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Multiple functionality (cleaving and transcriptional activation/repression) of the modified Cas9 protein, a Cas9 nuclease fused to an activation domain (VPR), is useful because it provides better flexibility to engineer complex and multilayer genetic switches since these functionalities are achieved by altering small and easy to engineer guide RNAs (gRNAs). This technology technology is based on the discovery by the Church lab that truncating gRNA from the 5’ end decreases nuclease activity of Cas9-VPR complex while retaining its DNA binding capacity. The inventors have developed several genetic kill switches (and off switches) with increasing complexity using shared and single Cas9-VPR and multiple gRNAs of different length. The lesser DNA footprint (sallows generation of circuits that can be better packaged into delivering vehicles such as viruses that contain load limit for therapeutic potentials.  Furthermore, this technology is easy to engineer and has great potential for therapeutic application (safety switches).