*Increasing the success rate of lantibiotic drug discovery by Synthetic Biology*
by Montalbán-López M, Zhou L, Buivydas A, van Heel AJ, Kuipers OP. "Introduction: Lantibiotics are post-translationally modified antimicrobial peptides produced by bacteria from diverse environments that exhibit an activity against pathogenic bacteria comparable to that of medically used antibiotics. The actual need for new antimicrobials in therapeutics has placed them in the pipeline of antibiotic research, due not only to their high antimicrobial activity but also to the fact that they are directed to novel targets. Areas covered: This review covers the different approaches traditionally used in bacteriocin discovery, based on the isolation of bacteria from different habitats and determining their inhibitory spectrum against a set of relevant strains. It also elaborates on more recent approaches covering organic synthesis and semi-synthesis of lantibiotics, genomic and proteomic approaches and the application of Synthetic Biology to the field of antimicrobial drug discovery. Expert opinion: Lantibiotics show a great potential in fulfilling the requirements for new antimicrobials. Culture-dependent techniques are still applied to lantibiotic discovery producing successful results that can be furthered by employing high-throughput screening techniques and peptidogenomics. The necessity of culturing bacteria and growing them in specific conditions for lantibiotic expression, can hamper the discovery rate, especially in exotic or unculturable bacteria. Thus, a combination of genome mining procedures, to detect novel lantibiotic-related sequences, with heterologous production systems and high-throughput screening, offers a promising strategy. Furthermore, the characterization of the mechanism of action of many lantibiotics, and the development of "plug and play" peptide biosynthesis systems, offers the possibility of initiating the rational design of non-natural lantibiotics based on structure-activity relationships." http://1.usa.gov/LR4W1c
"Inspired by advances in the ability to construct programmable circuits in living organisms, in vitro circuits are emerging as a viable platform for designing, understanding, and exploiting dynamic biochemical circuitry. In vitro systems allow researchers to directly access and manipulate biomolecular parts without the unwieldy complexity and intertwined dependencies that often exist in vivo. Experimental and computational foundations in DNA, DNA/RNA, and DNA/RNA/protein based circuitry have given rise to systems with more than 100 programmed molecular constituents. Functionally, they have diverse capabilities including: complex mathematical calculations, associative memory tasks, and sensing of small molecules. Progress in this field is showing that cell-free synthetic biology is a versatile testing ground for understanding native biological circuits and engineering novel functionality."
Mary Ann Blätke, Anna Dittrich2, Christian Rohr, Monika Heiner, Fred Schaper, Wolfgang Marwan "We describe a molecule-oriented modelling approach based on a collection of Petri net models organized in the form of modules into a prototype database accessible through a web interface. The JAK/STAT signalling pathway with the extensive cross- talk of its components is selected as case study. Each Petri net module represents the reactions of an individual protein with its specific interaction partners. These Petri net modules are graphically displayed, can be executed individually, and allow the automatic composition into coherent models containing an arbitrary number of molecular species chosen ad hoc by the user. Each module contains metadata for documentation purposes and can be extended to a wiki-like minireview. The database can manage multiple versions of each module. It supports the curation, documentation, version control, and update of individual modules and the subsequent automatic composition of complex models, without requiring mathematical skills. Modules can be (semi-) automatically recombined according to user defined scenarios e.g. gene expression patterns in given cell types, under certain physiological conditions, or states of disease. Adding a localisation component to the module database would allow to simulate models with spatial resolution in the form of coloured Petri nets. As synthetic biology application we propose the fully automated generation of synthetic or synthetically rewired network models by composition of metadata-guided automatically modified modules representing altered protein binding sites. Petri nets composed from modules can be executed as ODE system, stochastic, hybrid, or merely qualitative models and exported in SMBL format." http://bit.ly/LFjfb9
Biliouris K, Babson D, Schmidt-Dannert C, Kaznessis Y. Abstract ABSTRACT: BACKGROUND: The eld of synthetic biology has greatly evolved and numerous functions can now be implemented by articially engineered cells carrying the appropriate genetic information. However, in order for the cells to robustly perform complex or multiple tasks, co-operation between them may be necessary. Therefore, various synthetic biological systems whose functionality requires cell-cell communication are being designed. These systems, microbial consortia, are composed of engineered cells and exhibit a wide range of behaviors. These include yeast cells whose growth is dependent on one another, or bacteria that kill or rescue each other, synchronize, behave as predator-prey ecosystems or invade cancer cells. RESULTS: In this paper, we study a synthetic ecosystem comprising of bacteria and yeast that communicate with and benet from each other using small diffusible molecules. We explore the behavior of this heterogeneous microbial consortium, composed of Saccharomyces cerevisiae and Escherichia coli cells, using stochastic modeling. The stochastic model captures the relevant intra-cellular and inter-cellular interactions taking place in and between the eukaryotic and prokaryotic cells. Integration of well-characterized molecular regulatory elements into these two microbes allows for communication through quorum sensing. A gene controlling growth in yeast is induced by bacteria via chemical signals and vice versa. Interesting dynamics that are common in natural ecosystems, such as obligatory and facultative mutualism, extinction, commensalism and predator-prey like dynamics are observed. We investigate and report on the conditions under which the two species can successfully communicate and rescue each other. CONCLUSIONS: This study explores the various behaviors exhibited by the cohabitation of engineered yeast and bacterial cells. The way that the model is built allows for studying the dynamics of any system consisting of two species communicating with one another via chemical signals. Therefore, key information acquired by our model may potentially drive the experimental design of various synthetic heterogeneous ecosystems." http://1.usa.gov/LCXqoG
*Fine-Tuning Tomato Agronomic Properties by Computational Genome Redesign*
by Javier Carrera, Asun Fernández del Carmen, Rafael Fernández-Muñoz, Jose Luis Rambla, Clara Pons, Alfonso Jaramillo, Santiago F. Elena, Antonio Granell "Considering cells as biofactories, we aimed to optimize its internal processes by using the same engineering principles that large industries are implementing nowadays: lean manufacturing. We have applied reverse engineering computational methods to transcriptomic, metabolomic and phenomic data obtained from a collection of tomato recombinant inbreed lines to formulate a kinetic and constraint-based model that efficiently describes the cellular metabolism from expression of a minimal core of genes. Based on predicted metabolic profiles, a close association with agronomic and organoleptic properties of the ripe fruit was revealed with high statistical confidence. Inspired in a synthetic biology approach, the model was used for exploring the landscape of all possible local transcriptional changes with the aim of engineering tomato fruits with fine-tuned biotechnological properties. The method was validated by the ability of the proposed genomes, engineered for modified desired agronomic traits, to recapitulate experimental correlations between associated metabolites." http://bit.ly/KOq2RH
"The proteins build shells of silicon, titanium dioxide. Scientists have applied genetic engineering to create proteins that can be used to create electronics. They've used the tools of molecular biology and principles of evolution to find proteins that can make new structures of silicon dioxide, commonly found in computer chips, and titanium dioxide, often used in solar cells.
Traditional genetic engineering involves sticking a foreign gene into bacteria and using the bacteria as tiny factories to make the protein encoded by that gene. This approach wouldn’t work for all silica-forming proteins found in marine sponges. The minerals produced by these proteins, which the researchers want to study, can kill the cells.
So Daniel Morse, of the University of California, Santa Barbara, and his colleagues looked to another protein making strategy: synthetic cells with a tiny plastic bead nucleus surrounded by a bubble of oil that acts as a cell membrane.
The scientists attached a piece of DNA to each of the beads, encoding a unique silica-forming protein, or silicatein. This DNA is a random combination of genes from two related silicateins, interspersed with random mutations.
Then the scientists soaked the beads in watery mixture of the bacterial proteins necessary to turn the DNA into silicateins and covered each bead with a thin layer of oil, trapping water and the enzymes inside. With the artificial cell complete, the interior enzymes made the silicateins, which stuck to antibodies covering the bead’s surface......"
"The rise of synthetic biology as a tool to experiment what and what is not feasible is linked mostly to two endeavors: The accelerated pace of both sequencing and synthesis machines. In the sequencing realm, researchers need to change their slides every fifteen days but the most astounding area, i.e. where opportunities for high dimensional data understanding reside, stems from the faster-than-Moore's law cost decrease for these machines....."
ThermoDBP potentially usefully in #syntheticbiology:
*Study: Universal gene for life missing from volcanic microbes*
by Liat Clark "A DNA-binding protein which is supposedly present in all life on Earth is absent from certain microbes found living near volcanoes, a study says. The discovery challenges our present knowledge of the fundamental basis of living organisms.
In the place of the single-stranded DNA-binding protein (SSB), the single cell organism Thermoproteales has another gene, now named ThermoDBP. The functionality of the gene is not yet clear. However, the study, published in the Proceedings of the National Academy of Sciences (PNAS) journal, suggests it could be useful in the fields of biotechnology and synthetic biology.
"All cells, whether they are microbial or human, have some things in common," says Malcolm White of the University of St Andrews' School of Biology, one of the paper's authors. "These are the fundamental components or building blocks which were present in the first cells and have been passed on over 3.5 billion years. However, we have discovered that a gene normally thought to be absolutely essential and conserved throughout every form of life, is in fact lost in one group of volcanic bugs, and replaced by a completely novel gene."...."
*Displacement of the canonical single-stranded DNA-binding protein in the Thermoproteales* by Sonia Paytubia, Stephen A. McMahona, Shirley Grahama, Huanting Liua, Catherine H. Bottinga, Kira S. Makarovab, Eugene V. Kooninb, James H. Naismitha, and Malcolm F. White "ssDNA-binding proteins (SSBs) based on the oligonucleotide-binding fold are considered ubiquitous in nature and play a central role in many DNA transactions including replication, recombination, and repair. We demonstrate that the Thermoproteales, a clade of hyperthermophilic Crenarchaea, lack a canonical SSB. Instead, they encode a distinct ssDNA-binding protein that we term “ThermoDBP,” exemplified by the protein Ttx1576 from Thermoproteus tenax. ThermoDBP binds specifically to ssDNA with low sequence specificity. The crystal structure of Ttx1576 reveals a unique fold and a mechanism for ssDNA binding, consisting of an extended cleft lined with hydrophobic phenylalanine residues and flanked by basic amino acids. Two ssDNA-binding domains are linked by a coiled-coil leucine zipper. ThermoDBP appears to have displaced the canonical SSB during the diversification of the Thermoproteales, a highly unusual example of the loss of a “ubiquitous” protein during evolution." http://bit.ly/LS43aK
"Stanford President John Hennessy and Khan Academy founder Salman Khan are coming at online education from very different angles — one is an elite institution being shaken up by experiments, the other is a widely loved upstart that’s increasingly being used in traditional schools.
In conversation with Walt Mossberg at D10, Hennessy and Khan talked about the future of the education credential; the opportunities for “flipped classroom”-style education, where class time is spent on collaboration, tutoring and projects; the move away from lectures and toward social media; and the opportunity to provide practical education for kids in a sort of “shadow school district,” as Khan called it, with classes in computer science, statistics and law.... Video..."
Brune KD, Bayer TS. "In natural environments microorganisms commonly exist as communities of multiple species that are capable of performing more varied and complicated tasks than clonal populations. Synthetic biologists have engineered clonal populations with characteristics such as differentiation, memory, and pattern formation, which are usually associated with more complex multicellular organisms. The prospect of designing microbial communities has alluring possibilities for environmental, biomedical, and energy applications, and is likely to reveal insight into how natural microbial consortia function. Cell signaling and communication pathways between different species are likely to be key processes for designing novel functions in synthetic and natural consortia. Recent efforts to engineer synthetic microbial interactions will be reviewed here, with particular emphasis given to research with significance for industrial applications in the field of biomining and bioremediation of acid mine drainage." http://1.usa.gov/LKHeUm
"The aim of this paper is to review several computational tools for application in synthetic biology. Recently developed computational tools, for instance, for gap-filling, orphan reaction searching, metabolic engineering, pathway analysing, gene engineering, metabolic reconstruction and others, were reviewed and their functionality was described. Some tools have similar functionality and some tools can be used for different tasks. Tools for comparison were chosen from the most cited scientific literature." http://bit.ly/KTbIaG
Stephen Hilgartner "Synthetic biology is typically described as an arena in which new kinds of biological entities are being created via novel ‘engineering-based’ means of tinkering with life and its component parts. This research domain is also an arena of social experimentation, in that some advocates of synthetic biology are actively promoting new property regimes aimed at establishing various forms of ‘open biology’. This article considers how these emerging visions of open biology are implicated in the construction of political subjects and the relations among them. The article contrasts two policy discourses for understanding intellectual property: the traditional innovation perspective and the less well-institutionalized but clearly emerging politics-of-technology perspective. These discourses serve as heuristic devices that offer different perspectives from which to view emerging property regimes in the synthetic biology arena. As a concrete example of an open biology regime, the article then turns to the BioBricks initiative and examines the regime being imagined and constituted in its vision of open synthetic biology. In this way, the article explores the question of whether and in what ways the open source regimes currently being proposed actually address increasingly pressing questions about how property rights in emerging technology impinge on democratic decision making." http://bit.ly/Kagq35
"One of the long-term goals in synthetic biology is the construction of large-scale gene networks to control and manipulate cells. Such networks often tweak natural regulatory mechanisms, or ‘switches’, in order to achieve the desired function. Regulatory mechanisms that involve RNA building blocks such as messenger RNA, microRNA and riboswitches have become increasingly prominent in this regard. Recent achievements include prototype mRNA sensors, logic circuits that respond to small molecule cues to affect cell fate, and cell-state classifier networks that identify physiological states using multiple microRNA inputs. This Review describes these and other results in RNA-based synthetic biology." http://bit.ly/MhMKjn
Cobb RE, Si T, Zhao H. "Synthetic biology, with its goal of designing biological entities for wide-ranging purposes, remains a field of intensive research interest. However, the vast complexity of biological systems has heretofore rendered rational design prohibitively difficult. As a result, directed evolution remains a valuable tool for synthetic biology, enabling the identification of desired functionalities from large libraries of variants. This review highlights the most recent advances in the use of directed evolution in synthetic biology, focusing on new techniques and applications at the pathway and genome scale." http://1.usa.gov/K5fexP
Lukmaan A. Bawazera, Michi Izumib, Dmitriy Kolodinc, James R. Neilsona,, Birgit Schwenzer, and Daniel E. Morse "The way nature evolves and sculpts materials using proteins inspires new approaches to materials engineering but is still not completely understood. Here, we present a cell-free synthetic biological plat- form to advance studies of biologically synthesized solid-state materials. This platform is capable of simultaneously exerting many of the hierarchical levels of control found in natural biomineraliza- tion, including genetic, chemical, spatial, structural, and morpholog- ical control, while supporting the evolutionary selection of new mineralizing proteins and the corresponding genetically encoded materials that they produce. DNA-directed protein expression and enzymatic mineralization occur on polystyrene microbeads in water- in-oil emulsions, yielding synthetic surrogates of biomineralizing cells that are then screened by flow sorting, with light-scattering signals used to sort the resulting mineralized composites differen- tially. We demonstrate the utility of this platform by evolutionarily selecting newly identified silicateins, biomineralizing enzymes pre- viously identified from the silica skeleton of a marine sponge, for enzyme variants capable of synthesizing silicon dioxide (silica) or titanium dioxide (titania) composites. Mineral composites of in- termediate strength are preferentially selected to remain intact for identification during cell sorting, and then to collapse postsorting to expose the encoding genes for enzymatic DNA amplification. Some of the newly selected silicatein variants catalyze the formation of crystalline silicates, whereas the parent silicateins lack this ability. The demonstrated bioengineered route to previously undescribed materials introduces in vitro enzyme selection as a viable strategy for mimicking genetic evolution of materials as it occurs in nature.* http://bit.ly/KLyYY9
"Large protein complexes can be designed and created using smaller protein building blocks that self-assemble. David Baker at the University of Washington, Seattle, and his team report a method for producing such proteins. The authors simulate the docking of protein building blocks in desired architectures and then design amino-acid sequences for these blocks that result in low-energy interfaces between the blocks, driving self-assembly. The researchers incorporate the genes that encode the designed blocks into the bacterium Escherichia coli, which produces the proteins that then spontaneously self-assemble into the target architectures. The team created two cage-like proteins: one consisting of 24 building blocks in a 13-nanometre-wide complex with octahedral symmetry (pictured) and another comprising 12 subunits with an 11-nanometre-wide tetrahedral symmetry."
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