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Exploring the Future of Synthetic Biology in India and its Probable Pathways from Infancy to Maturity

Exploring the Future of Synthetic Biology in India and its Probable Pathways from Infancy to Maturity | SynBioFromLeukipposInstitute | Scoop.it
Gerd Moe-Behrens's insight:

by
Deepak Singh and Pawan K Dhar

"Synthetic biology is an engineering inspired approach for ground-up construction of biological systems leading to a preferred phenotypic outcome. Given that the rules of constructing biological systems are unknown, the synthetic biology approach of constructing a genome or pathways or networks is a novel effort and merits careful assessment. Though synthetic biology has made rapid strides in the US and Europe, in India the field is at an early stage. This Delphi study explores the institutional structure and investment scenarios of the evolving Indian Synthetic Biology sector. Comparisons are drawn with the global initiatives with a hope to identify probable future pathways. Here we have attempted to make a general assessment of the field using publications, patents, venture capital sources, legal provisions and a direct community opinion. This is the first Delphi study on synthetic biology in India and attempts to present various synthetic biology sub-domains. The study has potential to help policy makers and scientists on governing, prioritising, planning and funding of the sector and choosing the relevant research themes. The key chal- lenge of governance, accountability and social inclusion vis-à-vis this sector is important in the context of emerging situation in the country. The accuracy of the predictions is dependent upon respondents understanding of synthetic biology, technological breakthroughs, observational and experimental errors both in pre and post-facto scenarios of this exercise. Though interesting observations have been made in this work, there is a need to regularly conduct such studies in India and forecast the evolution of the field in future."

 http://bit.ly/1bAjmSQ

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Phillip Trotter's curator insight, December 11, 2013 6:50 AM

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Optogenetics: A Primer for Chemists

The field of optogenetics uses genetically encoded, light-responsive proteins to control physiological processes. This technology has been hailed as the one of the ten big ideas in brain science in the past decade,[1] the breakthrough of the decade,[2] and the method of the year in 2010[3] and again in 2014[4]. The excitement evidenced by these proclamations is confirmed by a couple of impressive numbers. The term "optogenetics" was coined in 2006.[5] As of December 2017, "optogenetics" is found in the title or abstract of almost 1600 currently funded National Institutes of Health grants. In addition, nearly 600 reviews on optogenetics have appeared since 2006, which averages out to approximately one review per week! However, in spite of these impressive numbers, the potential applications and implications of optogenetics are not even close to being fully realized. This is due, in large part, to the challenges associated with the design of optogenetic analogs of endogenous proteins. This review is written from a chemist's perspective, with a focus on the molecular strategies that have been developed for the construction of optogenetic proteins.
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Self-replication of DNA by its encoded proteins in liposome-based synthetic cells

Self-replication of DNA by its encoded proteins in liposome-based synthetic cells | SynBioFromLeukipposInstitute | Scoop.it
Replicating DNA and converting genetic information to protein is a feature of cellular life. Here the authors implement a coupled DNA replication and gene expression system inside vesicles.
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Rewritable multi-event analog recording in bacterial and mammalian cells

Recording cellular events could advance our understanding of cellular history and responses to stimuli. The construction of intracellular memory devices, however, is challenging. Tang and Liu used Cas9 nucleases and base editors to record amplitude, duration, and order of stimuli as stable changes in both genomic and extrachromosomal DNA content (see the Perspective by Ho and Bennett). The recording of multiple stimuli—including exposure to antibiotics, nutrients, viruses, and light, as well as Wnt signaling—was achieved in living bacterial and human cells. Recorded memories could be erased and re-recorded over multiple cycles.
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Improved memory devices for synthetic cells

Synthetic biologists have long sought to make cells more like computers. This is not because they think cells will be more efficient than silicon—current microelectronics make excellent computers and are less messy than cell cultures—but instead because synthetic cells can interface with biology to perform biochemical tasks. Synthetic cells might one day be capable of attacking tumors or releasing site-specific drugs inside the human body. But to carry out these tasks, synthetic biologists must be able to program cells much in the same way we program computers—by providing them with decision-making capabilities based on inputs. Indeed, prototypes of many of the genetic parts necessary for turning cells into biocomputers have been constructed, including transcriptional logic gates (1), timers (2, 3), counters (4), memory devices (5, 6), tunable sensors (7, 8), and even in vitro DNA systems that can perform complex calculations (9). On page 169 of this issue, Tang and Liu (10) expand the capabilities of cellular computers by engineering a new memory device that records events directly onto DNA.
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Phosphatase activity tunes two-component system sensor detection threshold

Phosphatase activity tunes two-component system sensor detection threshold | SynBioFromLeukipposInstitute | Scoop.it
Two-component systems (TCSs) are the largest family of multi-step signal transduction pathways in biology, and a major source of sensors for biotechnology. However, the input concentrations to which biosensors respond are often mismatched with application requirements. Here, we utilize a mathematical model to show that TCS detection thresholds increase with the phosphatase activity of the sensor histidine kinase. We experimentally validate this result in engineered Bacillus subtilis nitrate and E. coli aspartate TCS sensors by tuning their detection threshold up to two orders of magnitude. We go on to apply our TCS tuning method to recently described tetrathionate and thiosulfate sensors by mutating a widely conserved residue previously shown to impact phosphatase activity. Finally, we apply TCS tuning to engineer B. subtilis to sense and report a wide range of fertilizer concentrations in soil. This work will enable the engineering of tailor-made biosensors for diverse synthetic biology applications.
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Stanford biologist Drew Endy: We need transparency when synthesizing humans

Stanford biologist Drew Endy: We need transparency when synthesizing humans | SynBioFromLeukipposInstitute | Scoop.it
Perhaps more than anyone else working in synthetic biology, Endy has tried to hold the community to account. ... suggested that scientists needed to be as transparent as possible when discussing the possibility of writing and engineering human genomes. … I spoke to Endy in his airy, high-ceilinged lab at Stanford
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Synthetic biology and microbioreactor platforms for programmable production of biologics at the point-of-care

Synthetic biology and microbioreactor platforms for programmable production of biologics at the point-of-care | SynBioFromLeukipposInstitute | Scoop.it
Current biopharmaceutical manufacturing systems are not compatible with portable or distributed production of biologics, as they typically require the development of single biologic-producing cell lines followed by their cultivation at very large scales
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MIDAS: A modular DNA assembly system for synthetic biology

A modular and hierarchical DNA assembly platform for synthetic biology based on Golden Gate (Type IIS restriction enzyme) cloning is described. This enabling technology, termed MIDAS (for Modular Idempotent DNA Assembly System), can be used to precisely assemble multiple DNA fragments in a single reaction using a standardized assembly design. It can be used to build genes from libraries of sequence-verified, reusable parts and to assemble multiple genes in a single vector, with full user control over gene order and orientation, as well as control of the direction of growth (polarity) of the multigene assembly, a feature that allows genes to be nested between other genes or genetic elements. We describe the detailed design and use of MIDAS, and its exemplification by the reconstruction, in the filamentous fungus Penicillium paxilli, of the metabolic pathway for production of paspaline and paxilline, key intermediates in the biosynthesis of a range of indole diterpenes - a class of secondary metabolites produced by several species of filamentous fungi. MIDAS was used to efficiently assemble a 25.2 kb plasmid from 21 different modules (seven genes, each composed of three basic parts). By using a parts library-based system for construction of complex assemblies, and a unique set of vectors, MIDAS can provide a flexible route to assembling tailored combinations of genes and other genetic elements, thereby supporting synthetic biology applications in a wide range of expression hosts.
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Scientists combine CRISPR, DNA barcoding to track cancer growth

Scientists combine CRISPR, DNA barcoding to track cancer growth | SynBioFromLeukipposInstitute | Scoop.it
Cancer research that once involved years of painstaking work can now happen in months with a novel technique for studying cancer-related genes. The results reveal how combinations of mutations influence tumor growth.
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A Flawed Study Shows How Little We Understand Crispr's Effects

A Flawed Study Shows How Little We Understand Crispr's Effects | SynBioFromLeukipposInstitute | Scoop.it
A FLAWED STUDY SHOWS HOW LITTLE WE UNDERSTAND CRISPR'S EFFECTS
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Cell-free optogenetic gene expression system

Optogenetic tools provide a new and efficient way to dynamically program gene expression with unmatched spatiotemporal precision. To date, its vast potential remains untapped in the field of cell-free synthetic biology, largely due to the lack of simple and efficient light-switchable systems. Here, to bridge the gap between cell-free systems and optogenetics, we studied our previously engineered one component-based blue light-inducible Escherichia coli promoter in a cell-free environment through experimental characterization and mathematical modelling. We achieved >10-fold dynamic expression and demonstrated rapid and reversible activation of target gene to generate oscillatory waveform. Deterministic model developed was able to recapitulate the system behaviour and helped to provide quantitative insights to optimize dynamic response. This in vitro optogenetic approach could be a powerful new high-throughput screening technology for rapid prototyping of complex biological networks in both space and time without the need for chemical induction.
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First characterization of a biphasic, switch-like DNA amplification

We report the first DNA amplification chemistry with switch-like characteristics: the chemistry is biphasic, with an expected initial phase followed by an unprecedented high gain burst of product oligonucleotide in a second phase. The first and second phases are separated by a temporary plateau, with the second phase producing 10 to 100 times more product than the first. The reaction is initiated when an oligonucleotide binds and opens a palindromic looped DNA template with two binding domains. Upon loop opening, the oligonucleotide trigger is rapidly amplified through cyclic extension and nicking of the bound trigger. Loop opening and DNA association drive the amplification reaction, such that reaction acceleration in the second phase is correlated with DNA association thermodynamics. Without a palindromic sequence, the chemistry resembles the exponential amplification reaction (EXPAR). EXPAR terminates at the initial plateau, revealing a previously unknown phenomenon that causes early reaction cessation in this popular oligonucleotide amplification reaction. Here we present two distinct types of this biphasic reaction chemistry and propose dominant reaction pathways for each type based on thermodynamic arguments. These reactions create an endogenous switch-like output that reacts to approximately 1 pM oligonucleotide trigger. The chemistry is isothermal and can be adapted to respond to a broad range of input target molecules such as proteins, genomic bacterial DNA, viral DNA, and microRNA. This rapid DNA amplification reaction could potentially impact a variety of disciplines such as synthetic biology, biosensors, DNA computing, and clinical diagnostics.
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Synthetic biology-based cellular biomedical tattoo for detection of hypercalcemia associated with cancer

Diagnosis marks the beginning of any successful therapy. Because many medical conditions progress asymptomatically over extended periods of time, their timely diagnosis remains difficult, and this adversely affects patient prognosis. Focusing on hypercalcemia associated with cancer, we aimed to develop a synthetic biology-inspired biomedical tattoo using engineered cells that would (i) monitor long-term blood calcium concentration, (ii) detect onset of mild hypercalcemia, and (iii) respond via subcutaneous accumulation of the black pigment melanin to form a visible tattoo. For this purpose, we designed cells containing an ectopically expressed calcium-sensing receptor rewired to a synthetic signaling cascade that activates expression of transgenic tyrosinase, which produces melanin in response to persistently increased blood Ca2+ We confirmed that the melanin-generated color change produced by this biomedical tattoo could be detected with the naked eye and optically quantified. The system was validated in wild-type mice bearing subcutaneously implanted encapsulated engineered cells. All animals inoculated with hypercalcemic breast and colon adenocarcinoma cells developed tattoos, whereas no tattoos were seen in animals inoculated with normocalcemic tumor cells. All tumor-bearing animals remained asymptomatic throughout the 38-day experimental period. Although hypercalcemia is also associated with other pathologies, our findings demonstrate that it is possible to detect hypercalcemia associated with cancer in murine models using this cell-based diagnostic strategy.
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Synthetic biology-based cellular biomedical tattoo for detection of hypercalcemia associated with cancer

Diagnosis marks the beginning of any successful therapy. Because many medical conditions progress asymptomatically over extended periods of time, their timely diagnosis remains difficult, and this adversely affects patient prognosis. Focusing on hypercalcemia associated with cancer, we aimed to develop a synthetic biology-inspired biomedical tattoo using engineered cells that would (i) monitor long-term blood calcium concentration, (ii) detect onset of mild hypercalcemia, and (iii) respond via subcutaneous accumulation of the black pigment melanin to form a visible tattoo. For this purpose, we designed cells containing an ectopically expressed calcium-sensing receptor rewired to a synthetic signaling cascade that activates expression of transgenic tyrosinase, which produces melanin in response to persistently increased blood Ca2+. We confirmed that the melanin-generated color change produced by this biomedical tattoo could be detected with the naked eye and optically quantified. The system was validated in wild-type mice bearing subcutaneously implanted encapsulated engineered cells. All animals inoculated with hypercalcemic breast and colon adenocarcinoma cells developed tattoos, whereas no tattoos were seen in animals inoculated with normocalcemic tumor cells. All tumor-bearing animals remained asymptomatic throughout the 38-day experimental period. Although hypercalcemia is also associated with other pathologies, our findings demonstrate that it is possible to detect hypercalcemia associated with cancer in murine models using this cell-based diagnostic strategy.
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Yeast 2.0-connecting the dots in the construction of the world's first functional synthetic eukaryotic genome

Historians of the future may well describe 2018 as the year that the world's first functional synthetic eukaryotic genome became a reality. Without the benefit of hindsight, it might be hard to completely grasp the long-term significance of a breakthrough moment in the history of science like this. The role of synthetic biology in the imminent birth of a budding Saccharomyces cerevisiae yeast cell carrying 16 man-made chromosomes causes the world of science to teeter on the threshold of a future-defining scientific frontier. The genome-engineering tools and technologies currently being developed to produce the ultimate yeast genome will irreversibly connect the dots between our improved understanding of the fundamentals of a complex cell containing its DNA in a specialised nucleus and the application of bioengineered eukaryotes designed for advanced biomanufacturing of beneficial products. By joining up the dots between the findings and learnings from the international Synthetic Yeast Genome project (known as the Yeast 2.0 or Sc2.0 project) and concurrent advancements in biodesign tools and smart data-intensive technologies, a future world powered by a thriving bioeconomy seems realistic. This global project demonstrates how a collaborative network of dot connectors-driven by a tinkerer's indomitable curiosity to understand how things work inside a eukaryotic cell-are using cutting-edge biodesign concepts and synthetic biology tools to advance science and to positively frame human futures (i.e. improved quality of life) in a planetary context (i.e. a sustainable environment). Explorations such as this have a rich history of resulting in unexpected discoveries and unanticipated applications for the benefit of people and planet. However, we must learn from past explorations into controversial futuristic sciences and ensure that researchers at the forefront of an emerging science such as synthetic biology remain connected to all stakeholders' concerns about the biosafety, bioethics and regulatory aspects of their pioneering work. This article presents a shared vision of constructing a synthetic eukaryotic genome in a safe model organism by using novel concepts and advanced technologies. This multidisciplinary and collaborative project is conducted under a sound governance structure that does not only respect the scientific achievements and lessons from the past, but that is also focussed on leading the present and helping to secure a brighter future for all.
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Sensor strategy a boon for synthetic biology

Sensor strategy a boon for synthetic biology | SynBioFromLeukipposInstitute | Scoop.it
The lab of synthetic biologist Jeffrey Tabor has introduced a new technique to dial up or down the sensitivity of two-component systems – a class of proteins that bacteria use to sense a wide variety of stimuli.

The technique could enable the engineering of tailor-made biosensors for diagnostic gut bacteria, detection of environmental pollutants or automated control of nutrient levels in soil.
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Leading approaches in synthetic epigenetics for novel therapeutic strategies

In recent years, our knowledge of the epigenetic functions regulated by post-translational modifications (PTMs) of histones, and their role in various diseases, has expanded rapidly, opening the way to novel therapeutic strategies that treat epigenetic abnormalities. Many of the current approaches have been focusing on the chemical inhibition of histone-modifying enzymes to modulate histone PTM states for attaining therapeutic effects. However, recent developments in chemistry and molecular biology have contributed to the emergence of new methods that introduce histone PTMs entirely through artificial means, without reliance on endogenous enzymes. In this review article, we summarize several state-of-the-art approaches for the introduction of synthetic epigenetic modifications in cells, and discuss both their therapeutic potential and the possible challenges in developing novel therapeutic strategies utilizing them.
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Wild Biomorphic Spacesuits Designed to Survive Hostile Planets

Wild Biomorphic Spacesuits Designed to Survive Hostile Planets | SynBioFromLeukipposInstitute | Scoop.it
These speculative bio-augmenting spacesuits offer a wild glimpse of a future in which the barriers between biology and technology have fallen away.
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Synthetic gene network with positive feedback loop amplifies cellulase gene expression in Neurospora crassa

ACS Synth Biol. 2018 Apr 6. doi: 10.1021/acssynbio.8b00011. [Epub ahead of print]
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Synthetic Biology Makes Polymer Materials Count

Synthetic biology applies engineering concepts to build cellular systems that perceive and process information. This is achieved by assembling genetic modules according to engineering design principles. Recent advance in the field has contributed optogenetic switches for controlling diverse biological functions in response to light. Here, the concept is introduced to apply synthetic biology switches and design principles for the synthesis of multi-input-processing materials. This is exemplified by the synthesis of a materials system that counts light pulses. Guided by a quantitative mathematical model, functional synthetic biology-derived modules are combined into a polymer framework resulting in a biohybrid materials system that releases distinct output molecules specific to the number of input light pulses detected. Further demonstration of modular extension yields a light pulse-counting materials system to sequentially release different enzymes catalyzing a multistep biochemical reaction. The resulting smart materials systems can provide novel solutions as integrated sensors and actuators with broad perspectives in fundamental and applied research.
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Design, development and application of whole-cell based antibiotic-specific biosensor

Synthetic biology techniques hold great promise for optimising the production of natural products by microorganisms. However, evaluating the phenotype of a modified bacterium represents a major bottleneck to the engineering cycle - particularly for antibiotic-producing actinobacteria strains, which grow slowly and are challenging to genetically manipulate. Here, we report the generation and application of antibiotic-specific whole-cell biosensor derived from TetR transcriptional repressor for use in identifying and optimising antibiotic producers. The constructed biosensor was successfully used to improve production of polyketide antibiotic pamamycin. However, an initial biosensor based on native genetic elements had inadequate dynamic and operating ranges. To overcome these limitations, we fine-tuned biosensor performance through alterations of the promoter and operator of output module and the ligand affinity of transcription factor module, which enabled us to deduce recommendations for building and application of actinobacterial biosensors.
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Synthetic Biology Open Language (SBOL) Version 2.2.0

Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The synthetic biology open language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.2.0 of SBOL that builds upon version 2.1.0 published in last year's JIB special issue. In particular, SBOL 2.2.0 includes improved description and validation rules for genetic design provenance, an extension to support combinatorial genetic designs, a new class to add non-SBOL data as attachments, a new class for genetic design implementations, and a description of a methodology to describe the entire design-build-test-learn cycle within the SBOL data model.
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Characterization of noise in multistable genetic circuits reveals ways to modulate heterogeneity

Random fluctuations in the amount of cellular components like mRNA and protein molecules are inevitable due to the stochastic and discrete nature of biochemical reactions. If large enough, this so-called "cellular noise" can lead to random transitions between the expression states of a multistable genetic circuit. That way, heterogeneity within isogenic populations is created. Our aim is to understand which dynamical features of a simple autoregulatory system determine its intrinsic noise level, and how they can be modified in order to regulate state-transitions. To that end, novel mathematical methods for the state-dependent characterization and prediction of noise in multistable systems are developed. First, we introduce the hybrid LNA, a modified version of the Linear Noise Approximation. It yields good predictions on variances of mRNA and protein fluctuations, even for reaction systems comprising low-copy-number components (e.g. mRNA) and highly nonlinear reaction rates. Furthermore, the temporal structure of fluctuations and the skewness of the protein distribution are characterized via state-dependent protein burst sizes and burst frequencies. Based on this mathematical framework, we develop graphical methods which support the intuitive design of regulatory circuits with a desired noise pattern. The methods are then used to predict how overall noise in the system can be adapted, and how state-specific noise modifications are possible that allow, e.g., the generation of unidirectional transitions. Our considerations are validated by stochastic simulations. This way, a design of genetic circuits is possible that takes population heterogeneity into account and is valuable in applications of synthetic biology and biotechnology. Moreover, natural phenomena like the bimodal development of genetic competence can be studied
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