ElectroGene began with the vision of functionally coupling genetic and electronic circuits and connecting the human body and its metabolism to the Internet of Things. ElectroGene has exceeded its promises and launched the science of electrogenetics, including metabotronic interfaces that enable electronics to control target genes, target genes that report their metabolic state to electronics, and pioneering portable, self-sufficient power generators that provide electricity to power electrogenetic devices and implants. Key highlights include: (i) An electrogenetic interface that remotely fine-tunes therapeutic transgene expression or programs vesicle release using precise electric fields generated by alternating currents. These devices have been validated for the treatment of experimental type 1 diabetes. (ii) An electrical interface that is extremely power efficient and fine-tunes therapeutic transgene expression using direct current, in the power range to remotely control cellular behavior using commercially available batteries. This electrogenetic device utilizes the production of DC-induced reactive oxygen species, which are taken up by hypersensitized target cells to regulate the expression of specific target genes. DC-inducible electrogenetic interfaces enable extremely rapid expression control and compete favorably with other devices for the treatment of experimental type 1 diabetes. (iii) ElectroGene has also defined and implemented other strategies to control therapeutic transgene expression using electrical energy, including (a) temperature-inducible gene switches, in which electrothermal skin patches were able to fine-tune therapeutic transgene expression in subcutaneous implants, (b) electromagnetic gene switches, which consist of electromagnetic waves activating intracellular cells, (b) electromagnetic gene switches that consist of electromagnetic waves that activate intracellular nanocomposites to produce reactive oxygen species that in turn regulate the expression of therapeutic target genes, and (c) sonogenetic devices that use electrical energy to produce longitudinal air pressure waves, known as sound, that could be captured by mechanosensitive channels in designer cells to control therapeutic transgene expression when subcutaneously implanted designer cells are exposed to music. (iii) electrical power generators that provide portable electrical power to operate electrogenetic devices and bioelectronic implants, even obsolete and power-hungry optogenetic systems. ElectroGene's breakthrough power generators include (a) piezoelectric devices that provide in-situ power generation and control of the aforementioned electrogenetic interfaces, (b) solar cells that use sunlight-driven modulation of cellular ion gradients to produce biobatteries that produce enough power to light LEDs, (c) thermoelectric skin patches that convert body heat into electrical power, and (d) respiratory power generators that use composite nanomaterials laminated into face masks to convert moisture into electricity, providing power at night and in the Arctic when solar power is unavailable and batteries fail. The culmination of ElectroGene was the design of a bidirectional metabotronic interface for closed-loop cybernetic metabolic control. ElectroGene has ultimately led to the design of engineered human cells with genetic circuits that sense and report their metabolic state to electrical circuits that integrate, process, and coordinate feedback-controlled electrical fields to stimulate dosed systemic release of biopharmaceuticals from a subcutaneously implanted, wirelessly powered, and communicating bioelectronic device. Closed-loop cybernetic control of metabolism would enable electronic devices to interrogate cellular metabolic states and empower cells to report their metabolic activities to electronic devices, thereby providing autonomous homeostasis control and coordinated interventions that merge diagnosis, treatment, and prevention with the prospect of curing metabolic disorders.
