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De novo automated design of small RNA circuits for engineering synthetic riboregulation in living cells

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Rodrigo G, Landrain TE, Jaramillo A.

"A grand challenge in synthetic biology is to use our current knowledge of RNA science to perform the automatic engineering of completely synthetic sequences encoding functional RNAs in living cells. We report here a fully automated design methodology and experimental validation of synthetic RNA interaction circuits working in a cellular environment. The computational algorithm, based on a physicochemical model, produces novel RNA sequences by exploring the space of possible sequences compatible with predefined structures. We tested our methodology in Escherichia coli by designing several positive riboregulators with diverse structures and interaction models, suggesting that only the energy of formation and the activation energy (free energy barrier to overcome for initiating the hybridization reaction) are sufficient criteria to engineer RNA interaction and regulation in bacteria. The designed sequences exhibit nonsignificant similarity to any known noncoding RNA sequence. Our riboregulatory devices work independently and in combination with transcription regulation to create complex logic circuits. Our results demonstrate that a computational methodology based on first-principles can be used to engineer interacting RNAs with allosteric behavior in living cells."

http://bit.ly/Q7CASI

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Ewan's Blog; bioinformatician at large: ENCODE: My own thoughts

Ewan's Blog; bioinformatician at large: ENCODE: My own thoughts | SynBioFromLeukipposInstitute | Scoop.it
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2012 Release: ENCODE data describes function of human genome

2012 Release: ENCODE data describes function of human genome | SynBioFromLeukipposInstitute | Scoop.it

ENCODE data describes function of human genome

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ENCODE: The Encyclopedia of DNA Elements

Interviews with members of the ENCODE Project More: http://www.genome.gov/27549810...
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Stanford researchers create tiny, wirelessly powered cardiac device

Stanford researchers create tiny, wirelessly powered cardiac device | SynBioFromLeukipposInstitute | Scoop.it
It will be interesting to use such tiny devices in combination with synthetic biological systems.....

*Stanford researchers create tiny, wirelessly powered cardiac device*

BY ANDREW MYERS

"Stanford electrical engineers overturn existing models to demonstrate the feasibility of a millimeter-sized, wirelessly powered cardiac device. The findings, say the researchers, could dramatically alter the scale of medical devices implanted in the human body.

A team of engineers at Stanford has demonstrated the feasibility of a super-small, implantable cardiac device that gets its power not from batteries but from radio waves transmitted from a small power device on the surface of the body.

The implanted device is contained in a cube just 0.8 millimeter on a side. It could fit on the head of pin.

The findings were published in the journal Applied Physics Letters. In their paper, the researchers demonstrated wireless power transfer to a millimeter-sized device implanted 5 centimeters inside the chest on the surface of the heart – a depth once thought out of reach for wireless power transmission.

The engineers say the research is a major step toward a day when all implants are driven wirelessly. Beyond the heart, they believe such devices might include swallowable endoscopes – so-called "pillcams" that travel the digestive tract – permanent pacemakers and precision brain stimulators – virtually any medical applications where device size and power matter.

A revolution in the body

Implantable medical devices in the human body have revolutionized medicine....."

http://bit.ly/OUlIO6

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George Church outlines a pathway to indeterminant lifespans via Synthetic Biology

"George Church teases with some ideas he has for achieving physical immortality (indeterminant lifespans) via Synthetic biology.

George's idea is to bring in sections of DNA from exotic organisms or genes that are rare for humans to enable all people to have desired genetic capabilities. He describes capabilities such as immunity to all viruses and cellular immunity to radiation and creating immunity to diseases.

They are working to sequence and determine the genetic basis for long lived animals and humans and determine how to engineer longer lived people. ...."

http://bit.ly/NSzQqi

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Scalable Plasmid Transfer using Engineered P1-based Phagemids - ACS Synthetic Biology (ACS Publications)

Scalable Plasmid Transfer using Engineered P1-based Phagemids - ACS Synthetic Biology (ACS Publications) | SynBioFromLeukipposInstitute | Scoop.it

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Joshua T. Kittleson, Will DeLoache, Hsiao-Ying Cheng, and J. Christopher Anderson

"Dramatic improvements to computational, robotic, and biological tools have enabled genetic engineers to conduct increasingly sophisticated experiments. Further development of biological tools offers a route to bypass complex or expensive mechanical operations, thereby reducing the time and cost of highly parallelized experiments. Here, we engineer a system based on bacteriophage P1 to transfer DNA from one E. coli cell to another, bypassing the need for intermediate DNA isolation (e.g., minipreps). To initiate plasmid transfer, we refactored a native phage element into a DNA module capable of heterologously inducing phage lysis. After incorporating known cis-acting elements, we identified a novel cis-acting element that further improves transduction efficiency, exemplifying the ability of synthetic systems to offer insight into native ones. The system transfers DNAs up to 25 kilobases, the maximum assayed size, and operates well at microliter volumes, enabling manipulation of most routinely used DNAs. The system’s large DNA capacity and physical coupling of phage particles to phagemid DNA suggest applicability to biosynthetic pathway evolution, functional proteomics, and ultimately, diverse molecular biology operations including DNA fabrication."
http://bit.ly/O9i483

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Lirias: Synthetic biology & microdevices: a powerful combination

Lirias: Synthetic biology & microdevices: a powerful combination | SynBioFromLeukipposInstitute | Scoop.it

Recent developments demonstrate that the combination of microbiology with micro- and nanoelectronics is a successful approach to develop new miniaturized sensing devices and other technologies. In the last decade, there is a shift from the optimization of the abiotic components, e.g. the chip, to the improvement of the processing capabilities of cells through genetic engineering. The synthetic biology approach will not only give rise to systems with new functionalities, but will also improve the robustness and speed of their response towards applied signals. To this end, the development of new genetic circuits has to be guided by computational design methods that enable to tune and optimize the circuit response. As the successful design of genetic circuits is highly dependent on the quality and reliability of its composing elements, intense characterization of standard biological parts will be crucial for an efficient rational design process in the development of new genetic circuits. Microengineered devices can thereby offer a new analytical approach for the study of complex biological parts and systems. By summarizing the recent techniques in creating new synthetic circuits and in integrating biology with microdevices, this review aims at emphasizing the power of combining synthetic biology with microfluidics and microelectronics.

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Biomodel Engineering for Systems and Synthetic Biology – from Uniscale to Multiscale

http://bit.ly/QgWGfl

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New genome sequencing method gives 'near complete' picture of ancient human (Wired UK)

New genome sequencing method gives 'near complete' picture of ancient human (Wired UK) | SynBioFromLeukipposInstitute | Scoop.it

A team of paleogeneticists has published a paper revealing how they sequenced the genome of an 80,000-year-old Denisovan girl, a close relation to the Neanderthal, 31 times over by analysing manipulated single strands of DNA, a novel approach that...

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ncDNA and drift drive binding site accumulation - significant implications on synthetic biology

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Ruths T, Nakhleh L.

"The amount of transcription factor binding sites (TFBS) in an organism's genome positively correlates with the complexity of the regulatory network of the organism. However, the manner by which TFBS arise and accumulate in genomes and the effects of regulatory network complexity on the organism's fitness are far from being known. The availability of TFBS data from many organisms provides an opportunity to explore these issues, particularly from an evolutionary perspective.
RESULTS:
We analyzed TFBS data from five model organisms - E. coli K12, S. cerevisiae, C. elegans, D. melanogaster, A. thaliana - and found a positive correlation between the amount of non-coding DNA (ncDNA) in the organism's genome and regulatory complexity. Based on this finding, we hypothesize that the amount of ncDNA, combined with the population size, can explain the patterns of regulatory complexity across organisms. To test this hypothesis, we devised a genome-based regulatory pathway model and subjected it to the forces of evolution through population genetic simulations. The results support our hypothesis, showing neutral evolutionary forces alone can explain TFBS patterns, and that selection on the regulatory network function does not alter this finding.
CONCLUSIONS:
The cis-regulome is not a clean functional network crafted by adaptive forces alone, but instead a data source filled with the noise of non-adaptive forces. From a regulatory perspective, this evolutionary noise manifests as complexity on both the binding site and pathway level, which has significant implications on many directions in microbiology, genetics, and synthetic biology."

http://1.usa.gov/UjqZ5N

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Synthetic biology applications of engineered riboregulation

Synthetic biology applications of engineered riboregulation | SynBioFromLeukipposInstitute | Scoop.it

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by Callura, Jarred Matthew, BOSTON UNIVERSITY, 2012

"For synthetic biology to make a lasting impact on real-world problems, further increases in the complexity of biomolecular devices are required. Currently, there is a shortage of orthogonal parts that can be assembled to construct highly complex circuits and networks. RNA molecules are a popular source for synthetic biology parts, due to the versatility and predictability of RNA structures. Previously, our lab developed the engineered riboregulator, a RNA-based gene expression system. The advantages of synthetic riboregulation include: physiologically relevant protein production, component modularity, leakage minimization, rapid response time, tunable gene expression, and the ability to independently riboregulate multiple genes simultaneously using orthogonal riboregulator variants. We performed two sets of in vivo experiments that illustrate these unique features and developed two, higher-order synthetic devices based on orthogonal riboregulation: the programmable kill switch and the genetic switchboard. The in vivo experiments involved tracking the localization of the TonB protein and manipulating the SOS DNA damage repair network. These studies highlight the ability of our riboregulator to reveal new insights into microbial physiology. Addressing mounting biosecurity concerns, the programmable kill switch employs two riboregulator variants, which regulate two λ phage proteins, to induce cell lysis rapidly and selectively. Only when we co-expressed the phage proteins did cell suicide occur, and the circuit can link cell death to four different biological signals. To construct a genetic switchboard, we further increased the number of riboregulators in use by designing two new variants. We directly tested our switchboard in a biosensing setup that reports on four environmental signals in single cells using four differentiable reporters. Finally, we utilized the genetic switchboard in a proof-of-concept metabolic engineering application. The metabolism switchboard regulates four metabolic enzymes that control carbon flux through three, E. coli glucose utilization pathways, and we measured its impressive performance across the RNA, protein, and metabolome scales. All together, the applications described here showcase the considerable real-world potential of the engineered riboregulator."

http://bit.ly/OzSndg

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Nature ENCODE : Nature Publishing Group : A landmark in the understanding of the human genome

Nature ENCODE : Nature Publishing Group : A landmark in the understanding of the human genome | SynBioFromLeukipposInstitute | Scoop.it
Nature ENCODE: Explore the wealth of information about the project's key findings and numerous integrative analyses.
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New DNA Encyclopedia Attempts to Map Function of Entire Human Genome | Wired Science | Wired.com

New DNA Encyclopedia Attempts to Map Function of Entire Human Genome | Wired Science | Wired.com | SynBioFromLeukipposInstitute | Scoop.it
A torrent of new data charts the human genome in unprecedented detail, a landmark accomplishment compared by some scientists to the genome’s sequencing in 1999.
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ENCODE Project at UCSC

ENCODE Project at UCSC | SynBioFromLeukipposInstitute | Scoop.it

The Encyclopedia of DNA Elements (ENCODE) Consortium is an international collaboration of research groups funded by the National Human Genome Research Institute (NHGRI). The goal of ENCODE is to build a comprehensive parts list of functional elements in the human genome, including elements that act at the protein and RNA levels, and regulatory elements that control cells and circumstances in which a gene is active.

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Synthetic Biology: A new 'Age of Wonder'?

Synthetic Biology: A new 'Age of Wonder'? | SynBioFromLeukipposInstitute | Scoop.it

"Synthetic Biology approaches are catalysing a paradigm shift in genetic manipulation and the engineering of biology. Liberated by rapid, reliable methods for DNA synthesis and assembly, researchers are now able to routinely build synthetic circuits well beyond the scale and complexity of the single gene insertions that characterise the genetically engineered systems of the last forty years. Established design principles, facile assembly from standardised parts and predictable performance have long been the defining features of modern engineering and represent the core goals of Synthetic Biology. Of these, rational and reliable design remains the most challenging problem faced by the synthetic biologist. " 

http://bit.ly/SkPH8O

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Digital Data Storage in DNA | Bio 2.0 | Learn Science at Scitable

Digital Data Storage in DNA | Bio 2.0 | Learn Science at Scitable | SynBioFromLeukipposInstitute | Scoop.it

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Eric Sawyer

"In today's world of high technology, we usually associate digital information with computers, satellites, and smart phones. But don't forget that digital information storage far predates the digital age. When Watson and Crick discovered the structure of DNA, they also discovered that at the heart of living things is a massive digital information storage molecule. The digital information in the human genome encodes the instructions for building the human body that would ultimately go on to build digital computers.

Bringing this full circle, a recent paper1 explores the possibility of using synthetic DNA to store digital information of human design. We have a data problem. The future of science seems to be big data, and that's challenging and expensive to store. The CMS experiment at the Large Hadron Collider alone generates 1 terabyte of data every second and, more poetically, in its projected lifetime the LHC will give us a dataset comparable in size to a library containing every single word spoken by every human who has ever lived2. Big science aside, the internet and social media generate large quantities of digital information.

In their paper, George Church and colleagues combine recent advances in DNA synthesis and sequencing to create a data storage chip made of DNA. In the DNA chip they stored a HTML file of a synthetic biology book, containing 53,426 words of text, 11 black and white JPEG images, and a computer program written in Java. Since DNA contains four bases, two computer bits can be encoded per DNA base: e.g., A = 00, C = 01, G = 10, T = 11. The authors of this paper however decided to use a one base per bit code, A = 0, C = 0, G = 1, T = 1, which allows for many synonymous encodings to avoid sequences that are difficult to sequence such as long repeats.

In all, they synthesized 54,898 short pieces of DNA. Each contained 2 primer binding sites for PCR amplification and sequencing, a unique 19-base address, and 96 bases (96 bits, or 12 bytes) of stored data (see the figure). Their DNA chip represents the densest information storage (nearly 1016 bits/mm3) to date, beating the likes of in vivo experiments, flash memory, hard disks, and CDs. The error rate was an impressively low 10 bits out of the total 5.27 million.

The prospect of storing something like particle accelerator data on a synthetic DNA chip is intriguing and seductively poetic, but I'm a bit skeptical. The interface between computer chips and DNA chips will never be as seamless as the interface between computer chips and hard disks, flash memory storage devices, etc. And even though DNA sequencing is getting much cheaper, and even more portable, it seems unlikely that individuals would purchase sequencers. But maybe DNA will be used for long-term archiving as the authors suggest, where the need for high capacity, high longevity storage outweighs the costly and time-consuming process of writing and reading the stored data."

http://bit.ly/NP6E3y

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katielouisemilburn's curator insight, March 14, 2013 6:43 AM

phones are cool i take my everywhere and my i pad totally cool are you?

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A global sampling approach to designing and reengineering RNA secondary structures

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Levin A, Lis M, Ponty Y, O'Donnell CW, Devadas S, Berger B, Waldispühl J.

"The development of algorithms for designing artificial RNA sequences that fold into specific secondary structures has many potential biomedical and synthetic biology applications. To date, this problem remains computationally difficult, and current strategies to address it resort to heuristics and stochastic search techniques. The most popular methods consist of two steps: First a random seed sequence is generated; next, this seed is progressively modified (i.e. mutated) to adopt the desired folding properties. Although computationally inexpensive, this approach raises several questions such as (i) the influence of the seed; and (ii) the efficiency of single-path directed searches that may be affected by energy barriers in the mutational landscape. In this article, we present RNA-ensign, a novel paradigm for RNA design. Instead of taking a progressive adaptive walk driven by local search criteria, we use an efficient global sampling algorithm to examine large regions of the mutational landscape under structural and thermodynamical constraints until a solution is found. When considering the influence of the seeds and the target secondary structures, our results show that, compared to single-path directed searches, our approach is more robust, succeeds more often and generates more thermodynamically stable sequences. An ensemble approach to RNA design is thus well worth pursuing as a complement to existing approaches. RNA-ensign is available at http://csb.cs.mcgill.ca/RNAensign."
http://bit.ly/OMhREn

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Cientifica’s Tim Harper To Discuss Disruptive Technologies At Tech Tour Solutions 2012

Cientifica’s Tim Harper To Discuss Disruptive Technologies At Tech Tour Solutions 2012 | SynBioFromLeukipposInstitute | Scoop.it
From Graphene to Synthetic Biology - How Can Companies And Investors Manage Technological Change?
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Essential genes as antimicrobial targets and cornerstones of synthetic biology

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Mario Juhas, Leo Eberl, George M. Church

"Essential genes are absolutely required for the survival of any living entity. Investigation of essential genes is therefore expected to advance tremendously our understanding of the universal principles of life. Determination of a minimal set of essential genes needed to sustain life also plays an important role in the emerging field of synthetic biology, whose goals include creation of a stringently controlled minimal cell with predesigned phenotypic traits. In addition, due to their indispensability for survival of bacteria, genes encoding essential cellular functions have great potential in medicine as promising targets for the development of novel antimicrobials. Here, we review recent advances in the investigation of essential genes, with emphasis on the practical applications in medicine and synthetic biology."

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Life, simulated

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Natalie de Souza

A great comment to this Cell paper: Karr, J.R. et al. A whole-cell computational model predicts phenotype from genotype. Cell 150, 389–401 (2012).

"If you can build something from scratch, it follows that you understand how its parts can combine to produce the whole. This is the idea that underlies attempts to simulate cells with a computer. In recently published work, Markus Covert and colleagues at Stanford University have generated a whole-cell model of the human pathogen Mycoplasma genitalium in which they simulate the function of all of its genes.

Mycoplasma has only 525 genes, most of which have homologs that have been studied in other organisms even if some Mycoplasma genes have not been studied directly, Covert says, explaining his choice of organism. “We were guided very much by the Human Genome Project in this, which is to say to start with the simplest organism.” Also, Mycoplasma can be cultured in the laboratory, which Covert considered important as he wished to combine theoretical and experimental work, and Mycoplasma is the first organism to have had its chromosome synthesized de novo.

Using data gleaned from hundreds to thousands of published papers, on Mycoplasma as well as on Escherichia coli and other bacteria, the researchers set out to put the parts back together in the computer. They broke the cell's overall functions down into 28 separate functional modules describing different subprocesses—RNA decay, metabolism or DNA replication, for instance—and modeled each of these separately based on the information available about that subprocess in the literature...."

http://bit.ly/TbBU3j

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SynBioBeta

*SynBioBeta*

Nov 14th at Orrick, Menlo Park

An event that brings together synthetic biology startups, established players, bioengineers, investors
and scientists to meet, partner and hear about the latest advances in the industry.

http://bit.ly/OJsVR0

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The art of trans-boundary governance: the case of synthetic biology

The art of trans-boundary governance: the case of synthetic biology

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Joy Y. Zhang

"Synthetic biology raises few, if any, social concerns that are distinctively new. Similar to many other convergent technologies, synthetic biology’s interface across various scientific communities and interests groups presents an incessant challenge to political and conceptual boundaries. However, the scale and intensity of these interfaces seem to necessitate a reflection over how corresponding governance capacities can be developed. This paper argues that, in addition to existing regulatory approaches, such capacities may be gained through the art of trans-boundary governance, which is not only attentive to the crossing and erosion of particular boundaries but also adept in keeping up with the dynamics among evolving networks of actors."

http://bit.ly/S6NWvO

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