by Cheemeng Tan,Saumya Saurabh,Marcel P. Bruchez,Russell Schwartz& Philip LeDuc
"The integration of synthetic and cell-free biology has made tremendous strides towards creating artificial cellular nanosystems using concepts from solution-based chemistry, where only the concentrations of reacting species modulate gene expression rates. However, it is known that macromolecular crowding, a key feature in natural cells, can dramatically influence biochemical kinetics via volume exclusion effects, which reduce diffusion rates and enhance binding rates of macromolecules. Here, we demonstrate that macromolecular crowding can increase the robustness of gene expression by integrating synthetic cellular components of biological circuits and artificial cellular nanosystems. Furthermore, we reveal how ubiquitous cellular modules, including genetic components, a negative feedback loop and the size of the crowding molecules can fine-tune gene circuit response to molecular crowding. By bridging a key gap between artificial and living cells, our work has implications for efficient and robust control of both synthetic and natural cellular circuits." http://bit.ly/16MevdY
PLOS ONE: an inclusive, peer-reviewed, open-access resource from the PUBLIC LIBRARY OF SCIENCE. Reports of well-performed scientific studies from all disciplines freely available to the whole world.
Gerd Moe-Behrens's insight:
Hiromasa Tanaka, Tau-Mu Yi
"Designing the shape and size of a cell is an interesting challenge for synthetic biology. Prolonged exposure to the mating pheromone α-factor induces an unusual morphology in yeast cells: multiple mating projections. The goal of this work was to reproduce the multiple projections phenotype in the absence of α-factor using a gain-of-function approach termed “Alternative Inputs (AIs)”. An alternative input is defined as any genetic manipulation that can activate the signaling pathway instead of the natural input. Interestingly, none of the alternative inputs were sufficient to produce multiple projections although some produced a single projection. Then, we extended our search by creating all combinations of alternative inputs and deletions that were summarized in an AIs-Deletions matrix. We found a genetic manipulation (AI-Ste5p ste2Δ) that enhanced the formation of multiple projections. Following up this lead, we demonstrated that AI-Ste4p and AI-Ste5p were sufficient to produce multiple projections when combined. Further, we showed that overexpression of a membrane-targeted form of Ste5p alone could also induce multiple projections. Thus, we successfully re-engineered the multiple projections mating morphology using alternative inputs without α-factor." http://bit.ly/17drZAe
by Zengyi Shao, Guodong Rao Chun Li, Zhanar Abil, Yunzi Luo, and Huimin Zhao
"Natural products (secondary metabolites) are a rich source of compounds with important biological activities. Eliciting pathway expression is always challenging but extremely important in natural product discovery because an individual pathway is tightly controlled through a unique regulation mechanism and hence often remains silent under the routine culturing conditions. To overcome the drawbacks of the traditional approaches that lack general applicability, we developed a simple synthetic biology approach that decouples pathway expression from complex native regulations. Briefly, the entire silent biosynthetic pathway is refactored using a plug-and-play scaffold and a set of heterologous promoters that are functional in a heterologous host under the target culturing condition. Using this strategy, we successfully awakened the silent spectinabilin pathway from Streptomyces orinoci. This strategy bypasses the traditional laborious processes to elicit pathway expression and represents a new platform for discovering novel natural products."
by James Anderson, Natalja Strelkowa, Guy-Bart Stan, Thomas Douglas, Julian Savulescu, Mauricio Barahona & Antonis Papachristodoulou
"Synthetic biology has emerged as an exciting and promising new research field, garnering significant attention from both the scientific community and the general public. This interest results from a variety of striking features: synthetic biology is a truly interdisciplinary field that engages biologists, mathematicians, physicists and engineers; its research focus is applied; and it has enormous potential to harness the power of biology to provide scientific and engineering solutions to a wide range of problems and challenges that plague humanity. However, the power of synthetic biology to engineer organisms with custom-made functionality requires that researchers and society use this power safely and responsibly, in particular when it comes to releasing organisms into the environment. This creates new challenges for both the design of such organisms and the regulatory process governing their creation and use…."
*Signatures of mutational processes in human cancer*
by Ludmil B. Alexandrov,Serena Nik-Zainal,David C. Wedge,Samuel A. J. R. Aparicio,Sam Behjati,Andrew V. Biankin,Graham R. Bignell,Niccolò Bolli,Ake Borg,Anne-Lise Børresen-Dale,Sandrine Boyault,Birgit Burkhardt,Adam P. Butler,Carlos Caldas,Helen R. Davies, Christine Desmedt,Roland Eils,Jórunn Erla Eyfjörd,John A. Foekens, Mel Greaves,Fumie Hosoda,Barbara Hutter,Tomislav Ilicic,Sandrine Imbeaud,Marcin Imielinsket al.
"All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy."
by Stephanie Joyce, Anne-Marie Mazza, and Steven Kendall, Rapporteurs; Committee on Science, Technology, and Law; Policy and Global Affairs; Board on Life Sciences; Division on Earth and Life Sciences; National Academy of Engineering; National Research Council
"Synthetic biology -- unlike any research discipline that precedes it -- has the potential to bypass the less predictable process of evolution to usher in a new and dynamic way of working with living systems. Ultimately, synthetic biologists hope to design and build engineered biological systems with capabilities that do not exist in natural systems -- capabilities that may ultimately be used for applications in manufacturing, food production, and global health. Importantly, synthetic biology represents an area of science and engineering that raises technical, ethical, regulatory, security, biosafety, intellectual property, and other issues that will be resolved differently in different parts of the world. As a better understanding of the global synthetic biology landscape could lead to tremendous benefits, six academies -- the United Kingdom's Royal Society and Royal Academy of Engineering, the United States' National Academy of Sciences and National Academy of Engineering, and the Chinese Academy of Science and Chinese Academy of Engineering -- organized a series of international symposia on the scientific, technical, and policy issues associated with synthetic biology. Positioning Synthetic Biology to Meet the Challenges of the 21st Century summarizes the symposia proceedings."
Cheemeng Tan: Engineering Artificial Cellular Systems for Biotechnological Applications
Their "work is unified under one theme: the engineering of synthetic biological systems for therapeutic treatment. We approach this issue through two fundamental directions. To improve the control of synthetic cellular systems, we harness functioning mechanisms in natural cells to control dynamics of synthetic cells and organisms. In parallel, we investigate how heterogenous cellular populations respond to drug treatment. We aim to merge the two directions to create novel treatment strategies using artificial cellular systems. We are honored to work with biologists, statistician, engineers, physicist, and chemists in the pursue of our research goals. Our work is multi-disciplinary and strives to create new frontier in synthetic & quantitative biology by synergizing ideas from different fields."
Elizabeth Pennisi "Bacteria have a kind of adaptive immune system, which enables them to fight off repeated attacks by specific viruses, that works through precise targeting of DNA. In January, four research teams reported harnessing the system, called CRISPR, to target the destruction of specific genes in human cells. And in the following 8 months, various groups have used it to delete, add, activate or suppress targeted genes in human cells, mice, rats, zebrafish, bacteria, fruit flies, yeast, nematodes and crops, demonstrating broad utility for the technique. With CRISPR, scientists can create mouse models of human diseases much more quickly than before, study individual genes much faster, and easily change multiple genes in cells at once to study their interactions."
Raymond McCauley, bioinformatics expert at Singularity University in California, gives Wired six examples of future biotech products
Gerd Moe-Behrens's insight:
by by MADHUMITA VENKATARAMANAN
"There are two things happening right now that have transformed biotechnology," says Raymond McCauley, bioinformatics expert at Singularity University in California, whose job is to nurture ideas and mentor bio-startups. The first, he says, is the digitisation of biology -- gathering data, examining how human systems work and testing drugs can all be done in a computer. The other is the democratisation of the tools. "Hackers are taking $3.5 million [£2.2 million] DNA sequencers and building the same thing for 1/10,000 of the price," he says. "What was an infant science a few years ago can now be a commercial venture." McCauley gives Wired six examples of future biotech products….
With recent improvements of protocols for the assembly of transcriptional parts, synthetic biological devices can now more reliably be assembled according to a given design.
Gerd Moe-Behrens's insight:
by Heinz Koeppl, Marc Hafner and James Lu
"With recent improvements of protocols for the assembly of transcriptional parts, synthetic biological devices can now more reliably be assembled according to a given design. The standardization of parts open up the way for in silico design tools that improve the construct and optimize devices with respect to given formal design specifications. The simplest such optimization is the selection of kinetic parameters and protein abundances such that the specified design constraints are robustly satisfied. In this work we address the problem of determining parameter values that fulfill specifications expressed in terms of a functional on the trajectories of a dynamical model. We solve this inverse problem by linearizing the forward operator that maps parameter sets to specifications, and then inverting it locally. This approach has two advantages over brute-force random sampling. First, the linearization approach allows us to map back intervals instead of points and second, every obtained value in the parameter region is satisfying the specifications by construction. The method is general and can hence be incorporated in a pipeline for the rational forward design of arbitrary devices in synthetic biology."
*STANFORD BIOENGINEERING LAB BUILDS MOLECULAR ‘SWITCH’ TO REPROGRAM CONTROL PATHWAYS IN CELLS*
by Tom Abate
"A Stanford bioengineering lab has developed a technology that can tweak the control systems that regulate the inner workings of cells, pointing the way toward future medical interventions that could switch off diseased states or turn on healthy processes.
The research paper being published today by Science Express describes a biological tool that principal author Christina Smolke, PhD, associate professor of bioengineering, has dubbed a molecular network diverter. This molecular diverter utilizes the concerted action of three biological sub-systems to redirect signaling pathways – complex networks of molecular interactions that orchestrate the cellular machinery. The experiments described by Smolke and her collaborators, Kate Galloway, PhD, California Institute of Technology, and Elisa Franco, PhD, assistant professor of mechanical engineering at University of California, Riverside, were performed on yeast cells. But the principles and practices embodied in the molecular network diverter apply to signaling pathways that control the development, reproduction and death of all cells. When these signaling pathways go awry in humans, for instance, such malfunctions can cause many types of cancer as well as other diseases. “We’re doing this in yeast, but there’s a lot of conservation (similarity) of these pathways in higher organisms,” Smolke said. “The next step, now that we’ve shown this in simpler systems, is to take this technology into human cell cultures.” The Stanford team’s initial goal was to control the mating behavior of yeast, an activity that, in nature, is influenced by the presence or absence of pheromones. In a series of experiments, Smolke and her collaborators tried various techniques to induce or inhibit yeast mating behavior irrespective of pheromone activity. At first they found that the various techniques they used canceled each other out. But through computational modeling and fine-tuning of the chemical components they were able to build the molecular network diverter by joining three techniques into a unified technology whose elements they call: The transducer, which is an RNA-based system that gathers information about the chemical environment of the cell;The promoter, the molecular agent that helps to initiate and modulate the desired change; andThe pathway regulator, which finds the appropriate point in the cell’s signaling pathway to make the intervention.“The pieces that we used to build this control system existed,” Smolke said. “Combining them in a modular fashion into this molecular network diverter is what’s new.”.."
"The phenomenon of catabolite repression enables microorganisms to use their favourite carbon source first. New work reveals α-ketoacids as key effectors of this process, with their levels regulating gene expression"
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