scholarly journals Synthetic biology: paving the way with novel drug delivery

2019 ◽  
Vol 41 (3) ◽  
pp. 24-27 ◽  
Author(s):  
Lucas M. Bush ◽  
Chelsea Gibbs ◽  
Tara L. Deans
Keyword(s):  
Gene Expression ◽  
Drug Delivery ◽  
Synthetic Biology ◽  
Rational Design ◽  
Control Cell ◽  
Regulation Of Gene Expression ◽  
Modern Technology ◽  
Gene Circuits ◽  
Basic Concepts ◽  
Novel Drug

Synthetic biology is a multidisciplinary field that focuses on the rational design and construction of novel genetic tools for the purpose of engineering cells to behave in controllable and predictable ways. The promise of this modern technology relies on our understanding of basic genetics and gene expression to engineer cells with unique functions. This is accomplished by designing biological parts and assembling them into higher-order gene circuits that control cell operations through tight regulation of gene expression, effectively reprogramming and rewiring the cells. In this article, we review the basic concepts of gene expression, discuss the framework of how synthetic biologists reprogram cells and outline how cells can be engineered to function as new vehicles for delivering therapeutic proteins.

Detection of Synergistic Combinatorial Perturbations by a Bifurcation-Based Approach

2021 ◽  
Vol 31 (12) ◽  
pp. 2150175
Author(s):  
Min Luo ◽  
Dasong Huang ◽  
Jianfeng Jiao ◽  
Ruiqi Wang
Keyword(s):  
Gene Expression ◽  
Rational Design ◽  
Epithelial To Mesenchymal Transition ◽  
Regulation Of Gene Expression ◽  
Drug Combinations ◽  
Bifurcation Curve ◽  
Combinatorial Regulation ◽  
Mesenchymal Transition ◽  
Combinatorial Control ◽  
Two Parameters

Drug combination has become an attractive strategy against complex diseases, despite the challenges in handling a large number of possible combinations among candidate drugs. How to detect effective drug combinations and determine the dosage of each drug in the combination is still a challenging task. When regarding a drug as a perturbation, we propose a bifurcation-based approach to detect synergistic combinatorial perturbations. In the approach, parameters of a dynamical system are divided into two groups according to their responses to perturbations. By combining two parameters chosen from two groups, three types of combinations can be obtained. Synergism for different perturbation combinations can be detected by relative positions of the bifurcation curve and the isobole. The bifurcation-based approach can be used not only to detect combinatorial perturbations but also to determine their perturbation quantities. To demonstrate the effectiveness of the approach, we apply it to the epithelial-to-mesenchymal transition (EMT) network. The approach has implications for the rational design of drug combinations and other combinatorial control, e.g. combinatorial regulation of gene expression.

scholarly journals Dual UTR-A novel 5′ untranslated region design for synthetic biology applications

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Simone Balzer Le ◽  
Ingerid Onsager ◽  
Jon Andreas Lorentzen ◽  
Rahmi Lale
Keyword(s):  
Gene Expression ◽  
Synthetic Biology ◽  
De Novo ◽  
Expression Profiles ◽  
Regulation Of Gene Expression ◽  
Design Concept ◽  
Fine Tuning ◽  
The Novel ◽  
Wide Range ◽  
Application Potential

Abstract Bacterial 5′ untranslated regions of mRNA (UTR) involve in a complex regulation of gene expression; however, the exact sequence features contributing to gene regulation are not yet fully understood. In this study, we report the design of a novel 5′ UTR, dual UTR, utilizing the transcriptional and translational characteristics of 5′ UTRs in a single expression cassette. The dual UTR consists of two 5′ UTRs, each separately leading to either increase in transcription or translation of the reporter, that are separated by a spacer region, enabling de novo translation initiation. We rationally create dual UTRs with a wide range of expression profiles and demonstrate the functionality of the novel design concept in Escherichia coli and Pseudomonas putida using different promoter systems and coding sequences. Overall, we demonstrate the application potential of dual UTR design concept in various synthetic biology applications ranging from fine-tuning of gene expression to maximization of protein production.

scholarly journals Engineered phenotype patterns in microbial populations

2019 ◽  
Author(s):  
Philip Bittihn ◽  
Andriy Didovyk ◽  
Lev S. Tsimring ◽  
Jeff Hasty
Keyword(s):  
Gene Expression ◽  
Synthetic Biology ◽  
Expression Patterns ◽  
Local Environment ◽  
Heterogeneous Environments ◽  
Gene Circuits ◽  
Sensor Module ◽  
Dividing Cells ◽  
Actuator Module ◽  
And Control

AbstractRapid advances in cellular engineering1,2have positioned synthetic biology to address therapeutic3,4and industrial5problems, but a significant obstacle is the myriad of unanticipated cellular responses in heterogeneous environments such as the gut6,7, solid tumors8,9, bioreactors10or soil11. Complex interactions between the environment and cells often arise through non-uniform nutrient availability, which can generatebidirectionalcoupling as cells both adjust to and modify their local environment through different growth phenotypes across a colony.12,13While spatial sensing14and gene expression patterns15–17have been explored under homogeneous conditions, the mutual interaction between gene circuits, growth phenotype, and the environment remains a challenge for synthetic biology. Here, we design gene circuits which sense and control spatiotemporal phenotype patterns in a model system of heterogeneous microcolonies containing both growing and dormant bacteria. We implement pattern control by coupling different downstream modules to a tunable sensor module that leveragesE. coli⁉sstress response and is activated upon growth arrest. One is an actuator module that slows growth and thereby creates an environmental negative feedback via nutrient diffusion. We build a computational model of this system to understand the interplay between gene regulation, population dynamics, and chemical transport, which predicts oscillations in both growth and gene expression. Experimentally, this circuit indeed generates robust cycling between growth and dormancy in the interior of the colony. We also use the stress sensor to drive an inducible gating module that enables selective gene expression in non-dividing cells. The ‘stress-gated lysis circuit’ derived from this module radically alters the growth pattern through elimination of the dormant phenotype upon a chemical cue. Our results establish a strategy to leverage and control the presence of distinct microbial growth phenotypes for synthetic biology applications in complex environments.

scholarly journals Advances in Non-Animal Testing Approaches towards Accelerated Clinical Translation of Novel Nanotheranostic Therapeutics for Central Nervous System Disorders

Nanomaterials ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 2632
Author(s):  
Mark J. Lynch ◽  
Oliviero L. Gobbo
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Rational Design ◽  
In Vitro Models ◽  
Clinical Translation ◽  
Clinical Testing ◽  
Cns Disorders ◽  
Novel Drug

Nanotheranostics constitute a novel drug delivery system approach to improving systemic, brain-targeted delivery of diagnostic imaging agents and pharmacological moieties in one rational carrier platform. While there have been notable successes in this field, currently, the clinical translation of such delivery systems for the treatment of neurological disorders has been limited by the inadequacy of correlating in vitro and in vivo data on blood–brain barrier (BBB) permeation and biocompatibility of nanomaterials. This review aims to identify the most contemporary non-invasive approaches for BBB crossing using nanotheranostics as a novel drug delivery strategy and current non-animal-based models for assessing the safety and efficiency of such formulations. This review will also address current and future directions of select in vitro models for reducing the cumbersome and laborious mandate for testing exclusively in animals. It is hoped these non-animal-based modelling approaches will facilitate researchers in optimising promising multifunctional nanocarriers with a view to accelerating clinical testing and authorisation applications. By rational design and appropriate selection of characterised and validated models, ranging from monolayer cell cultures to organ-on-chip microfluidics, promising nanotheranostic particles with modular and rational design can be screened in high-throughput models with robust predictive power. Thus, this article serves to highlight abbreviated research and development possibilities with clinical translational relevance for developing novel nanomaterial-based neuropharmaceuticals for therapy in CNS disorders. By generating predictive data for prospective nanomedicines using validated in vitro models for supporting clinical applications in lieu of requiring extensive use of in vivo animal models that have notable limitations, it is hoped that there will be a burgeoning in the nanotherapy of CNS disorders by virtue of accelerated lead identification through screening, optimisation through rational design for brain-targeted delivery across the BBB and clinical testing and approval using fewer animals. Additionally, by using models with tissue of human origin, reproducible therapeutically relevant nanomedicine delivery and individualised therapy can be realised.

scholarly journals Targeting riboswitches with synthetic small RNAs for metabolic engineering

2021 ◽  
Author(s):  
Milca Rachel da Costa Ribeiro Lins ◽  
Laura Araujo da Silva Amorim ◽  
Graciely Gomes Correa ◽  
Bruno Willian Picao ◽  
Matthias Mack ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rational Design ◽  
Regulation Of Gene Expression ◽  
Cellular Systems ◽  
Producer Strain ◽  
Natural Systems ◽  
Single Genome ◽  
Non Coding Rnas ◽  
And Function ◽  
Activate Gene

Our growing knowledge of the diversity of non-coding RNAs in natural systems and our deepening knowledge of RNA folding and function have fomented the rational design of RNA regulators. Based on that knowledge, we designed and implemented a small RNA (sRNA) tool to target bacterial riboswitches and activate gene expression. The synthetic sRNA is suitable for the regulation of gene expression both in cell-free and in cellular systems. It targets riboswitches to promote the antitermination folding regardless the cognate metabolite concentration. Therefore, it prevents transcription termination increasing gene expression up to 103-fold. We successfully used sRNA arrays for multiplex targeting of riboswitches. Finally, we used the synthetic sRNA to engineer an improved riboflavin producer strain. The easiness to design and construct, and the fact that the riboswitch-targeting sRNA works as a single genome copy, make it an attractive tool for engineering industrial metabolite-producing strains.

scholarly journals Regulation of Gene Expression in Diverse Cyanobacterial Species by Using Theophylline-Responsive Riboswitches

2014 ◽  
Vol 80 (21) ◽  
pp. 6704-6713 ◽  
Author(s):  
Amy T. Ma ◽  
Calvin M. Schmidt ◽  
James W. Golden
Keyword(s):  
Gene Expression ◽  
Synthetic Biology ◽  
Atmospheric Carbon Dioxide ◽  
Fluorescent Protein ◽  
Genetic Manipulation ◽  
Yellow Fluorescent Protein ◽  
Regulation Of Gene Expression ◽  
Ease Of Use ◽  
Algal Biotechnology ◽  
Content Type

ABSTRACTCyanobacteria are photosynthetic bacteria that are currently being developed as biological production platforms. They derive energy from light and carbon from atmospheric carbon dioxide, and some species can fix atmospheric nitrogen. One advantage of developing cyanobacteria for renewable production of biofuels and other biological products is that they are amenable to genetic manipulation, facilitating bioengineering and synthetic biology. To expand the currently available genetic toolkit, we have demonstrated the utility of synthetic theophylline-responsive riboswitches for effective regulation of gene expression in four diverse species of cyanobacteria, including two recent isolates. We evaluated a set of six riboswitches driving the expression of a yellow fluorescent protein reporter inSynechococcus elongatusPCC 7942,Leptolyngbyasp. strain BL0902,Anabaenasp. strain PCC 7120, andSynechocystissp. strain WHSyn. We demonstrated that riboswitches can offer regulation of gene expression superior to that of the commonly used isopropyl-β-d-thiogalactopyranoside induction of alacIq-Ptrcpromoter system. We also showed that expression of the toxic protein SacB can be effectively regulated, demonstrating utility for riboswitch regulation of proteins that are detrimental to biomass accumulation. Taken together, the results of this work demonstrate the utility and ease of use of riboswitches in the context of genetic engineering and synthetic biology in diverse cyanobacteria, which will facilitate the development of algal biotechnology.

scholarly journals Dual UTR-A novel 5′ untranslated region design for synthetic biology applications

2019 ◽  
Author(s):  
Simone Balzer Le ◽  
Ingerid Onsager ◽  
Jon Andreas Lorentzen ◽  
Rahmi Lale
Keyword(s):  
Gene Expression ◽  
Synthetic Biology ◽  
De Novo ◽  
Expression Profiles ◽  
Regulation Of Gene Expression ◽  
Design Concept ◽  
Fine Tuning ◽  
The Novel ◽  
Wide Range ◽  
Application Potential

ABSTRACTBacterial 5′ untranslated regions of mRNA (UTR) involve in a complex regulation of gene expression; however, the exact sequence features contributing to gene regulation are not yet fully understood. In this study, we report the design of a novel 5′ UTR, dual UTR, utilising the transcriptional and translational characteristics of 5′ UTRs in a single expression cassette. The dual UTR consists of two 5′ UTRs, each separately leading to either increase in transcription or translation of the reporter, that are separated by a spacer region, enabling de novo translation initiation. We rationally create dual UTRs with a wide range of expression profiles and demonstrate the functionality of the novel design concept in Escherichia coli and in Pseudomonas putida using different promoter systems and coding sequences. Overall, we demonstrate the application potential of dual UTR design concept in various synthetic biology applications ranging from fine-tuning of gene expression to maximisation of protein production.

scholarly journals Mammalian synthetic biology: emerging medical applications

2015 ◽  
Vol 12 (106) ◽  
pp. 20141000 ◽  
Author(s):  
Zoltán Kis ◽  
Hugo Sant'Ana Pereira ◽  
Takayuki Homma ◽  
Ryan M. Pedrigi ◽  
Rob Krams
Keyword(s):  
Drug Delivery ◽  
Synthetic Biology ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Logic Gates ◽  
Boolean Logic ◽  
Synthetic Gene ◽  
Medical Applications ◽  
Synthetic Gene Networks ◽  
Gene Circuits

In this review, we discuss new emerging medical applications of the rapidly evolving field of mammalian synthetic biology. We start with simple mammalian synthetic biological components and move towards more complex and therapy-oriented gene circuits. A comprehensive list of ON–OFF switches, categorized into transcriptional, post-transcriptional, translational and post-translational, is presented in the first sections. Subsequently, Boolean logic gates, synthetic mammalian oscillators and toggle switches will be described. Several synthetic gene networks are further reviewed in the medical applications section, including cancer therapy gene circuits, immuno-regulatory networks, among others. The final sections focus on the applicability of synthetic gene networks to drug discovery, drug delivery, receptor-activating gene circuits and mammalian biomanufacturing processes.

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