Engineering living therapeutics with synthetic biology

Cubillos-Ruiz, Andrés; Guo, Tingxi; Sokolovska, Anna; Miller, Paul; Collins, James J.; Lu, Timothy K.; Lora, José M.

doi:10.1038/s41573-021-00285-3

Cited by 195 publications

(124 citation statements)

References 189 publications

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“…However, full efficiency of CAR-T cells has been hampered by the chemical and physical tumor environment and the inherent inhibitory mechanisms of T cells [177,178]. Benefits of CAR-T cell therapy appear clearly; however, problems of tumor specificity, toxicity, and lack of flexibility toward improvement still remain and limit their use in patients [179].…”

Section: Chimeric Antigen Receptor (Car)-t Cellsmentioning

confidence: 99%

Emerging Therapeutic Agents for Colorectal Cancer

et al. 2021

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There are promising new therapeutic agents for CRC patients, including novel small-molecule inhibitors and immune checkpoint blockers. We focused on emerging CRC’s therapeutic agents that have shown the potential for progress in clinical practice. This review provides an overview of tyrosine kinase inhibitors targeting VEGF and KIT, BRAF and MEK inhibitors, TLR9 agonist, STAT3 inhibitors, and immune checkpoint blockers (PD1/PDL-1 inhibitors), for which recent advances have been reported. These new agents have the potential to provide benefits to CRC patients with unmet medical needs.

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Section: Chimeric Antigen Receptor (Car)-t Cellsmentioning

confidence: 99%

Emerging Therapeutic Agents for Colorectal Cancer

et al. 2021

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“…Employing live cellular actuators in synthetic polymer networks allows the cross-linking chemistry to remain independent of the input signal and logical architecture. This orthogonality vastly broadens the scope of inputs and computations that can regulate a cross-linking event, including signals such as specific DNA/RNA sequences 50,51 , clinical biomarkers 56,57 , or environmental contaminants 58 . Applying recent advancements in genetic circuit standardization, such as gate matching 37 , could further tune network performance and sensitivity to tailor the cross-linking response from signal concentration-dependent (analog) to binary (digital).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Synthetic Polymer Networks

Graham

Dundas

Partipilo

et al. 2021

Preprint

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Individual cells direct non-equilibrium processes through coordinated signal transduction and gene expression, allowing for dynamic control over multicellular, system-wide behavior. This behavior extends to remodeling the extracellular polymer matrix that encases biofilms and tissues, where constituent cells dictate spatiotemporal network properties including stiffness, pattern formation, and transport properties. The majority of synthetic polymer networks cannot recreate these phenomena due to their lack of autonomous centralized actuators (i.e., cells). In addition, non-living polymer networks that perform computation are generally restricted to a few inputs (e.g., light, pH, enzymes), limiting the logical complexity available to a single network chemistry. Toward synergizing the advantages of living and synthetic systems, engineered living materials leverage genetic and metabolic programming to establish control over material-wide properties. Here we demonstrate that a bacterial metal respiration mechanism, extracellular electron transfer (EET), can control metal-catalyzed radical cross-linking of polymer networks. Linking metabolic electron flux to a synthetic redox catalyst allows dynamic, tunable, and predictable control over material formation and bulk polymer network mechanics using genetic circuits. By programming key EET genes with transcriptional Boolean logic, we rationally design computational networks that sense-and-respond to multiple inputs in biological contexts. Finally, we capitalize on the wide reactivity of EET and redox catalyses to predictably control another class of living synthetic materials using copper(I) alkyne-azide cycloaddition click chemistry. Our results demonstrate the utility of EET as a bridge for controlling abiotic materials and how the design rules of synthetic biology can be applied to emulate physiological behavior in polymer networks.

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“…Currently, UAA-engineered virus retaining the full infectious form presents diverse antigens that, within artificial thresholds, would efficiently prime the human immune system with transient delivery of PylRS-tRNA Pyl pairs and oral UAA uptake 19 , a novel and convenient vaccine strategy for combating emerging viruses. More generally, with advances in synthetic biology in smart materials and cell therapies 44 , the development of synthetic gene circuits for sensing immune responses and outputting UAAs to control viral replication could become the basis of a potential immunization program.…”

Section: Discussionmentioning

confidence: 99%

Engineering RNA viruses with unnatural amino acid to evoke adjustable immune response in mice

Zheng

Wang

et al. 2021

Preprint

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Ribonucleic acid (RNA) viruses pose heavy burdens on public-health systems. Synthetic biology holds great potential for artificially controlling their replication, a strategy that could be used to attenuate infectious viruses but is still in the exploratory stage. Herein, we used the genetic-code expansion technique to convert Enterovirus 71 (EV71), a model of RNA virus, into a controllable EV71 strain carrying the unnatural amino acid (UAA) Nε-2-azidoethyloxycarbonyl-L-lysine (NAEK), which we termed an EV71-NAEK virus. EV71-NAEK could recapitulate an authentic NAEK time- and dose-dependent infection in vitro and in vivo, which could serve as a novel method to manipulate virulent viruses in conventional laboratories. We further validated the prophylactic effect of EV71-NAEK in two mouse models. In susceptible parent mice, vaccination with EV71-NAEK elicited a strong immune response and potentially protected their neonatal offspring from lethal challenge similar to that of commercial vaccines. Meanwhile, in transgenic mice harboring a PylRS-tRNAPyl CUA pair, substantial elements of genetic-code expansion technology, EV71-NAEK evoked an adjustable neutralizing-antibody response in a strictly external NAEK dose-dependent manner. These findings suggested that EV71-NAEK could be the basis of a feasible immunization program for populations with different levels of immunity. Moreover, we expanded the strategy to generate controllable coxsackieviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for conceptual verification. In combination, these results could underlie a competent strategy for attenuating viruses and priming the immune system via artificial control, which might be a promising direction for the development of amenable vaccine candidates and be broadly applied to other RNA viruses.

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Engineering living therapeutics with synthetic biology

Cited by 195 publications

References 189 publications

Emerging Therapeutic Agents for Colorectal Cancer

Emerging Therapeutic Agents for Colorectal Cancer

Transcriptional Regulation of Synthetic Polymer Networks

Engineering RNA viruses with unnatural amino acid to evoke adjustable immune response in mice

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