Targeting evolutionarily encoded molecular antennae to wirelessly reprogram systemic metabolism

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Project Summary / Abstract Metabolic dysfunction is a central mechanism in the etiology of numerous metabolic diseases, including type 2 diabetes (T2D). These perturbations are driven by the aberrant redirection of glucose, fatty acid and redox metabolic pathways, favoring fat accumulation and insulin resistance. The development of innovative and targeted strategies to precisely reprogram these pathways would serve as a breakthrough for the treatment of metabolic disease. A long history of work demonstrates that animals across all major phyla possess undiscovered mechanisms that enable biological systems to sense and respond to static electromagnetic fields (EMFs). In humans such mechanisms unconsciously detect changes in the orientation of static EMFs and trigger physiological changes. If these evolutionarily conserved mechanisms could be harnessed, they would lead to the development of automated, targeted and drug-free therapies, which precisely reprogram cellular processes to treat disease. However, a major obstacle is that these mechanisms remain among the least well understood in biology; we understand neither the fundamental mechanisms nor the full range of physiological effects of EMFs. The goal of this proposal is to decipher an undiscovered multicellular network of biological sensors that receive and relay EMF signals. We aim to harness these mechanisms to develop new therapeutic strategies and medical technologies that enable the wireless reprogramming of metabolism. Emerging evidence suggests that endogenous EMF-sensing mechanisms involve short-lived, tightly regulated paramagnetic radicals, such as superoxide. Intriguingly, the paramagnetic radicals which have been proposed to facilitate EMF-sensing in animals, also sense nutrient availability and are implicated in the pathophysiology of type 2 diabetes (T2D). In this proposal, we will leverage our recent serendipitous findings that exposure of diabetic animal models to static EMFs treats T2D in a superoxide-dependent mechanisms to illuminate an undiscovered network of EMF- sensitive sensors and metabolic pathways that may be targeted to wirelessly reprogram metabolism. Our central hypothesis is that weak static EMFs activate an evolutionarily conserved nutrient sensing pathway, representing a novel fundamental unit of biology that relays sub-atomic spin-state signals into systemic metabolic responses. Using state-of-the-art, multidisciplinary approaches to probe the deepest levels of systemic metabolism in healthy and diabetic states, we will decipher a novel endogenous signaling strategy that receives EMF-signals and transmits this information into precise metabolic responses. This work will establish a comprehensive metabolic map of the effects of static EMFs that has the potential to reveal new metabolic pathways, which remain undiscovered in the absence of EMF manipulations. In the process of our work, we will also determine the impact that Earth EMFs have on metabolic pathways. Ultimately, this proposal will pave the way for the development of new approaches which precisely tune metabolic programming, wirelessly.