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Circadian clocks integrate external environmental and internal physiological cues to generate oscillations of secreted endocrine signals. Here the authors build a melatonin-based circadian biomarker-driven gene switch in mammalian cells for type-2 diabetes treatment by oscillatory GLP-1 release.

Toggle switches can be engineered using pairs of transcriptional repressors; however, their bistability depends on nonlinear DNA-binding properties. Lebar et al. design a circuit that ensures bistability by artificially generating nonlinearity and use it to construct a toggle from programmable DNA-binding domains.

In synthetic biology, the use of regulatory proteins that bind either DNA or RNA to reprogram mammalian cellular functions allows a variety of computational ‘logic circuits’ to be built in a plug-and-play manner, which may pave the way for precise and robust control of future gene-based and cell-based therapies.

Current synthetic gene switches face limitations including cytotoxicity and long-term side-effects. Here, authors present an aspirin-activated system, demonstrating the regulation of insulin expression in diabetic mice, restoring glucose levels, alleviating pain, and reducing biomarkers of inflammation.

SARS-CoV-2 proteases are key targets for anti-viral drug development. Here the authors present modular tunable autoproteolytic gene switches for virus free cell culture screening of inhibitors.

A synthetic biology approach involving engineered mammalian cell consortia converts analog sensing of fragrance molecules into control of reporter-gene expression and amplifies the signal, thus enabling the digitization of molecular signals for cybernetic devices.

Wireless magnetic control of gene expression in mammalian cells has been developed based on intracellular nanointerface and ROS-mediated signalling. The approach allows remotely tunable insulin release and regulates blood glucose in diabetic mice.

Clinically licensed nitroglycerin patches allowed for the on-demand and sustained expression of glucagon-like peptide-1 by human cells engineered with a nitroglycerin-responsive gene switch subcutaneously implanted in mice with type 2 diabetes.

Ultrasensitive, real-time profiling of bio-analytes is a prerequisite for precision medicine. Here, the authors present a versatile bio-electronic interface (VIBE) to sense signaling cascade-guided receptor-ligand interactions and show that it can detect hormone levels in blood samples and differentiate individual metabolic conditions.

The authors show modular functionality of TetR-like proteins in mammalian cells, separating the protein–DNA and the protein–protein interaction. This allows for engineered ON- and OFF-type responses to stimuli, higher order and multi-input logics.

Phosphoregulation is a key mechanism of signal processing. Here the authors build a phosphoregulated relay system in mammalian cells for orthogonal signal transduction.

Artificial receptors targeted to the secretory pathway often fail to exhibit the expected activity due to post-translational modifications and/or improper folding. Here, the authors engineer diverse synthetic receptors that reside in the cytoplasm, inside the endoplasmic reticulum, or on the plasma membrane through orientation adjustment of the receptor parts and by elimination of dysfunctional PTMs sites.

Merging the generalized extracellular molecule sensor (GEMS) system with screening designed ankyrin repeat proteins (DARPins) identifies an advanced modular bispecific extracellular receptor (AMBER) for detection of fibrinogen degradation products.

Wearable smart devices often have green light diodes to monitor health. Here the authors use this to control a light-activated genetic switch for GLP1 production in diabetic mice.

Engineered erythropoietin receptor scaffolds equipped with extracellular sensor domains and modular intracellular domains that couple to endogenous signaling pathways enable modular reprogramming of designer membrane-bound receptors.

One method of controlling protein degradation is through the use of degrons. Here the authors present a toolbox of characterised degrons as a library to fine-tune biological gene-expression systems. Its application is demonstrated by a set of tunable synthetic pulse generators in mammalian cells.

Current cellular rewiring designs are typically tailored to detect single inputs. Here the authors present GEARs that function independently of engineered receptor/reporter systems and directly reroute endogenous signaling pathways to alternative genomic loci using dCas9-directed gene expression.

Huang et al. develop an interface to allow electrode-mediated stimulation of gene expression in human cells, utilizing direct current-generated reactive oxygen species to stimulate transgene expression downstream of the KEAP1–NRF2 biosensor. In a type 1 diabetic mouse model, this interface is demonstrated to ameliorate hyperglycemia by stimulating insulin expression.

The development of RNA-based devices called toehold switches that regulate translation might usher in an era in which protein production can be linked to almost any RNA input and provide precise, low-cost diagnostics.

By synchronizing clocks, humans make more efficient use of their time and orchestrate their activities in different places. Bacteria have now been engineered that similarly coordinate their molecular timepieces.

Artificial enzymes can be used to elicit reactions in cells. Here, the authors developed such an artificial catalyst combined with a genetic switch, and showed that it was readily taken up by human cells and able to kick off a reaction cascade resulting in the biosynthesis of the desired product.

Designer ribozymes show protein-responsive translational control and can be combined with transcriptional control elements to program complex gene circuits.

Designer gene circuits allow the controlled expression of proteins in response to specific stimuli. Here, Rössger et al.use synthetic biology approaches to create a fatty-acid biosensor that controls the production of a satiety hormone and use it to control diet-induced obesity in mice.

A self-adjusting synthetic gene circuit in implanted mammalian cells senses insulin concentration and reverses the insulin-resistance syndrome in three mouse models by coordinating the expression of the insulin-sensitizing compound adiponectin.

The advancement of sensitive, accurate and non-invasive methods to identify the allergen that drives allergic disease in an individual remains a challenge. Here, the authors develop a synthetic biology approach using human designer cells to profile allergic reactions against an array of allergens measuring histamine release from whole blood.

Synthetic biological devices can be engineered to achieve high levels of precision and specificity, which makes them ideally suited for use in clinical settings. Devices are being developed to meet a range of biomedical needs, including specific cancer therapies and metabolic control.

Control of transgene expression should ideally be easy and with minimal side effects. Here the authors present a synthetic biology-based approach in which the caffeine in coffee regulates a genetic circuit controlling glucagon-like peptide 1 expression in diabetic mice.

Stimuli-responsive hydrogels show potential as smart materials for drug delivery, however, the triggers used must be applicable in vivo. Now, a hydrogel has been synthesized that contains protein–protein interactions that respond to a specific pharmaceutical drug and enable the hydrogel to controllably release its load of a human growth factor, which increases cell proliferation.

Engineering of nonimmune cells with a cell-contact sensor and antigen recognition domains enables cell-contact-dependent sensor cell signaling and effector molecule production directed to attack target cells, providing an alternative strategy to chimeric antigen receptor T-cell (CAR-T) technology.

Brain–machine interfaces offer the possibility of controlling prosthetic devices using changes in brain activity. Folcher et al.couple such a system wirelessly to an optogenetic implant in mice to control expression of a transgene, demonstrating its potential for mind-controlled drug delivery.

Synthetic biology offers the potential for the design and implementation of rationally designed, complex genetic programmes. Here the authors design a genetic network to trigger the differentiation of patient derived IPSCs into beta-like cells.

Exosomes function as intercellular information transmitters and are candidates for delivery of therapeutic agents. Here the authors present EXOtic, a synthetic biology device for in-situ production of designer exosomes and demonstrate in vivo application in models of Parkinson's disease.

Bacterial populations communicate with AI-2 signaling molecules, helping to coordinate biofilm development and other group behaviors. Here the authors design a genetic circuit for mammalian cells that allows them to sense bacterial populations and interfere with quorum communication.

Supramolecular nanocatalysts, composed of peptides, chemicals and/or biogenic inorganics, mimic enzymes and offer affordable, precise medicines of the future. This Review explores their role in programming mammalian metabolism and their potential for therapeutic applications.

Cells engineered to produce an analgesic in response to spearmint aroma and implanted in mouse models of chronic pain reduce the pain-associated behaviour after oral intake of spearmint essential oil with no adverse effects.

The standard treatment for an allergic response is anti-histamines, steroids and anti-IgE antibodies. Here the authors present a genetic circuit that senses IL-4 and IL-13 and responses with DARPin production to bind IgE.

Beginning with a functional site and building a supporting scaffold around it enables the de novo design of proteins with distinct binding motifs for use in biosensors to detect antibody responses and as ligands of synthetic signaling receptors.

Genetically modified bacteria provide a long-lasting record of intestinal inflammation in mice.

Biotechnology is a central focus in efforts to provide sustainable solutions for the provision of fuels, chemicals and materials. On the basis of a recent open discussion, we summarize the development of this field, highlighting the distinct but complementary approaches provided by metabolic engineering and synthetic biology for the creation of efficient cell factories to convert biomass and other feedstocks to desired chemicals.

Synthetic gene circuits can endow cells with therapeutic functions. This Review discusses synthetic macromolecular systems, encompassing transcriptional, translational and post-translational mechanisms, that conditionally regulate protein expression and activity in response to specific internal or external stimuli, and their role in enhancing the therapeutic efficacy and safety of engineered cell therapies.

Engineering of a menthol-controlled gene switch whose components are all of human origin may facilitate clinical translation of this approach, in which therapeutic protein production is triggered by topical application of menthol to the skin.

Bacchus et al. describe the first experiments in mammalian cells that distribute complex behavior across several types of engineered cells, thereby mimicking natural multicellular systems.