Reward-based hypertension control by a synthetic brain–dopamine interface

Abstract

Synthetic biology has significantly advanced the design of synthetic trigger-controlled devices that can reprogram mammalian cells to interface with complex metabolic activities. In the brain, the neurotransmitter dopamine coordinates communication with target neurons via a set of dopamine receptors that control behavior associated with reward-driven learning. This dopamine transmission has recently been suggested to increase central sympathetic outflow, resulting in plasma dopamine levels that correlate with corresponding brain activities. By functionally rewiring the human dopamine receptor D1 (DRD1) via the second messenger cyclic adenosine monophosphate (cAMP) to synthetic promoters containing cAMP response element-binding protein 1 (CREB1)-specific cAMP-responsive operator modules, we have designed a synthetic dopamine-sensitive transcription controller that reversibly fine-tunes specific target gene expression at physiologically relevant brain-derived plasma dopamine levels. Following implantation of circuit-transgenic human cell lines insulated by semipermeable immunoprotective microcontainers into mice, the designer device interfaced with dopamine-specific brain activities and produced a systemic expression response when the animal's reward system was stimulated by food, sexual arousal, or addictive drugs. Reward-triggered brain activities were able to remotely program peripheral therapeutic implants to produce sufficient amounts of the atrial natriuretic peptide, which reduced the blood pressure of hypertensive mice to the normal physiologic range. Seamless control of therapeutic transgenes by subconscious behavior may provide opportunities for treatment strategies of the future.

Synthetic protein switches: design principles and applications

“…This has been realized predominantly through top-down designs; for instance, by artificially rewiring key signaling nodes of modularly organized signaling pathways. In the simplest case, ectopic overexpression of G protein-coupled receptors (GPCR) was sufficient to reprogram input control of GPCR signaling and yield various designer cell-based therapeutics [76][77][78][79]. Alternatively, key regulatory and catalytic domains in the yeast mating pathway were interchanged to improve mating efficiency [80], and artificial protein-protein interactions (PPIs) were sufficient to reprogram input and/ or output control of the MAPK pathway [81] and alter its signaling dynamics [82].…”

A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes

“…[43][44][45] This clinically validated implant technology enables the free diffusion of metabolites, nutrients, and proteins of lower molecular weight (<72 kDa) [46][47][48][49][50] across the biocompatible capsule membrane while shielding their cellular content from physical contact with the host's immune system ( Figure 5A). 51,52 Notably, SEAP levels in the bloodstream of mice were correlated with increased doses of OA administered via either the injection of PBS-buffered 3b-hydroxyolean-12-en-28-oic acid pure compounds (Figure 5B) or the oral uptake of solubilized OA tablets at clinically approved dosages ( Figure 5C).…”

Engineering Gene Circuits for Mammalian Cell–Based Applications

“…The latter harbors a synthetic promoter sequence with cognate DNA response elements (CRE, SRE, NFAT-RE) that recruit signaling pathway-specific transcription factors. Thus far, synthetic GPCRbased gene control systems have been engineered that respond to metabolites, hormones, and drug ligands, including luteinizing hormone (Kemmer et al 2011), histamine (Ausländer et al 2014b), dopamine (Rössger et al 2013a), and guanabenz (Ye et al 2013), in addition to other signals, such as pH changes (Ausländer et al 2014a), heat (Stanley et al 2012), and blue light (Ye et al 2011). The orthogonal usage of multiple GPCRs in individual cells is impeded if they use the same signaling pathway.…”