Thus, there is a need for a device to permit direct battery-powered, cofactor-free, time- and voltage-dependent electrical fine-tuning of mammalian gene expression to set the stage for wearable-based electro-controlled gene expression with the potential to connect medical interventions to an internet of the body or the internet of things. As differences in bioavailability, pleiotropic side effects and pharmacodynamics may jeopardize the overall regulatory performance of such triggers in a mammalian host, attention has increasingly turned to non-molecular traceless physical cues such as electromagnetic waves, including light 18, 19, magnetic fields 20, radio waves 21 and heat 22 however, physically triggered gene switches may require high energy input 21, may involve unphysiological chemical or inorganic cofactors with side effects 19, poor bioavailability 23 or short half-lives 24, may suffer from illumination-based cytotoxicity 25 and may be confounded by any fever-associated medical condition 22. Gene circuits typically incorporate trigger-inducible gene switches that are controlled by small-molecular compounds such as antibiotics 14, vitamins 15, food additives 16, cosmetics 17 or volatile fragrances 8. The utility of many of these gene circuits has been demonstrated in the experimental control of diverse medical conditions, including cancer 3, bacterial infections 11, chronic pain 12 and diabetes 13. Synthetic biology has taken up this challenge by assembling simple analog gene switches into complex gene circuits that can program cellular behavior with the logic-processing functionality of electronic circuits such as oscillators 3, timers 4, memories 5, band-pass filters 6 and relay switches 7 as well as analog-to-digital converters 8, half-adders 9 and even full-adders 10. Electrogenetic interfaces that would enable electronic devices to control gene expression remain the missing link in the path to full compatibility and interoperability of the electronic and genetic worlds 2. While biological systems are analog, programmed by genetics, updated slowly by evolution and controlled by ions flowing through insulated membranes, electronic systems are digital, programmed by readily updatable software and controlled by electrons flowing through insulated wires. Interconnected smart electronic devices are increasingly dominating our daily lives and shaping our health awareness 1 however, electronic and biological systems function in radically different ways and are largely incompatible due to the lack of a functional communication interface. We believe this technology will enable wearable electronic devices to directly program metabolic interventions. In a proof-of-concept study in a type 1 diabetic male mouse model, a once-daily transdermal stimulation of subcutaneously implanted microencapsulated engineered human cells by energized acupuncture needles (4.5 V DC for 10 s) stimulated insulin release and restored normoglycemia. DART utilizes a DC supply to generate non-toxic levels of reactive oxygen species that act via a biosensor to reversibly fine-tune synthetic promoters. Here we provide the missing link by developing an electrogenetic interface that we call direct current (DC)-actuated regulation technology (DART), which enables electrode-mediated, time- and voltage-dependent transgene expression in human cells using DC from batteries. Wearable electronic devices are playing a rapidly expanding role in the acquisition of individuals’ health data for personalized medical interventions however, wearables cannot yet directly program gene-based therapies because of the lack of a direct electrogenetic interface.
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