Reversing pathological cell states: the road less travelled can extend the therapeutic horizon.

Acquisition of omics data advances at a formidable pace. Yet, our ability to utilize these data to control cell phenotypes and design interventions that reverse pathological states lags behind. Here, we posit that cell states are determined by core networks that control cell-wide networks. To steer cell fate decisions, core networks connecting genotype to phenotype must be reconstructed and understood. A recent method, cell state transition assessment and regulation (cSTAR), applies perturbation biology to quantify causal connections and mechanistically models how core networks influence cell phenotypes. cSTAR models are akin to digital cell twins enabling us to purposefully convert pathological states back to physiologically normal states. While this capability has a range of applications, here we discuss reverting oncogenic transformation.