Abstract
Programming cellular behavior using trigger-inducible gene switches is integral to synthetic biology. Although significant progress has been achieved in trigger-induced transgene expression, side-effect-free remote control of transgenes continues to challenge cell-based therapies. Here, utilizing a caffeine-binding single-domain antibody we establish a caffeine-inducible protein dimerization system, enabling synthetic transcription factors and cell-surface receptors that enable transgene expression in response to physiologically relevant concentrations of caffeine generated by routine intake of beverages such as tea and coffee. Coffee containing different caffeine concentrations dose-dependently and reversibly controlled transgene expression by designer cells with this caffeine-stimulated advanced regulators (C-STAR) system. Type-2 diabetic mice implanted with microencapsulated, C-STAR-equipped cells for caffeine-sensitive expression of glucagon-like peptide 1 showed substantially improved glucose homeostasis after coffee consumption compared to untreated mice. Biopharmaceutical production control by caffeine, which is non-toxic, inexpensive and only present in specific beverages, is expected to improve patient compliance by integrating therapy with lifestyle.
Highlights
Programming cellular behavior using trigger-inducible gene switches is integral to synthetic biology
Cell-based therapies capitalizing on the complexity of mammalian cells are taking the lead in the advent of personalized medicine[8], as exemplified by applications of chimeric antigen receptor (CAR)—T cells[9] or designer cell implants to treat various common diseases[2,10]
Controlling the dynamics of gene expression is essential for the functionality of synthetic gene circuits. This is especially relevant in synthetic biology-inspired therapies, where gene expression regulation determines the dosage of the produced therapeutic and allows for considerable control over the designer cell implant
Summary
Programming cellular behavior using trigger-inducible gene switches is integral to synthetic biology. Plug-and-play combinations of carefully designed biological modules have enabled major advances in therapies for personalized medicine[2,3], as well as in the challenging endeavor of lineage control[4,5], bringing achievements in the laboratory ever closer to rewarding real-world applications[6,7]. The quest for better inducers has progressed rapidly Antibiotics such as tetracycline or doxycycline[13] were used for the control of gene expression, raising issues such as antibiotic resistance[14] and side effects[15]. The generation of inducers were designed to be safe and orthogonal, such as the apple tree leaf metabolite phloretin[16] or the food additives benzoate and vanillic acid[17] These inducers still suffer from potential side effects, especially in longterm applications, and have to be exogenously added. The ideal inducer would be inexpensive, would have no side effects, and would be present in only a specific set of known sources
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