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The state of the art in biomimetics

The state of the art in biomimetics | SynBioFromLeukipposInstitute | Scoop.it
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by
Lepora NF, Verschure P, Prescott TJ.

"Biomimetics is a research field that is achieving particular prominence through an explosion of new discoveries in biology and engineering. The field concerns novel technologies developed through the transfer of function from biological systems. To analyze the impact of this field within engineering and related sciences, we compiled an extensive database of publications for study with network-based information analysis techniques. Criteria included publications by year and journal or conference, and subject areas judged by popular and common terms in titles. Our results reveal that this research area has expanded rapidly from less than 100 papers per year in the 1990s to several thousand papers per year in the first decade of this century. Moreover, this research is having impact across a variety of research themes, spanning robotics, computer science and bioengineering. In consequence, biomimetics is becoming a leading paradigm for the development of new technologies that will potentially lead to significant scientific, societal and economic impact in the near future."



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Optogenetics in cancer drug discovery: Expert Opinion on Drug Discovery

Introduction: The discovery and domestication of biomolecules that respond to light has taken a light of its own, providing new molecular tools with incredible spatio-temporal resolution to manipulate cellular behavior.

Areas covered: The authors herein analyze the current optogenetic tools in light of their current, and potential, uses in cancer drug discovery, biosafety and cancer biology.

Expert opinion: The pipeline from drug discovery to the clinic is plagued with drawbacks, where most drugs fail in either efficacy or safety. These issues require the redesign of the pipeline and the development of more controllable/personalized therapies. Light is, aside from inexpensive, almost harmless if used appropriately, can be directed to single cells or organs with controllable penetration, and comes in a variety of wavelengths. Light-responsive systems can activate, inhibit or compensate cell signaling pathways or specific cellular events, allowing the specific control of the genome and epigenome, and modulate cell fate and transformation. These synthetic molecular tools have the potential to revolutionize drug discovery and cancer research.
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Unexpected evolutionary benefit to phages imparted by bacterial CRISPR-Cas9

Bacteria and bacteriophages arm themselves with various defensive and counterdefensive mechanisms to protect their own genome and degrade the other’s. CRISPR (clustered regularly interspaced short palindromic repeat)–Cas (CRISPR-associated) is an adaptive bacterial defense mechanism that recognizes short stretches of invading phage genome and destroys it by nuclease attack. Unexpectedly, we discovered that the CRISPR-Cas system might also accelerate phage evolution. When Escherichia coli bacteria containing CRISPR-Cas9 were infected with phage T4, its cytosine hydroxymethylated and glucosylated genome was cleaved poorly by Cas9 nuclease, but the continuing CRISPR-Cas9 pressure led to rapid evolution of mutants that accumulated even by the time a single plaque was formed. The mutation frequencies are, remarkably, approximately six orders of magnitude higher than the spontaneous mutation frequency in the absence of CRISPR pressure. Our findings lead to the hypothesis that the CRISPR-Cas might be a double-edged sword, providing survival advantages to both bacteria and phages, leading to their coevolution and abundance on Earth.
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Synthetic biology: Reframing cell therapy for cancer

Synthetic biology: Reframing cell therapy for cancer
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Engineered Living Materials: Prospects and Challenges for Using Biological Systems to Direct the Assembly of Smart Materials

Engineered Living Materials: Prospects and Challenges for Using Biological Systems to Direct the Assembly of Smart Materials | SynBioFromLeukipposInstitute | Scoop.it
Vast potential exists for the development of novel, engineered platforms that manipulate biology for the production of programmed advanced materials. Such systems would possess the autonomous, adaptive, and self-healing characteristics of living organisms, but would be engineered with the goal of assembling bulk materials with designer physicochemical or mechanical properties, across multiple length scales. Early efforts toward such engineered living materials (ELMs) are reviewed here, with an emphasis on engineered bacterial systems, living composite materials which integrate inorganic components, successful examples of large-scale implementation, and production methods. In addition, a conceptual exploration of the fundamental criteria of ELM technology and its future challenges is presented. Cradled within the rich intersection of synthetic biology and self-assembling materials, the development of ELM technologies allows the power of biology to be leveraged to grow complex structures and objects using a palette of bio-nanomaterials.
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Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing

Genome editing with CRISPR/Cas9 is a promising new approach for correcting or mitigating disease-causing mutations. Duchenne muscular dystrophy (DMD) is associated with lethal degeneration of cardiac and skeletal muscle caused by more than 3000 different mutations in the X-linked dystrophin gene (DMD). Most of these mutations are clustered in “hotspots.” There is a fortuitous correspondence between the eukaryotic splice acceptor and splice donor sequences and the protospacer adjacent motif sequences that govern prokaryotic CRISPR/Cas9 target gene recognition and cleavage. Taking advantage of this correspondence, we screened for optimal guide RNAs capable of introducing insertion/deletion (indel) mutations by nonhomologous end joining that abolish conserved RNA splice sites in 12 exons that potentially allow skipping of the most common mutant or out-of-frame DMD exons within or nearby mutational hotspots. We refer to the correction of DMD mutations by exon skipping as myoediting. In proof-of-concept studies, we performed myoediting in representative induced pluripotent stem cells from multiple patients with large deletions, point mutations, or duplications within the DMD gene and efficiently restored dystrophin protein expression in derivative cardiomyocytes. In three-dimensional engineered heart muscle (EHM), myoediting of DMD mutations restored dystrophin expression and the corresponding mechanical force of contraction. Correcting only a subset of cardiomyocytes (30 to 50%) was sufficient to rescue the mutant EHM phenotype to near-normal control levels. We conclude that abolishing conserved RNA splicing acceptor/donor sites and directing the splicing machinery to skip mutant or out-of-frame exons through myoediting allow correction of the cardiac abnormalities associated with DMD by eliminating the underlying genetic basis of the disease.
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Selenzyme: Enzyme selection tool for pathway design

Synthetic biology applies the principles of engineering to biology in order to create biological functionalities not seen before in nature. One of the most exciting applications of synthetic biology is the design of new organisms with the ability to produce valuable chemicals including pharmaceuticals and biomaterials in a greener; sustainable fashion. Selecting the right enzymes to catalyze each reaction step in order to produce a desired target compound is, however, not trivial. Here, we present Selenzyme, a free online enzyme selection tool for metabolic pathway design. The user is guided through several decision steps in order to shortlist the best candidates for a given pathway step. The tool graphically presents key information about enzymes based on existing databases and tools such as: similarity of sequences and of catalyzed reactions; phylogenetic distance between source organism and intended host species; multiple alignment highlighting conserved regions, predicted catalytic site, and active regions; and relevant properties such as predicted solubility and transmembrane regions. Selenzyme provides bespoke sequence selection for automated workflows in biofoundries.
AVAILABILITY AND IMPLEMENTATION:
The tool is integrated as part of the pathway design stage into the design-build-test-learn SYNBIOCHEM pipeline. The Selenzyme web server is available at http://selenzyme.synbiochem.co.uk.
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Computation by natural systems | Royal Society

Computation by natural systems | Royal Society | SynBioFromLeukipposInstitute | Scoop.it
Computation by natural systems Theo Murphy Meeting The Royal Society
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Unnatural Base Pairs for Synthetic Biology

In this review, we have summarized the research effort into the development of unnatural base pairs beyond standard Watson-Crick (WC) base pairs for synthetic biology. Prior to introducing our research results, we present investigations by four outstanding groups in the field. Their research results demonstrate the importance of shape complementarity and stacking ability as well as hydrogen-bonding (H-bonding) patterns for unnatural base pairs. On the basis of this research background, we developed unnatural base pairs consisting of imidazo[5',4':4.5]pyrido[2,3-d]pyrimidines and 1,8-naphthyridines, i.e., Im : Na pairs. Since Im bases are recognized as ring-expanded purines and Na bases are recognized as ring-expanded pyrimidines, Im : Na pairs are expected to satisfy the criteria of shape complementarity and enhanced stacking ability. In addition, these pairs have four non-canonical H-bonds. Because of these preferable properties, ImNN : NaOO, one of the Im : Na pairs, is recognized as a complementary base pair in not only single nucleotide insertion, but also the PCR.
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Dynamic metabolic control: towards precision engineering of metabolism

Advances in metabolic engineering have led to the synthesis of a wide variety of valuable chemicals in microorganisms. The key to commercializing these processes is the improvement of titer, productivity, yield, and robustness. Traditional approaches to enhancing production use the "push-pull-block" strategy that modulates enzyme expression under static control. However, strains are often optimized for specific laboratory set-up and are sensitive to environmental fluctuations. Exposure to sub-optimal growth conditions during large-scale fermentation often reduces their production capacity. Moreover, static control of engineered pathways may imbalance cofactors or cause the accumulation of toxic intermediates, which imposes burden on the host and results in decreased production. To overcome these problems, the last decade has witnessed the emergence of a new technology that uses synthetic regulation to control heterologous pathways dynamically, in ways akin to regulatory networks found in nature. Here, we review natural metabolic control strategies and recent developments in how they inspire the engineering of dynamically regulated pathways. We further discuss the challenges of designing and engineering dynamic control and highlight how model-based design can provide a powerful formalism to engineer dynamic control circuits, which together with the tools of synthetic biology, can work to enhance microbial production.
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The extent of ribosome queuing in budding yeast

Ribosome queuing is a fundamental phenomenon suggested to be related to topics such as genome evolution, synthetic biology, gene expression regulation, intracellular biophysics, and more. However, this phenomenon hasn't been quantified yet at a genomic level. Nevertheless, methodologies for studying translation (e.g. ribosome footprints) are usually calibrated to capture only single ribosome protected footprints (mRPFs) and thus limited in their ability to detect ribosome queuing. On the other hand, most of the models in the field assume and analyze a certain level of queuing. Here we present an experimental-computational approach for studying ribosome queuing based on sequencing of RNA footprints extracted from pairs of ribosomes (dRPFs) using a modified ribosome profiling protocol. We combine our approach with traditional ribosome profiling to generate a detailed profile of ribosome traffic. The data are analyzed using computational models of translation dynamics. The approach was implemented on the Saccharomyces cerevisiae transcriptome. Our data shows that ribosome queuing is more frequent than previously thought: the measured ratio of ribosomes within dRPFs to mRPFs is 0.2-0.35, suggesting that at least one to five translating ribosomes is in a traffic jam; these queued ribosomes cannot be captured by traditional methods. We found that specific regions are enriched with queued ribosomes, such as the 5'-end of ORFs, and regions upstream to mRPF peaks, among others. While queuing is related to higher density of ribosomes on the transcript (characteristic of highly translated genes), we report cases where traffic jams are relatively more severe in lowly expressed genes and possibly even selected for. In addition, our analysis demonstrates that higher adaptation of the coding region to the intracellular tRNA levels and longer genes are associated with lower queuing levels. Our analysis also suggests that the Saccharomyces cerevisiae transcriptome undergoes selection for eliminating traffic jams. Thus, our proposed approach is an essential tool for high resolution analysis of ribosome traffic during mRNA translation and understanding its evolution.
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Engineered bacteria to detect gut inflammation

Engineered bacteria to detect gut inflammation | SynBioFromLeukipposInstitute | Scoop.it
I wrote about engineered probiotics at the beginning of 2017, and the field continued throughout 2017 with more papers and startup news using engineered
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Scientists are closer to making artificial brains that operate like ours do

Scientists are closer to making artificial brains that operate like ours do | SynBioFromLeukipposInstitute | Scoop.it
A new electronic synapse may improve the ability of artificial brains to respond to external inputs and make decisions much like humans do.
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CRISPR-Based Chromatin Remodeling of the Endogenous Oct4 or Sox2 Locus Enables Reprogramming to Pluripotency

Generation of induced pluripotent stem cells typically requires the ectopic expression of transcription factors to reactivate the pluripotency network. However, it remains largely unclear what remodeling events on endogenous chromatin trigger reprogramming toward induced pluripotent stem cells (iPSCs). Toward this end, we employed CRISPR activation to precisely target and remodel endogenous gene loci of Oct4 and Sox2. Interestingly, we found that single-locus targeting of Sox2 was sufficient to remodel and activate Sox2, which was followed by the induction of other pluripotent genes and establishment of the pluripotency network. Simultaneous remodeling of the Oct4 promoter and enhancer also triggered reprogramming. Authentic pluripotent cell lines were established in both cases. Finally, we showed that targeted manipulation of histone acetylation at the Oct4 gene locus could also initiate reprogramming. Our study generated authentic iPSCs with CRISPR activation through precise epigenetic remodeling of endogenous loci and shed light on how targeted chromatin remodeling triggers pluripotency induction.
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Multiplexed and portable nucleic acid detection platform with Cas13, Cas12a, and Csm6

Multiplexed and portable nucleic acid detection platform with Cas13, Cas12a, and Csm6 | SynBioFromLeukipposInstitute | Scoop.it
Rapid detection of nucleic acids is integral for clinical diagnostics and biotechnological applications. We recently developed a platform termed SHERLOCK (Specific High Sensitivity Enzymatic Reporter UnLOCKing) that combines isothermal pre-amplification with Cas13 to detect single molecules of RNA or DNA. Through characterization of CRISPR enzymology and application development, we report here four advances integrated into SHERLOCKv2: 1) 4-channel single reaction multiplexing using orthogonal CRISPR enzymes; 2) quantitative measurement of input down to 2 aM; 3) 3.5-fold increase in signal sensitivity by combining Cas13 with Csm6, an auxilary CRISPR-associated enzyme; and 4) lateral flow read-out. SHERLOCKv2 can detect Dengue or Zika virus ssRNA as well as mutations in patient liquid biopsy samples via lateral flow, highlighting its potential as a multiplexable, portable, rapid, and quantitative detection platform of nucleic acids.
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Genome editor CRISPR’s latest trick? Offering a sharper snapshot of activity inside the cell

Genome editor CRISPR’s latest trick? Offering a sharper snapshot of activity inside the cell | SynBioFromLeukipposInstitute | Scoop.it
Airplane flight recorders and body cameras help investigators make sense of complicated events. Biologists studying cells have tried to build their own data recorders, for example by linking the activity of a gene of interest to one making a fluorescent protein. Their goal is to clarify processes such as the emergence of cancer, aging, environmental impacts, and embryonic development. A new cellular recorder that borrows from CRISPR, the revolutionary genome editing tool, now offers what could be a better taping device that captures data on DNA.

In Science online this week, chemist David Liu and postdoc Weixin Tang, both of Harvard University, unveil two forms of what they call a CRISPR-mediated analog multievent recording apparatus, or CAMERA. In proof-of-concept experiments, they show in both bacterial and human cells how this tool can record exposure to light, antibiotics, and viral infection or document internal molecular events. "The study highlights the really creative ways people are harnessing discoveries in CRISPR to build these synthetic pathways," says Dave Savage, a protein engineer at the University of California, Berkeley.

Other investigators have created recording devices with CRISPR components, among them Timothy Lu of the Massachusetts Institute of Technology in Cambridge. But Lu notes that his system was limited to bacteria, and compared with CAMERA it required "an order of magnitude" more cells to reliably record signals and had a much poorer signal-to-noise ratio. The new work, he says, "is really beautiful stuff" and has "a level of efficiency and precision that goes beyond what we did earlier." (Lu this week plans to release a preprint describing a system similar to one version of CAMERA.)
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Synthetic Cells Synthesize Therapeutic Proteins inside Tumors

Synthetic cells, artificial cell-like particles, capable of autonomously synthesizing RNA and proteins based on a DNA template, are emerging platforms for studying cellular functions and for revealing the origins-of-life. Here, it is shown for the first time that artificial lipid-based vesicles, containing the molecular machinery necessary for transcription and translation, can be used to synthesize anticancer proteins inside tumors. The synthetic cells are engineered as stand-alone systems, sourcing nutrients from their biological microenvironment to trigger protein synthesis. When pre-loaded with template DNA, amino acids and energy-supplying molecules, up to 2 × 107 copies of green fluorescent protein are synthesized in each synthetic cell. A variety of proteins, having molecular weights reaching 66 kDa and with diagnostic and therapeutic activities, are synthesized inside the particles. Incubating synthetic cells, encoded to secrete Pseudomonas exotoxin A (PE) with 4T1 breast cancer cells in culture, resulted in killing of most of the malignant cells. In mice bearing 4T1 tumors, histological evaluation of the tumor tissue after a local injection of PE-producing particles indicates robust apoptosis. Synthetic cells are new platforms for synthesizing therapeutic proteins on-demand in diseased tissues.
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Synthetic biology approaches for protein production optimization in bacterial cell factories

Society’s strong dependence on fossil fuels and petroleum-based products leads not only to a rapid decline of natural oil reserves but contributes massively to global warming and environmental damage. This consequently urges society to look into more sustainable alternatives. Microorganisms present such sustainable alternative if converted into so-called microbial cell factories. Instead of crude oil, cell factories use renewable resources or waste products as source material. The challenge is, however, that microbial production needs to be economically feasible to compete with the classical chemical production. The development of a microbial cell factory typically takes up to 8 years of research and costs over $50 million. The production and selection of heterologous pathway proteins are major bottlenecks encountered in the construction of a cell factory. Thus, new approaches for the optimization of recombinant protein production and screening techniques with high capacity for the identification of the best performing enzymes are continually developed. This thesis aims to equip researchers with a fundamental knowledge about protein biosynthesis necessary for the understanding of protein production bottlenecks. Moreover, the thesis guides through the possible causes of low protein yields and presents available approaches for optimization of the protein and the host. The main work presented in this thesis provides and applies a new synthetic biology approach for the optimization and selection of recombinant proteins. A major bottleneck during production is translation initiation. By creating sequence libraries of the translation initiation region, protein production can be improved substantially in Gram-negative and Gram-positive bacteria. The design of versatile and tuneable translational coupling devices and their fusion to antibiotic selection markers enables subsequent selection of high-expressing constructs. The approach is a simple and inexpensive alternative to advanced screening techniques. In addition, a second synthetic biology approach provides the means for fast and efficient plasmid backbone swapping and is a versatile tool for the design and construction of optimal protein production constructs.
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Programming gene and engineered-cell therapies with synthetic biology

Toward programmed therapeutics
Advances in synthetic biology are enabling the development of new gene and cell therapies. Kitada et al. review recent successes in areas such as cancer immunotherapy and stem cell therapy, point out the limitations of current approaches, and describe prospects for using synthetic biology to overcome these challenges. Broader adoption of these therapies requires precise, context-specific control over cellular behavior. Gene circuits can be built to give sophisticated control over cellular behaviors so that therapeutic functions can, for example, be programmed to activate in response to disease biomarkers.
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Circuit-Host Coupling Induces Multifaceted Behavioral Modulations of a Gene Switch

Quantitative modeling of gene circuits is fundamentally important to synthetic biology, as it offers the potential to transform circuit engineering from trial-and-error construction to rational design and, hence, facilitates the advance of the field. Currently, typical models regard gene circuits as isolated entities and focus only on the biochemical processes within the circuits. However, such a standard paradigm is getting challenged by increasing experimental evidence suggesting that circuits and their host are intimately connected, and their interactions can potentially impact circuit behaviors. Here we systematically examined the roles of circuit-host coupling in shaping circuit dynamics by using a self-activating gene switch as a model circuit. Through a combination of deterministic modeling, stochastic simulation, and Fokker-Planck equation formalism, we found that circuit-host coupling alters switch behaviors across multiple scales. At the single-cell level, it slows the switch dynamics in the high protein production regime and enlarges the difference between stable steady-state values. At the population level, it favors cells with low protein production through differential growth amplification. Together, the two-level coupling effects induce both quantitative and qualitative modulations of the switch, with the primary component of the effects determined by the circuit's architectural parameters. This study illustrates the complexity and importance of circuit-host coupling in modulating circuit behaviors, demonstrating the need for a new paradigm-integrated modeling of the circuit-host system-for quantitative understanding of engineered gene networks.
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A novel optogenetically tunable frequency modulating oscillator

Synthetic biology has enabled the creation of biological reconfigurable circuits, which perform multiple functions monopolizing a single biological machine; Such a system can switch between different behaviours in response to environmental cues. Previous work has demonstrated switchable dynamical behaviour employing reconfigurable logic gate genetic networks. Here we describe a computational framework for reconfigurable circuits in E.coli using combinations of logic gates, and also propose the biological implementation. The proposed system is an oscillator that can exhibit tunability of frequency and amplitude of oscillations. Further, the frequency of operation can be changed optogenetically. Insilico analysis revealed that two-component light systems, in response to light within a frequency range, can be used for modulating the frequency of the oscillator or stopping the oscillations altogether. Computational modelling reveals that mixing two colonies of E.coli oscillating at different frequencies generates spatial beat patterns. Further, we show that these oscillations more robustly respond to input perturbations compared to the base oscillator, to which the proposed oscillator is a modification. Compared to the base oscillator, the proposed system shows faster synchronization in a colony of cells for a larger region of the parameter space. Additionally, the proposed oscillator also exhibits lesser synchronization error in the transient period after input perturbations. This provides a strong basis for the construction of synthetic reconfigurable circuits in bacteria and other organisms, which can be scaled up to perform functions in the field of time dependent drug delivery with tunable dosages, and sets the stage for further development of circuits with synchronized population level behaviour.
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Ribosomal incorporation of backbone modified amino acids via an editing-deficient aminoacyl-tRNA synthetase

Ribosomal incorporation of backbone modified amino acids via an editing-deficient aminoacyl-tRNA synthetase | SynBioFromLeukipposInstitute | Scoop.it
The ability to incorporate non-canonical amino acids (ncAA) using translation offers researchers the ability to extend the functionality of proteins and peptides for many applications including synthetic biology, biophysical and structural studies, and discovery of novel ligands. Here we describe the high promiscuity of an editing-deficient valine-tRNA synthetase (ValRS T222P). Using this enzyme, we demonstrate ribosomal translation of 11 ncAAs including those with novel side chains, α,α-disubstitutions, and cyclic β-amino acids.
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In vivo biosensors: mechanisms, development, and applications

In vivo biosensors can recognize and respond to specific cellular stimuli. In recent years, biosensors have been increasingly used in metabolic engineering and synthetic biology, because they can be implemented in synthetic circuits to control the expression of reporter genes in response to specific cellular stimuli, such as a certain metabolite or a change in pH. There are many types of natural sensing devices, which can be generally divided into two main categories: protein-based and nucleic acid-based. Both can be obtained either by directly mining from natural genetic components or by engineering the existing genetic components for novel specificity or improved characteristics. A wide range of new technologies have enabled rapid engineering and discovery of new biosensors, which are paving the way for a new era of biotechnological progress. Here, we review recent advances in the design, optimization, and applications of in vivo biosensors in the field of metabolic engineering and synthetic biology.
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Yeast-based synthetic biology platform for antimicrobial peptide production

Antibiotic resistance represents one of the most challenging global health threats in our society. Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics for the treatment of drug-resistant infections. However, they are limited by their high manufacturing cost. Engineering living organisms represents a promising approach to produce such molecules in an inexpensive manner. Here, we genetically modified the yeast Pichia pastoris to produce the prototypical AMP apidaecin Ia using a fusion protein approach that leverages the beneficial properties (e.g., stability) of human serum albumin. The peptide was successfully isolated from the fusion protein construct, purified, and demonstrated to have bioactivity against Escherichia coli. To demonstrate this approach as a manufacturing solution to AMPs, we scaled-up production in bioreactors to generate high AMP yields. We envision that this system could lead to improved AMP biomanufacturing platforms.
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How a Computing System That Mimics Neural Processing Could Make A.I. More Efficient

How a Computing System That Mimics Neural Processing Could Make A.I. More Efficient | SynBioFromLeukipposInstitute | Scoop.it
After the discovery that computing chips modelled after neurons can process information faster than the human brain, there is new potential for more natural machine-learning software.
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CRISPR/Cas9-Mediated Fluorescent Tagging of Endogenous Proteins in Human Pluripotent Stem Cells

Human induced pluripotent stem cells (hiPSCs) can be used to mass produce surrogates of human tissues, enabling new advances in drug screening, disease modeling, and cell therapy. Recent developments in clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing technology use homology-directed repair (HDR) to efficiently generate custom hiPSC lines harboring a variety of genomic insertions and deletions. Thus, hiPSCs that encode an endogenous protein fused to a fluorescent reporter protein can be rapidly created by employing CRISPR/Cas9 genome editing, enhancing HDR efficiency and optimizing homology arm length. These fluorescently tagged hiPSCs can be used to visualize protein function and dynamics in real time as cells proliferate and differentiate. Given that nearly any intracellular protein can be fluorescently tagged, this system serves as a powerful tool to facilitate new discoveries across many biological disciplines. In this unit, we present protocols for the design, generation, and monoclonal expansion of genetically customized hiPSCs encoding fluorescently tagged endogenous proteins.
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