals, is contributing to this mission by leveraging CRISPR in whole genome screening.
Dahlem mentioned that his company uses a foundational systems biology approach called phenomics to capture any holistic changes to cellular systems biology. When the same cell types have been perturbed in various ways, their morphologies change. With the phenomics platform, the team can model diverse biological perturbations, and each perturbant represents a unique action taken on the cells that induces a change in cellular state. Then, using CRISPR, they can profile secreted factors, toxins, and cell stress.
Recursion relies on arrayed CRISPR-Cas9 RNPs in high-throughput 1536-well formats to knock out genes and observe morphological effects. Dahlem uses this information to build a map of biology by comparing the phenotypic effects of knocking out every gene in the genome. The platform can distinguish between genes with similar or distinct biological impacts. In fact, it can pinpoint non-functional guides or genes with no morphological effect.
Instead of depending on traditional drug screening, Dahlem suggested an inferential screening approach. This technique uses phenoprints to infer relationships between genes and compounds, enhancing drug discovery efficiency. This gives important insights into the relationships between genes and compounds, facilitating novel target discovery and safety profiling.
To showcase the applicability of this screening method, Dahlem presented a few case studies. The JAK-STAT pathway showed clustering of compounds that inhibit or activate the pathway, which reaffirms the platform’s ability to capture biological relationships. Another study on a BRAF V600E Mutation showed that upon inserting this mutation at an endogenous site in cells using CRISPR HDR, it could identify compounds that reversed the disease phenotype in the phenomics space.
