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posted to evolution synthetic_biology
by pablocarb
on 2013-05-19 18:16:57
Abstract
Evolutionary systems biology (ESB) is a rapidly growing integrative approach that has the core aim of generating mechanistic and evolutionary understanding of genotype-phenotype relationships at multiple levels. ESB's more specific objectives include extending knowledge gained from model organisms to non-model organisms, predicting the effects of mutations, and defining the core network structures and dynamics that have evolved to cause particular intracellular and intercellular responses. By ...
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Abstract
We have demonstrated the portability of theophylline-dependent synthetic riboswitches for the conditional control of gene expression in Streptomyces coelicolor. The riboswitches mediate dose-dependent, up to 260-fold activation of reporter gene expression. The riboswitch regulation offers a simple method since only a sequence of ~85 nucleotides has to be inserted between a transcriptional start site and the start codon and no further auxiliary factors are necessary. The promoters galP2, ermEp1 and SF14 worked well in concert with the riboswitches. They allowed theophylline-dependent ...
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Abstract
BACKGROUND:Realizing constructive applications of synthetic biology requires continued development of enabling technologies as well as policies and practices to ensure these technologies remain accessible for research. Broadly defined, enabling technologies for synthetic biology include any reagent or method that, alone or in combination with associated technologies, provides the means to generate any new research tool or application. Because applications of synthetic biology likely will embody multiple patented inventions, it will be important to create structures for managing intellectual property rights that ...
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Abstract
Automatic design of synthetic gene circuits poses a significant challenge to synthetic biology, primarily due to the complexity of biological systems, and the lack of rigorous optimization methods that can cope with the combinatorial explosion as the number of biological parts increases. Current optimization methods for synthetic gene design rely on heuristic algorithms that are usually not deterministic, deliver sub-optimal solutions, and provide no guaranties on convergence or error bounds. Here, we introduce an optimization framework for the problem of part ...
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Abstract
The emergence of synthetic biology is holding great hopes for providing solutions to the unmet needs of humankind. This review article describes how synthetic biology can deliver on this promise in the field of drug discovery by providing novel opportunities throughout the entire drug discovery process. Synthetic biology tools enable disease mechanisms and target identification to be elucidated and also provide avenues to discover small chemotherapeutic molecules or design novel biopharmaceuticals. Furthermore, synthetic biologists can design cost-effective microbial production processes for ...
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Abstract
Whole-cell biosensors are a good alternative to enzyme-based biosensors since they offer the benefits of low cost and improved stability. In recent years, live cells have been employed as biosensors for a wide range of targets. In this review, we will focus on the use of microorganisms that are genetically modified with the desirable outputs in order to improve the biosensor performance. Different methodologies based on genetic/protein engineering and synthetic biology to construct microorganisms with the required signal outputs, sensitivity, and ...
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posted to synthetic_biology
by Borelli
on 2013-05-11 20:22:47
Abstract
Genetic circuits that process and permanently store information are created with recombinases that flip the orientation of DNA cassettes. ...
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Abstract
The reliable forward engineering of genetic systems remains limited by the ad hoc reuse of many types of basic genetic elements. Although a few intrinsic prokaryotic transcription terminators are used routinely, termination efficiencies have not been studied systematically. Here, we developed and validated a genetic architecture that enables reliable measurement of termination efficiencies. We then assembled a collection of 61 natural and synthetic terminators that collectively encode termination efficiencies across an ∼800-fold dynamic range within Escherichia coli. We simulated co-transcriptional RNA ...
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Abstract
Synthetic biologists typically construct new pathways within existing cells. While useful, this approach in many ways ignores the undefined but necessary components of life. A growing number of laboratories have begun to try to remove some of the mysteries of cellular life by building life-like systems from non-living component parts. Some of these attempts rely on purely chemical and physical forces alone without the aid of biological molecules, while others try to build artificial cells from the parts of life, such ...
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posted to synthetic_biology tweet
by pablocarb
on 2013-05-07 19:44:42
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Abstract
Multiplex recombineering presents unique opportunities for protein engineering. Recombination enables rapid creation of comprehensive protein engineering libraries. Recombineering-based libraries enable searching of unparalleled genetic diversity. Combinatorial mutation space may be rationally searched in laboratory timescales. Protein engineering has traditionally relied on random mutagenesis strategies to generate diverse libraries, which require high-throughput screening or selection methods to identify rare variants. Alternatively, approaches to semi-rational library construction can be used to minimize the screening load and enhance the efficiency by which improved ...
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Abstract
The regulatory and metabolic networks that rule biodegradation of pollutants by environmental bacteria are wired to the rest of the cellular physiology through both transcriptional factors and intermediary signal molecules. In this review, we examine some formalisms for describing catalytic/regulatory circuits of this sort and advocate the adoption of Boolean logic for combining transcriptional and enzymatic occurrences in the same biological system. As an example, we show how known regulatory and metabolic actions that bring about biodegradation of m-xylene by Pseudomonas ...
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Abstract
The plausible release of deeply engineered or even entirely synthetic/artificial microorganisms raises the issue of their intentional (e.g. bioremediation) or accidental interaction with the Environment. Containment systems designed in the 1980s–1990s for limiting the spread of genetically engineered bacteria and their recombinant traits are still applicable to contemporary Synthetic Biology constructs. Yet, the ease of DNA synthesis and the uncertainty on how non-natural properties and strains could interplay with the existing biological word poses yet again the challenge of designing safe ...
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Abstract
Modeling tools can play an important role in synthetic biology the same way modeling helps in other engineering disciplines: simulations can quickly probe mechanisms and provide a clear picture of how different components influence the behavior of the whole. We present a brief review of available tools and present SynBioSS Designer. The Synthetic Biology Software Suite (SynBioSS) is used for the generation, storing, retrieval and quantitative simulation of synthetic biological networks. SynBioSS consists of three distinct components: the Desktop Simulator, the ...
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Abstract
A transistor is a device that amplifies and switches electronic signals. Bonnet et al. (p. 599, published online 28 March; see the Perspective by Benenson) engineered a genetic circuit to behave like a transistor in individual living cells. Instead of regulating messenger RNA levels, which has been used previously in designing such systems, the approach relied on changing the state of double-stranded DNA. Six basic logic gates were designed and constructed that were based on the activity of two serine recombinases. ...
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Abstract
Generating a defined set of genetic constructs within a large combinatorial space provides a powerful method for engineering novel biological functions. However, the process of assembling more than a few specific DNA sequences can be costly, time consuming and error prone. Even if a correct theoretical construction scheme is developed manually, it is likely to be suboptimal by any number of cost metrics. Modular, robust and formal approaches are needed for exploring these vast design spaces. By automating the design of ...
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Abstract
BACKGROUND:The engineering of many-component, synthetic biological systems is being made easier by the development of collections of reusable, standard biological parts. However, the complexity of biology makes it difficult to predict the extent to which such efforts will succeed. As a first practical example, the Registry of Standard Biological Parts started at MIT now maintains and distributes thousands of BioBrickTM standard biological parts. However, BioBrick parts are only standardized in terms of how individual parts are physically assembled into multi-component systems, ...
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Abstract
Microbial engineering often requires fine control over protein expression--for example, to connect genetic circuits or control flux through a metabolic pathway. To circumvent the need for trial and error optimization, we developed a predictive method for designing synthetic ribosome binding sites, enabling a rational control over the protein expression level. Experimental validation of >100 predictions in Escherichia coli showed that the method is accurate to ...
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Abstract
Engineering artificial gene networks from modular components is a major goal of synthetic biology. However, the construction of gene networks with predictable functions remains hampered by a lack of suitable components and the fact that assembled networks often require extensive, iterative retrofitting to work as intended. Here we present an approach that couples libraries of diversified components (synthesized with randomized nonessential sequence) with in silico modeling to guide predictable gene network construction without the need for post hoc tweaking. We demonstrate ...
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Abstract
Identifying multiple enzyme targets for metabolic engineering is very critical for redirecting cellular metabolism to achieve desirable phenotypes, e.g., overproduction of a target chemical. The challenge is to determine which enzymes and how much of these enzymes should be manipulated by adding, deleting, under-, and/or over-expressing associated genes. In this study, we report the development of a systematic multiple enzyme targeting method (SMET), to rationally design optimal strains for target chemical overproduction. The SMET method combines both elementary mode analysis and ...
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Abstract
The finite reservation of fossil fuels accelerates the necessity of development of renewable energy sources. Recent advances in synthetic biology encompassing systems biology and metabolic engineering enable us to engineer and/or create tailor made microorganisms to produce alternative biofuels for the future bio-era. For the efficient transformation of biomass to bioenergy, microbial cells need to be designed and engineered to maximize the performance of cellular metabolisms for the production of biofuels during energy flow. Toward this end, two different conceptual approaches ...
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by C. J. Paddon, P. J. Westfall, D. J. Pitera, et al.K. Benjamin, K. Fisher, D. McPhee, M. D. Leavell, A. Tai, A. Main, D. Eng, D. R. Polichuk, K. H. Teoh, D. W. Reed, T. Treynor, J. Lenihan, M. Fleck, S. Bajad, G. Dang, D. Diola, G. Dorin, K. W. Ellens, S. Fickes, J. Galazzo, S. P. Gaucher, T. Geistlinger, R. Henry, M. Hepp, T. Horning, T. Iqbal, H. Jiang, L. Kizer, B. Lieu, D. Melis, N. Moss, R. Regentin, S. Secrest, H. Tsuruta, R. Vazquez, L. F. Westblade, L. Xu, M. Yu, Y. Zhang, L. Zhao, J. Lievense, P. S. Covello, J. D. Keasling, K. K. Reiling, N. S. Renninger, J. D. Newman
Abstract
In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price ...
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Abstract
Accelerating the process of industrial bacterial host strain development, aimed at increasing productivity, generating new bio-products or utilizing alternative feedstocks, requires the integration of complementary approaches to manipulate cellular metabolism and regulatory networks. Systems metabolic engineering extends the concept of classical metabolic engineering to the systems level by incorporating the techniques used in systems biology and synthetic biology, and offers a framework for the development of the next generation of industrial strains. As one of the most useful tools of systems ...
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Abstract
Computation underlies the organization of cells into higher-order structures, for example during development or the spatial association of bacteria in a biofilm. Each cell performs a simple computational operation, but when combined with cell-cell communication, intricate patterns emerge. Here we study this process by combining a simple genetic circuit with quorum sensing to produce more complex computations in space. We construct a simple NOR logic gate in Escherichia coli by arranging two tandem promoters that function as inputs to drive the ...
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posted to synthetic_biology tweet
by pablocarb
on 2013-04-20 22:25:54
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Abstract
Intracellular organization is a key factor in cell metabolism. Cells have evolved various organizational systems to solve the challenges of toxic pathway intermediates, competing metabolic reactions, and slow turnover rates. Inspired by nature, synthetic biologists have utilized proteins, nucleic acids, and lipids to construct synthetic organizational systems that mimic natural systems. Many of these systems have been applied to metabolic pathways and shown to significantly ...
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Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences (April 2013), doi:10.1016/j.shpsc.2013.03.016
Abstract
We discuss the importance attributed to genetic causes in synthetic biology. We distinguish three concepts of genetic material differing in the emphasis on genetic control. Genetic causes are established using a difference-making approach that does not commit to a specific notion of genetic control. A strong program view of genes is used as a heuristic based on controlling causal context and seeking component modularity. Synthetic biology research is often described in terms of programming cells through the introduction of synthetic ...
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by Vivek K. Mutalik, Joao C. Guimaraes, Guillaume Cambray, et al.Colin Lam, Marc J. Christoffersen, Quynh-Anh Mai, Andrew B. Tran, Morgan Paull, Jay D. Keasling, Adam P. Arkin, Drew Endy
Abstract
An inability to reliably predict quantitative behaviors for novel combinations of genetic elements limits the rational engineering of biological systems. We developed an expression cassette architecture for genetic elements controlling transcription and translation initiation in Escherichia coli: transcription elements encode a common mRNA start, and translation elements use an overlapping genetic motif found in many natural systems. We engineered libraries of constitutive and repressor-regulated promoters ...
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ACS Synth. Biol. In ACS Synthetic Biology, Vol. 2, No. 1. (6 November 2012), pp. 47-58, doi:10.1021/sb300091d
Abstract
Continued advances in metabolic engineering are increasing the number of small molecules being targeted for microbial production. Pathway yields and productivities, however, are often suboptimal, and strain improvement remains a persistent challenge given that the majority of small molecules are difficult to screen for and their biosynthesis does not improve host fitness. In this work, we have developed a generalized approach to screen or select for improved small-molecule biosynthesis using transcription factor-based biosensors. Using a tetracycline resistance gene 3? of a ...
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Abstract
Synthetic signaling networks contain exogenous, modified, or rationally designed components involved in sending, receiving, and processing information from the environment and other cells. Advances in the input, output, and processing elements for such networks hold promise towards developing new therapies and prophylactics for disease. Therapeutic synthetic signaling systems are still in their infancy, but are progressing into mouse models of disease and even into clinical trials. As signaling technology matures, we will see an increase in implanted and ingested cellular therapies ...
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posted to synthetic_biology
by karthikraman
on 2013-04-13 07:57:44
Abstract
: The main goal of cell-free protein synthesis is to produce correctly folded and functional proteins in reasonable amounts for further downstream applications. Especially for eukaryotic proteins, functionality is often directly linked to the presence of posttranslational modifications. Thus, it is of highest interest to develop novel cell-free expression systems that enable the synthesis of posttranslationally modified proteins. Here we present recent advances for the ...
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Abstract
Microorganisms transform inexpensive carbon sources into highly functionalized compounds without toxic by-product generation or significant energy consumption. By redesigning the natural biosynthetic pathways in an industrially suited host, microbial cell factories can produce complex compounds for a variety of industries. Isoprenoids include many medically important compounds such as antioxidants and anticancer and antimalarial drugs, all of which have been produced microbially. While a biosynthetic pathway ...
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Abstract
Bioprospecting of natural sources for new medicines has a long and successful history, exemplified by the fact that over 50% of all drugs currently on the market are either derived from or inspired by natural products. However, development of new natural product-based therapeutics has been on the decline over the past 20 years, mainly owing to frequent re-discovery of already known compounds coupled with high costs for screening, characterization and development. With the onset of the genomic era allowing rapid sequencing ...
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Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences, Vol. 44, No. 2. (June 2013), pp. 150-157, doi:10.1016/j.shpsc.2013.03.010
Abstract
Synthetic biology aims at the de-novo design of generic objects like switches, oscillators, gates. Rational design methods based on computational techniques are used to improve the design of generic objects. Thus, Mathematical and computational strategies have been introduced to biology to tackle the problem of complexity. The core question is: Will synthetic biology will merge with system biology due to the use of computational techniques ? Synthetic biology and systems biology are often highlighted as antagonistic strategies for dealing with ...
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Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences (April 2013), doi:10.1016/j.shpsc.2013.03.015
Abstract
Biological engineering has to address context-sensitivity of biological entities. Thinking of ‘parts’ and their ‘properties’ does not help to tackle context issue. Potential alternative: biological entities as ‘capacities’ with condition spaces. Cummins’ account of functional analysis is used to develop a capacity-based view. This new perspective allows to explain successes in the parts-based approach. The parts-based engineering approach in synthetic biology aims to create pre-characterised biological parts that can be used for the rational design of novel functional systems. Given ...
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Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences (April 2013), doi:10.1016/j.shpsc.2013.03.017
Abstract
Computer-aided design software is an epistemological modality with its own means. Software bridges and black boxes the experimental challenges in synthetic biology. Graphical interfaces enable experimenters to visually program new organisms. Human-amendable diagrammatic surfaces cover and mirror algorithmic processes. Machine-readable subfaces foster efforts of model standardization and distribution. In silicio design plays a fundamental role in the endeavour to synthesise biological systems. In particular, computer-aided design software enables users to manage the complexity of biological entities that is connected to ...
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Abstract
Isoprenoids are the most numerous and structurally diverse family of natural products. Terpenoids, a class of isoprenoids often isolated from plants, are used as commercial flavor and fragrance compounds and antimalarial or anticancer drugs. Because plant tissue extractions typically yield low terpenoid concentrations, we sought an alternative method to produce high-value terpenoid compounds, such as the antimalarial drug artemisinin, in a microbial host. We engineered ...
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Abstract
Synthetic biology aims at producing novel biological systems to carry out some desired and well-defined functions. An ultimate dream is to design these systems at a high level of abstraction using engineering-based tools and programming languages, press a button, and have the design translated to DNA sequences that can be synthesized and put to work in living cells. We introduce such a programming language, which ...
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Abstract
Engineered biological systems have been used to manipulate information, construct materials, process chemicals, produce energy, provide food, and help maintain or enhance human health and our environment. Unfortunately, our ability to quickly and reliably engineer biological systems that behave as expected remains quite limited. Foundational technologies that make routine the engineering of biology are needed. Vibrant, open research communities and strategic leadership are necessary to ensure that the development and application of biological technologies remains overwhelmingly constructive. ...
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Abstract
A biomolecular network is called adaptive if its output returns to the original value after a transient response even under a persisting stimulus. The conditions for adaptation have been investigated thoroughly with systems theory approaches in the literature and it is easy to check whether they are satisfied in the linear approximation. In contrast, it is in general not easy to modify a non-adaptive network model such that it gains adaptive behaviour, especially for medium- and large-scale networks. The authors present ...
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Abstract
Accurate and controllable regulatory elements such as promoters and ribosome binding sites (RBSs) are indispensable tools to quantitatively regulate gene expression for rational pathway engineering. Therefore, de novo designing regulatory elements is brought back to the forefront of synthetic biology research. Here we developed a quantitative design method for regulatory elements based on strength prediction using artificial neural network (ANN). One hundred mutated Trc promoter & RBS sequences, which were finely characterized with a strength distribution from 0 to 3.559 (relative ...
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by Judith A. H. Wodke, Jacek Puchalka, Maria Lluch-Senar, et al.Josep Marcos, Eva Yus, Miguel Godinho, Ricardo Gutierrez-Gallego, Vitor A. dos Santos, Luis Serrano, Edda Klipp, Tobias Maier
Abstract
Mycoplasma pneumoniae, a threatening pathogen with a minimal genome, is a model organism for bacterial systems biology for which substantial experimental information is available. With the goal of understanding the complex interactions underlying its metabolism, we analyzed and characterized the metabolic network of M. pneumoniae in great detail, integrating data from different omics analyses under a range of conditions into a constraint-based model backbone. Iterating model predictions, hypothesis generation, experimental testing, and model refinement, we accurately curated the network and quantitatively ...
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Abstract
Biological systems are inherently variable, with their dynamics influenced by intrinsic and extrinsic sources. These systems are often only partially characterized, with large uncertainties about specific sources of extrinsic variability and biochemical properties. Moreover, it is not yet well understood how different sources of variability combine and affect biological systems in concert. To successfully design biomedical therapies or synthetic circuits with robust performance, it is crucial to account for uncertainty and effects of variability. Here we introduce an efficient modeling and ...
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Abstract
Microbial genomes encode thousands of biosynthetic gene clusters for unknown compounds. Such gene clusters can be computationally detected and prioritized effectively. Synthetic biology approaches allow comprehensive re-engineering of gene clusters. During re-engineering, native regulation can be replaced by synthetic regulation. Re-engineered gene clusters can be used for plug-and-play screening in optimized hosts. Synthetic biology is revolutionizing the way in which the biosphere is explored for natural products. Through computational genome mining, thousands of biosynthetic gene clusters are being identified in ...
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