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Abstract Here we present a technology to facilitate synthetic memory in a living system via repurposing Transcriptional Programming (i.e., our decision-making technology) parts, to regulate (intercept) recombinase function post-translation. We show that interception synthetic memory can facilitate programmable loss-of-function via site-specific deletion, programmable gain-of-function by way of site-specific inversion, and synthetic memory operations with nested Boolean logical operations. We can expand interception synthetic memory capacity more than 5-fold for a single recombinase, with reconfiguration specificity for multiple sites in parallel. Interception synthetic memory is ~10-times faster than previous generations of recombinase-based memory. We posit that the faster recombination speed of our next-generation memory technology is due to the post-translational regulation of recombinase function. This iteration of synthetic memory is complementary to decision-making via Transcriptional Programming – thus can be used to develop intelligent synthetic biological systems for myriad applications. 

Traditional therapeutics aim to diagnose, treat, and cure diseases through various synthetic and natural approaches. The emerging field of engineered living therapeutics (ELTs) genetically functionalizes living cells to alter the paradigm of designed solutions. In this review, we focus on ELTs derived from microbial cell scaffolds. We propose three synergistic modalities for the rational design of ELTs: first, use of regulatory operations to regulate genetic expression; second, integration of alternative biosensing inputs for directed application; third, choice of microbial chassis to deliver solutions. We highlight the challenges and future opportunities within each group and conclude by providing a prospective outlook for ELTs.