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Original Article from The New England Journal of Medicine — Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV
*Biological Time Travel*"FROM GLOWING FISH to bacteria that can count, synthetic biologists are now able to create life forms never before seen on earth. “Historians and Ecclesiastes be damned,” says Sophia Roosth, assistant professor in the history of science. “In the first decades of the twenty-first century, a number of things are new under the sun.”
Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation. Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions. Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate. The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-derived iPSCs devoid of the original chromosomal aberration. Our results suggest a fundamentally different function for cellular reprogramming as a means of /`chromosome therapy/' to reverse combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. In addition, our work provides an experimentally tractable human cellular system for studying mechanisms of chromosomal number control, which is of critical relevance to human development and disease.
A great review by Yamanaka et al
byMacia J, Sole R"Biological systems perform computations at multiple scales and they do so in a robust way. Engineering metaphors have often been used in order to provide a rationale for modeling cellular and molecular computing networks and as the basis for their synthetic design. However, a major constraint in this mapping between electronic and wet computational circuits is the wiring problem. Although wires are identical within electronic devices, they must be different when using synthetic biology designs. Moreover, in most cases the designed molecular systems cannot be reused for other functions. A new approximation allows us to simplify the problem by using synthetic cellular consortia where the output of the computation is distributed over multiple engineered cells. By evolving circuits in silico, we can obtain the minimal sets of Boolean units required to solve the given problem at the lowest cost using cellular consortia. Our analysis reveals that the basic set of logic units is typically non-standard. Among the most common units, the so called inverted IMPLIES (N-Implies) appears to be one of the most important elements along with the NOT and AND functions. Although NOR and NAND gates are widely used in electronics, evolved circuits based on combinations of these gates are rare, thus suggesting that the strategy of combining the same basic logic gates might be inappropriate in order to easily implement synthetic computational constructs. The implications for future synthetic designs, the general view of synthetic biology as a standard engineering domain, as well as potencial drawbacks are outlined."http://bit.ly/NseMxD
byAna Lúcia Leitãoa, Francisco J. Enguita"Secondary metabolic pathways of fungal origin provide an almost unlimited resource of new compounds for medical applications, which can fulfill some of the, currently unmet, needs for therapeutic alternatives for the treatment of a number of diseases. Secondary metabolites secreted to the extracellular medium (extrolites) belong to diverse chemical and structural families, but the majority of them are synthesized by the condensation of a limited number of precursor building blocks including amino acids, sugars, lipids and low molecular weight compounds also employed in anabolic processes. In fungi, genes related to secondary metabolic pathways are frequently clustered together and show a modular organization within fungal genomes. The majority of fungal gene clusters responsible for the biosynthesis of secondary metabolites contain genes encoding a high molecular weight condensing enzyme which is responsible for the assembly of the precursor units of the metabolite. They also contain other auxiliary genes which encode enzymes involved in subsequent chemical modification of the metabolite core. Synthetic biology is a branch of molecular biology whose main objective is the manipulation of cellular components and processes in order to perform logically connected metabolic functions. In synthetic biology applications, biosynthetic modules from secondary metabolic processes can be rationally engineered and combined to produce either new compounds, or to improve the activities and/or the bioavailability of the already known ones. Recently, advanced genome editing techniques based on guided DNA endonucleases have shown potential for the manipulation of eukaryotic and bacterial genomes. This review discusses the potential application of genetic engineering and genome editing tools in the rational design of fungal secondary metabolite pathways by taking advantage of the increasing availability of genomic and biochemical data."http://bit.ly/NsbMRQ
Synthetic Aesthetics: Investigating Synthetic Biology's Designs on Nature [Alexandra Daisy Ginsberg, Jane Calvert, Pablo Schyfter, Alistair Elfick, Drew Endy] on Amazon.com. *FREE* shipping on qualifying offers.
mRNA translation involves simultaneous movement of multiple ribosomes on the mRNA and is also subject to regulatory mechanisms at different stages. Translation can be described by various codon-based models, including ODE, TASEP, and Petri net models. Although such models have been extensively used, the overlap and differences between these models and the implications of the assumptions of each model has not been systematically elucidated. The selection of the most appropriate modelling framework, and the most appropriate way to develop coarse-grained/fine-grained models in different contexts is not clear.
byATHANIEL RICH"The first time Ben Novak saw a passenger pigeon, he fell to his knees and remained in that position, speechless, for 20 minutes. He was 16. At 13, Novak vowed to devote his life to resurrecting extinct animals. At 14, he saw a photograph of a passenger pigeon in an Audubon Society book and “fell in love.” But he didn’t know that the Science Museum of Minnesota, which he was then visiting with a summer program for North Dakotan high-school students, had them in their collection, so he was shocked when he came across a cabinet containing two stuffed pigeons, a male and a female, mounted in lifelike poses. He was overcome by awe, sadness and the birds’ physical beauty: their bright auburn breasts, slate-gray backs and the dusting of iridescence around their napes that, depending on the light and angle, appeared purple, fuchsia or green. Before his chaperones dragged him out of the room, Novak snapped a photograph with his disposable camera. The flash was too strong, however, and when the film was processed several weeks later, he was haunted to discover that the photograph hadn’t developed. It was blank, just a flash of white light.
bySarpeshkar R."We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog-digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA-protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations."http://1.usa.gov/1dA9Lcp
byMarkus Gershater"Synthetic biology is a new field, but it sometimes feels like we already have dogma. The idea that de novo DNA synthesis costs are limiting seems so ingrained: many of the major news stories we hear in synthetic biology are the latest milestones of ever larger chunks of DNA being stitched together, ever increasing numbers of strains being created, and the cost of DNA synthesis falling exponentially. There’s no doubt that the advances to date have been phenomenal, and I certainly tell anyone who gives me half a chance about how processes that took months when I was a PhD student can now be solved in minutes (and it really wasn’t that long ago). The problem is, I’m not sure our attitudes have kept up with this pace of change: it’s the thesis of this post that due to these immensely rapid advances, DNA synthesis is no longer such an issue and we should now focus as a community on the bigger problem of effectively addressing biological complexity.
Open questions in origin of life: experimental studies on the origin of nucleic acids and proteins with specific and functional sequences by a chemical synthetic biology approach
Drew Endy today at Stanford 11.30 am: What is synthetic biology and why does it matter? http://stanford.io/1fNZnyl
Agilis Biotherapeutics, LLC, a synthetic biology-based company focused on developing DNA-based therapeutics for rare genetic diseases, announced today
SYS-CON Media, NJ, The world's leading i-technology media company on breaking technology news.
bySamuel H. Sternberg, Sy Redding, Martin Jinek, Eric C. Greene & Jennifer A. Doudna"The clustered regularly interspaced short palindromic repeats (CRISPR)-associated enzyme Cas9 is an RNA-guided endonuclease that uses RNA–DNA base-pairing to target foreign DNA in bacteria. Cas9–guide RNA complexes are also effective genome engineering agents in animals and plants. Here we use single-molecule and bulk biochemical experiments to determine how Cas9–RNA interrogates DNA to find specific cleavage sites. We show that both binding and cleavage of DNA by Cas9–RNA require recognition of a short trinucleotide protospacer adjacent motif (PAM). Non-target DNA binding affinity scales with PAM density, and sequences fully complementary to the guide RNA but lacking a nearby PAM are ignored by Cas9–RNA. Competition assays provide evidence that DNA strand separation and RNA–DNA heteroduplex formation initiate at the PAM and proceed directionally towards the distal end of the target sequence. Furthermore, PAM interactions trigger Cas9 catalytic activity. These results reveal how Cas9 uses PAM recognition to quickly identify potential target sites while scanning large DNA molecules, and to regulate scission of double-stranded DNA."http://bit.ly/1cdwW1l
byPatrick M. Shi1, Jan Zarzycki, Krishna K. Niyogi and Cheryl A. Kerfeld"Global photosynthetic productivity is limited by the enzymatic assimilation of CO2 into organic carbon compounds. Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), the carboxylating enzyme of the Calvin-Benson (CB) cycle, poorly discriminates between CO2 and O2, leading to photorespiration and the loss of fixed carbon and nitrogen. With the advent of synthetic biology, it is now feasible to design, synthesize and introduce biochemical pathways in vivo. We engineered a synthetic photorespiratory bypass based on the 3-hydroxypropionate bi-cycle into the model cyanobacterium, Synechococcus elongatus sp. PCC 7942. The heterologously expressed cycle is designed to function as both a photorespiratory bypass and an additional CO2-fixing pathway, supplementing the CB cycle. We demonstrate the function of all six introduced enzymes and identify bottlenecks to be targeted in subsequent bioengineering. These results have implications for efforts to improve photosynthesis, and for the "green" production of high-value products of biotechnological interest." http://bit.ly/1kvbwPS
George Church, Ph.D., a Core Faculty member at the Wyss Institute and Professor of Genetics at Harvard Medical School, explains how fluorescent in situ sequencing…
Nanotube twins - Coupled carbon and peptide nanotubes achieved for the first time
byChiang AW, Hwang MJ."An increasing number of genetic components are available in several depositories of such components to facilitate synthetic biology research, but picking out those that will allow a designed circuit to achieve the specified function still requires multiple cycles of testing. Here, we addressed this problem by developing a computational pipeline to mathematically simulate a gene circuit for a comprehensive range and combination of the kinetic parameters of the biological components that constitute the gene circuit.
byDepaoli HC, Borland AM, Tuskan GA, Cushman JC, Yang X."To meet future food and energy security needs, which are amplified by increasing population growth and reduced natural resource availability, metabolic engineering efforts have moved from manipulating single genes/proteins to introducing multiple genes and novel pathways to improve photosynthetic efficiency in a more comprehensive manner. Biochemical carbon-concentrating mechanisms such as crassulacean acid metabolism (CAM), which improves photosynthetic, water-use, and possibly nutrient-use efficiency, represent a strategic target for synthetic biology to engineer more productive C3 crops for a warmer and drier world. One key challenge for introducing multigene traits like CAM onto a background of C3 photosynthesis is to gain a better understanding of the dynamic spatial and temporal regulatory events that underpin photosynthetic metabolism. With the aid of systems and computational biology, vast amounts of experimental data encompassing transcriptomics, proteomics, and metabolomics can be related in a network to create dynamic models. Such models can undergo simulations to discover key regulatory elements in metabolism and suggest strategic substitution or augmentation by synthetic components to improve photosynthetic performance and water-use efficiency in C3 crops. Another key challenge in the application of synthetic biology to photosynthesis research is to develop efficient systems for multigene assembly and stacking. Here, we review recent progress in computational modelling as applied to plant photosynthesis, with attention to the requirements for CAM, and recent advances in synthetic biology tool development. Lastly, we discuss possible options for multigene pathway construction in plants with an emphasis on CAM-into-C3 engineering."http://bit.ly/1o6oPUg
bySleator RD."Herein, I track the evolution of synthetic biology from its earliest incarnations more than 50 years ago, through the DIYbio revolution, to the next 50 years." http://1.usa.gov/1o3EcwH
COLD SPRING HARBOR ASIA CONFERENCES: Synthetic Biology - Suzhou, China
December 1-5, 2014 http://bit.ly/MUVtN4