Periodic Reporting for period 4 - ElectroGene (Electrogenetics – Shaping Electrogenetic Interfaces for Closed-Loop Voltage-Controlled Gene Expression)
Reporting period: 2023-05-01 to 2025-01-31
Physical objects with sensors and machine learning software are increasingly exchanging data via the Internet of Things (IoT) to shape our future. However, living systems, including humans, are evolving too slowly to integrate with the digital world. While smart wearables track habits and fitness, they cannot directly control genes or metabolism. Despite fundamental differences, biological and electronic systems share core principles: biological systems use ion gradients and protein-receptor interactions for analog signaling, while electronic devices rely on electron flow for digital communication. In addition, biological systems use airborne molecules for messaging, while electronics use wireless signals. While single cells process large amounts of analog data in parallel at slow speeds, CPUs process digital data sequentially at high speeds-parallelism requires multi-core architectures and hyper-threading. As the complexity of the IoT approaches that of biology, electrogenetic interfaces can enable seamless communication between genes, metabolism, and electronics, leading to new strategies for disease diagnosis, treatment, and prevention. ElectroGene aims to pioneer this interface, allowing electronic devices to communicate with genes and metabolism in real time through closed-loop systems. For example, engineered cells could report blood glucose levels to an electronic device that would process the data and trigger insulin production as needed - optimized by AI-based algorithms or physician oversight.
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.
ElectroGene pioneered and implemented direct interfaces between the electronic and genetic worlds, bringing the vision of the Internet of the Body to life and seamlessly connecting human metabolism to the Internet of Things. Through iterative design cycles, the ElectroGene team developed and validated a range of electro-genetic interfaces—transforming electrical signals into genetic control—and gene-electric interfaces—converting genetic information into electrical signals. These groundbreaking technologies were tested for their potential in treating experimental medical conditions, including Diabetes Mellitus. Eventually, two-way electrogenetic interfaces were integrated to create a revolutionary closed-loop metabolic control system. This system continuously monitored metabolic disturbances through electronics, storing, analyzing, and processing the data before electronically regulating and restoring metabolic balance. By enabling self-sufficient, closed-loop metabolic control circuits, ElectroGene not only forged an Internet of the Body but also established a direct link between human metabolism and the Internet of Things. As a result, ElectroGene introduced a transformative class of diagnostic, treatment, and preventive solutions—akin to an electronic pill—with the potential to eradicate major metabolic disorders, redefining the future of medicine.