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Genome-scale engineering for systems and synthetic biology

Genome-scale engineering for systems and synthetic biology | SynBioFromLeukipposInstitute | Scoop.it
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by
Kevin M Esvelt & Harris H Wang

"Genome-modification technologies enable the rational engineering and perturbation of biological systems. Historically, these methods have been limited to gene insertions or mutations at random or at a few pre-defined locations across the genome. The handful of methods capable of targetedgene editing suffered from low efficiencies, significant labor costs, or both. Recent advances have dramatically expanded our ability to engineer cells in a directed and combinatorial manner. Here, we review current technologies and methodologies for genome-scale engineering, discuss the prospects for extending efficient genome modification to new hosts, and explore the implications of continued advances toward the development of flexibly programmable chasses, novel biochemistries, and safer organismal and ecological engineering."

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Autodesk Gallery Exhibits | Bio Computation and Aerospace

Autodesk Gallery Exhibits | Bio Computation and Aerospace | SynBioFromLeukipposInstitute | Scoop.it
The Airbus concept plane uses synthetic biology, embodying what air transport could look like in 2050.
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Synthetic biology – Engineering cell-based biomedical devices

Synthetic biology – Engineering cell-based biomedical devices | SynBioFromLeukipposInstitute | Scoop.it
Synthetic biology applies rational bottom-up engineering principles to create cell-based biological systems with novel and enhanced functionality to address currently unmet clinical needs. In this review, we provide a brief overview of the state-of-the-art in cell-based therapeutic solutions, focusing on how these integrated biological devices can enhance and complement the natural functionality of cells in order to provide novel treatments. We also highlight some blueprints for synthetic biology-inspired approaches to developing cell-based cancer therapies, and briefly discuss their future clinical potential.
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Genetic Constructor: An online DNA design platform

Genetic Constructor is a cloud Computer Aided Design (CAD) application developed to support synthetic biologists from design intent through DNA fabrication and experiment iteration. The platform allows users to design, manage, and navigate complex DNA constructs and libraries, using a new visual language that focuses on functional parts abstracted from sequence. Features like combinatorial libraries and automated primer design allow the user to separate design from construction by focusing on functional intent, and design constraints aid iterative refinement of designs. A plugin architecture enables contributions from scientists and coders to leverage existing powerful software and connect to DNA foundries. The software is easily accessible and platform agnostic, free for academics, and available in an open-source community edition. Genetic Constructor seeks to democratize DNA design, manufacture, and access to tools and services from the synthetic biology community.
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Engineers develop a programmable 'camouflaging' material inspired by octopus skin

Engineers develop a programmable 'camouflaging' material inspired by octopus skin | SynBioFromLeukipposInstitute | Scoop.it
For the octopus and cuttlefish, instantaneously changing their skin color and pattern to disappear into the environment is just part of their camouflage prowess. These animals can also swiftly and reversibly morph their ski
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RNA targeting with CRISPR–Cas13

RNA targeting with CRISPR–Cas13 | SynBioFromLeukipposInstitute | Scoop.it
RNA has important and diverse roles in biology, but molecular tools to manipulate and measure it are limited. For example, RNA interference1, 2, 3 can efficiently knockdown RNAs, but it is prone to off-target effects4, and visualizing RNAs typically relies on the introduction of exogenous tags5. Here we demonstrate that the class 2 type VI6, 7 RNA-guided RNA-targeting CRISPR–Cas effector Cas13a8 (previously known as C2c2) can be engineered for mammalian cell RNA knockdown and binding. After initial screening of 15 orthologues, we identified Cas13a from Leptotrichia wadei (LwaCas13a) as the most effective in an interference assay in Escherichia coli. LwaCas13a can be heterologously expressed in mammalian and plant cells for targeted knockdown of either reporter or endogenous transcripts with comparable levels of knockdown as RNA interference and improved specificity. Catalytically inactive LwaCas13a maintains targeted RNA binding activity, which we leveraged for programmable tracking of transcripts in live cells. Our results establish CRISPR–Cas13a as a flexible platform for studying RNA in mammalian cells and therapeutic development.
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Meet the scientist leading the charge to bring morality to genetic engineering

Meet the scientist leading the charge to bring morality to genetic engineering | SynBioFromLeukipposInstitute | Scoop.it
To avoid missteps with a powerful genetic engineering technology that can modify species, one scientist demands total transparency.
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Microbes Might Paint Your Next Party Dress

Microbes Might Paint Your Next Party Dress | SynBioFromLeukipposInstitute | Scoop.it
The official “fashion month,” September has concluded its parade of gorgeous outfits. These contain harmful dyes, though. Can microbes make safer colors?
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Return of Analog Computing for Cell Simulation

Return of Analog Computing for Cell Simulation | SynBioFromLeukipposInstitute | Scoop.it
Return of Analog Computing for Cell Simulation http://evolving-science.com/bioengineering-computational-synthetic-biology/return-analog-computing-cell-simulation-00135
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Engineering the Genetic Code in Cells and Animals: Biological Considerations and Impacts

Expansion of the genetic code allows unnatural amino acids (Uaas) to be site-specifically incorporated into proteins in live biological systems, thus enabling novel properties selectively introduced into target proteins in vivo for basic biological studies and for engineering of novel biological functions. Orthogonal components including tRNA and aminoacyl-tRNA synthetase (aaRS) are expressed in live cells to decode a unique codon (often the amber stop codon UAG) as the desired Uaa. Initially developed in E. coli, this methodology has now been expanded in multiple eukaryotic cells and animals. In this Account, we focus on addressing various biological challenges for rewriting the genetic code, describing impacts of code expansion on cell physiology and discussing implications for fundamental studies of code evolution. Specifically, a general method using the type-3 polymerase III promoter was developed to efficiently express prokaryotic tRNAs as orthogonal tRNAs and a transfer strategy was devised to generate Uaa-specific aaRS for use in eukaryotic cells and animals. The aaRSs have been found to be highly amenable for engineering substrate specificity toward Uaas that are structurally far deviating from the native amino acid, dramatically increasing the stereochemical diversity of Uaas accessible. Preparation of the Uaa in ester or dipeptide format markedly increases the bioavailability of Uaas to cells and animals. Nonsense-mediated mRNA decay (NMD), an mRNA surveillance mechanism of eukaryotic cells, degrades mRNA containing a premature stop codon. Inhibition of NMD increases Uaa incorporation efficiency in yeast and Caenorhabditis elegans. In bacteria, release factor one (RF1) competes with the orthogonal tRNA for the amber stop codon to terminate protein translation, leading to low Uaa incorporation efficiency. Contradictory to the paradigm that RF1 is essential, it is discovered that RF1 is actually nonessential in E. coli. Knockout of RF1 dramatically increases Uaa incorporation efficiency and enables Uaa incorporation at multiple sites, making it feasible to use Uaa for directed evolution. Using these strategies, the genetic code has been effectively expanded in yeast, mammalian cells, stem cells, worms, fruit flies, zebrafish, and mice. It is also intriguing to find out that the legitimate UAG codons terminating endogenous genes are not efficiently suppressed by the orthogonal tRNA/aaRS in E. coli. Moreover, E. coli responds to amber suppression pressure promptly using transposon insertion to inactivate the introduced orthogonal aaRS. Persistent amber suppression evading transposon inactivation leads to global proteomic changes with a notable up-regulation of a previously uncharacterized protein YdiI, for which an unexpected function of expelling plasmids is discovered. Genome integration of the orthogonal tRNA/aaRS in mice results in minor changes in RNA transcripts but no significant physiological impairment. Lastly, the RF1 knockout E. coli strains afford a previously unavailable model organism for studying otherwise intractable questions on code evolution in real time in the laboratory. We expect that genetically encoding Uaas in live systems will continue to unfold new questions and directions for studying biology in vivo, investigating the code itself, and reprograming genomes for synthetic biology.
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Biosensors detect harmful bugs in the lungs of cystic fibrosis patients

Biosensors detect harmful bugs in the lungs of cystic fibrosis patients | SynBioFromLeukipposInstitute | Scoop.it
A team of Imperial researchers has developed a tool which 'lights up' when it detects the chemical signature of harmful bacteria in the lung. In a clinical first, the group from the Department of Medicine used the tools, called cell-free biosensors, to test samples of sputum (phlegm) from patients...
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Expanding and reprogramming the genetic code

Nature uses a limited, conservative set of amino acids to synthesize proteins. The ability to genetically encode an expanded set of building blocks with new chemical and physical properties is transforming the study, manipulation and evolution of proteins, and is enabling diverse applications, including approaches to probe, image and control protein function, and to precisely engineer therapeutics. Underpinning this transformation are strategies to engineer and rewire translation. Emerging strategies aim to reprogram the genetic code so that noncanonical biopolymers can be synthesized and evolved, and to test the limits of our ability to engineer the translational machinery and systematically recode genomes.
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Synthetic biology and the gut microbiome

The gut microbiome plays a crucial role in maintaining human health. Functions performed by gastrointestinal microbes range from regulating metabolism to modulating immune and nervous system development. Scientists have attempted to exploit this importance through the development of engineered probiotics that are capable of producing and delivering small molecule therapeutics within the gut. However, existing synthetic probiotics are simplistic and fail to replicate the complexity and adaptability of native homeostatic mechanisms. In this review, we discuss the ways in which the tools and approaches of synthetic biology have been applied to improve the efficacy of therapeutic probiotics, and the ways in which they might be applied in the future. Simple devices, such as a bistable switches and integrase memory arrays, have been successfully implemented in the mammalian gut, and models for targeted delivery in this environment have also been developed. In the future, it will be necessary to introduce concepts such as logic-gating and biocontainment mechanisms into synthetic probiotics, as well as to expand the collection of relevant biosensors. Ideally, this will bring us closer to a reality in which engineered therapeutic microbes will be able to accurately diagnose and effectively respond to a variety of disease states.
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Making DNA Data Storage a Reality

Making DNA Data Storage a Reality | SynBioFromLeukipposInstitute | Scoop.it
A few kilograms of DNA could theoretically store all of humanity’s data, but there are practical challenges to overcome.
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Autodesk Gallery Exhibits | Digital Tools In Life Sciences

Autodesk Gallery Exhibits | Digital Tools In Life Sciences | SynBioFromLeukipposInstitute | Scoop.it
Digital technology for manufacturing, film, and video games may provide tools to help scientists tackle some of the most pressing challenges to human health.
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Biohacking Resources for Kids

A simple set of resources to get kids or families started in the world of biohacking. Created for Luis Rey and the folks at the Colegio de San Francisco de Paula on the occasion of the Singularity Summit in Sevilla, March 2015.
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Commentary: CRISPR-Cas Encoding of a Digital Movie into the Genomes of a Population of Living Bacteria

Comment on
CRISPR-Cas encoding of a digital movie into the genomes of a population of living bacteria. [Nature. 2017]
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Stretchable surfaces with programmable 3D texture morphing for synthetic camouflaging skins

Some animals, such as cephalopods, use soft tissue to change shape reversibly for camouflage and object manipulation. Pikul et al. used fixed-length fiber mesh embedded in a silicone elastomer to transform a flat object into a 3D structure by inflating membranes (see the Perspective by Laschi). Painted models of rocks and plants were also created that could be morphed to fully blend into their surroundings.
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How switches work in bacteria

How switches work in bacteria | SynBioFromLeukipposInstitute | Scoop.it
Many bacteria have molecular control elements, via which they can switch on and off genes. These riboswitches also open up new options in the development of antibiotics or for the detection and decomposition of environmental toxins. Researchers of Karlsruhe Institute of Technology (KIT), Heidelberg University, and Freie Universität Berlin have now used light optical microscopy of single molecules to fundamentally study the way riboswitches work. This is reported in Nature Chemical Biology. (DOI: 10.1038/nchembio.2476)
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Chemical Neuroscience | The New York Academy of Sciences

Chemical Neuroscience | The New York Academy of Sciences | SynBioFromLeukipposInstitute | Scoop.it
This symposium will explore how chemical biology is being used to increase our understanding of the human brain in health and disease.
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Droplet microfluidics for synthetic biology - Lab on a Chip 

Droplet microfluidics for synthetic biology - Lab on a Chip  | SynBioFromLeukipposInstitute | Scoop.it
Synthetic biology is an interdisciplinary field that aims to engineer biological systems for useful purposes. Organism engineering often requires the optimization of individual genes and/or entire biological pathways (consisting of multiple genes). Advances in DNA sequencing and synthesis have recently begun to ena
Lab on a Chip Recent Review Articles
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Programmable assembly of pressure sensors using pattern-forming bacteria

Programmable assembly of pressure sensors using pattern-forming bacteria | SynBioFromLeukipposInstitute | Scoop.it
Biological systems can generate microstructured materials that combine organic and inorganic components and possess diverse physical and chemical properties. However, these natural processes in materials fabrication are not readily programmable. Here, we use a synthetic-biology approach to assemble patterned materials. We demonstrate programmable fabrication of three-dimensional (3D) materials by printing engineered self-patterning bacteria on permeable membranes that serve as a structural scaffold. Application of gold nanoparticles to the colonies creates hybrid organic-inorganic dome structures. The dynamics of the dome structures' response to pressure is determined by their geometry (colony size, dome height, and pattern), which is easily modified by varying the properties of the membrane (e.g., pore size and hydrophobicity). We generate resettable pressure sensors that process signals in response to varying pressure intensity and duration.
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A Cell-Free Biosensor for Detecting Quorum Sensing Molecules in P. aeruginosa-Infected Respiratory Samples

A Cell-Free Biosensor for Detecting Quorum Sensing Molecules in P. aeruginosa-Infected Respiratory Samples | SynBioFromLeukipposInstitute | Scoop.it
Synthetic biology designed cell-free biosensors are a promising new tool for the detection of clinically relevant biomarkers in infectious diseases. Here, we report that a modular DNA-encoded biosensor in cell-free protein expression systems can be used to measure a bacterial biomarker of Pseudomonas aeruginosa infection from human sputum samples. By optimizing the cell-free system and sample extraction, we demonstrate that the quorum sensing molecule 3-oxo-C12-HSL in sputum samples from cystic fibrosis lungs can be quantitatively measured at nanomolar levels using our cell-free biosensor system, and is comparable to LC–MS measurements of the same samples. This study further illustrates the potential of modular cell-free biosensors as rapid, low-cost detection assays that can inform clinical practice.
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How type II CRISPR–Cas establish immunity through Cas1–Cas2-mediated spacer integration

How type II CRISPR–Cas establish immunity through Cas1–Cas2-mediated spacer integration | SynBioFromLeukipposInstitute | Scoop.it
CRISPR (clustered regularly interspaced short palindromic repeats) and the nearby Cas (CRISPR-associated) operon establish an RNA-based adaptive immunity system in prokaryotes1, 2, 3, 4, 5. Molecular memory is created when a short foreign DNA-derived prespacer is integrated into the CRISPR array as a new spacer6, 7, 8, 9. Whereas the RNA-guided CRISPR interference mechanism varies widely among CRISPR–Cas systems, the spacer integration mechanism is essentially identical7, 8, 9. The conserved Cas1 and Cas2 proteins form an integrase complex consisting of two distal Cas1 dimers bridged by a Cas2 dimer6, 10. The prespacer is bound by Cas1–Cas2 as a dual-forked DNA, and the terminal 3′-OH of each 3′ overhang serves as an attacking nucleophile during integration11, 12, 13, 14. The prespacer is preferentially integrated into the leader-proximal region of the CRISPR array1, 7, 10, 15, guided by the leader sequence and a pair of inverted repeats inside the CRISPR repeat7, 15, 16, 17, 18, 19, 20. Spacer integration in the well-studied Escherichia coli type I–E CRISPR system also relies on the bacterial integration host factor21, 22. In type II–A CRISPR, however, Cas1–Cas2 alone integrates spacers efficiently in vitro18; other Cas proteins (such as Cas9 and Csn2) have accessory roles in the biogenesis phase of prespacers17, 23. Here we present four structural snapshots from the type II–A system24 of Enterococcus faecalis Cas1 and Cas2 during spacer integration. Enterococcus faecalis Cas1–Cas2 selectively binds to a splayed 30-base-pair prespacer bearing 4-nucleotide 3′ overhangs. Three molecular events take place upon encountering a target: first, the Cas1–Cas2–prespacer complex searches for half-sites stochastically, then it preferentially interacts with the leader-side CRISPR repeat, and finally, it catalyses a nucleophilic attack that connects one strand of the leader-proximal repeat to the prespacer 3′ overhang. Recognition of the spacer half-site requires DNA bending and leads to full integration. We derive a mechanistic framework to explain the stepwise spacer integration process and the leader-proximal preference.
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BioBuilder: Synthetic Biology In The Lab Free Download

BioBuilder: Synthetic Biology In The Lab Free Download | SynBioFromLeukipposInstitute | Scoop.it
BioBuilder: Synthetic Biology in the Lab free download by Natalie Kuldell PhD, Rachel Bernstein, Karen Ingram, Kathryn M. Hart ISBN: 9781491904299 with BooksBob. Fast and free eBooks download.
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Using synthetic biology to study gene regulatory evolution

Transcriptional enhancers specify the precise time, level, and location of gene expression. Disentangling and characterizing the components of enhancer activity in multicellular eukaryotic development has proven challenging because enhancers contain activator and repressor binding sites for multiple factors that each exert nuanced, context-dependent control of enhancer activity. Recent advances in synthetic biology provide an almost unlimited ability to create and modify regulatory elements and networks, offering unprecedented power to study gene regulation. Here we review several studies demonstrating the utility of synthetic biology for studying enhancer function during development and evolution. These studies clearly show that synthetic biology can provide a way to reverse-engineer and reengineer transcriptional regulation in animal genomes with enormous potential for understanding evolution.
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