by Yuchen Liu,Yayue Zeng,Li Liu,Chengle Zhuang,Xing Fu,Weiren Huang& Zhiming Cai
"The conventional strategy for cancer gene therapy offers limited control of specificity and efficacy. A possible way to overcome these limitations is to construct logic circuits. Here we present modular AND gate circuits based on CRISPR-Cas9 system. The circuits integrate cellular information from two promoters as inputs and activate the output gene only when both inputs are active in the tested cell lines. Using the luciferase reporter as the output gene, we show that the circuit specifically detects bladder cancer cells and significantly enhances luciferase expression in comparison to the human telomerase reverse transcriptase-renilla luciferase construct. We also test the modularity of the design by replacing the output with other cellular functional genes including hBAX, p21 and E-cadherin. The circuits effectively inhibit bladder cancer cell growth, induce apoptosis and decrease cell motility by regulating the corresponding gene. This approach provides a synthetic biology platform for targeting and controlling bladder cancer cells in vitro."
"New research from ETH Zurich has made progress towards achieving bio-computers by developing a biological circuit that controls individual sensory components. Future developments of this technology could enable complex, cancer-hunting bio-computers.
Creating logic-based circuits from biological components has been challenging because of the nature of neural cells and how they interact. While an electronic computer is based on the discrete on and off signals that ones and zeros represent, biological circuits are much less predictable. Action potentials, the primary signal type that is transmitted by neural circuits, are subject to many influences, making signal transfer more unpredictable.
A reliable computer must be predictable, which is what researchers from ETH Zurich (Eidgenössische Technische Hochschule Zürich) may have done for biological computer systems. The technology may soon come to a point where a bio-computer could be feasible, according to a recent press release from the university.
“The ability to combine biological components at will in a modular, plug-and-play fashion means that we now approach the stage when the concept of programming as we know it from software engineering can be applied to biological computers,” said Yaakov Benenson, professor of synthetic biology in the Department of Biosystems Science and Engineering at ETH Zurich in Basel, in the press release. “Bio-engineers will literally be able to program in future.”
The technology combines genetics and signals from a special enzyme — called a recombinase — to activate a biological sensor only when it is signaled to do so. Essentially, the active gene is installed in the biosensor’s DNA in the wrong orientation, which makes it inactive, according to the press release. When a recombinase enzyme is put in the cellular environment, the gene is reoriented into the proper position, making the circuit active.
The new method enables sensors with a dynamic range that is up to 1,000-fold that of the originally configured systems, according to study published by the team in Nature Chemical Biology. The team foresees that this technology may be able to force cancer cells to undergo programmed cell death, while normal cells would remain inactivated.
While controlling the internal cellular machinery may be critical to generating bio-computers, directing and controlling where neurons grow may also be important in the design process. Directing neural cell growth in culture using fluid flow was recently discussed in an article published on Med Device Online."
*Just add water* — *programmable in vitro diagnostics*
by Linda Koch
"Concerns about biosafety, practicality and costs have traditionally confined engineered synthetic gene circuits hosted in living cells to research environments, despite the great potential that these molecular tools hold for biotechnology and medical applications. Now, US researchers have circumvented these difficulties by using porous materials such as paper as host substrates for cell-free synthetic…"
"In the developing world, multi-drug resistant malaria caused by the parasite Plasmodium falciparum is an epidemic that claims the lives of 1–3 million people per year. Artemisinin, a naturally occurring small molecule that has seen little resistance from malarial parasites, is a valuable weapon in the fight against this disease. Several easily accessible artemisinin derivatives, including artesunate and artemether, display potent antimalarial activity against drug-resistant malaria strains; however, the global supply of artemisinin from natural sources alone remains highly inconsistent and unreliable. As a result, several approaches to artemisinin production have been developed, spanning areas such as total synthesis, flow chemistry, synthetic biology, and semi-synthesis. This review highlights achievements in all areas, in addition to the interplay between synthetic biology and synthetic chemistry that has fueled the recent industrial-scale production of artemisinin."
*‘STARFISH’ CRYSTALS COULD LEAD TO 3D-PRINTED PILLS*
by Nicole Casal Moore-Michigan
"Engineers have figured out how to make rounded crystals with no facets, a design that mimics the hard-to-duplicate texture of starfish shells.
The discovery could one day lead to 3D-printed medications that absorb better into the body.
Both the crystals’ shape and the way they’re made—using organic vapor jet printing—have other promising applications, researchers say. The geometry could potentially be useful to guide light in advanced LEDs, solar cells, and nonreflective surfaces...."
"A cell free protein synthesis approach is extensively used for biochemical and synthetic biology researches. Unlike lysate based cell free systems, the PURE system is reconstituted with individually purified factors essential for transcriptional and translational processes. Hence, the components in the PURE system can be definitely manipulated as per the desired situation. Because of this high controllability, the PURE system has been applied to a wide range of research scene, such as biochemical analysis in reconstructed system, in vitro protein engineering, reconstitution of an artificial cell. We believe that this purified cell-free protein synthesis system become a basal technology to advance synthetic biology."
*Mind-controlled transgene expression by a wireless-powered optogenetic designer cell implant*
by Marc Folcher,Sabine Oesterle,Katharina Zwicky,Thushara Thekkottil,Julie Heymoz,Muriel Hohmann,Matthias Christen,Marie Daoud El-Baba,Peter Buchmann& Martin Fussenegger
"Synthetic devices for traceless remote control of gene expression may provide new treatment opportunities in future gene- and cell-based therapies. Here we report the design of a synthetic mind-controlled gene switch that enables human brain activities and mental states to wirelessly programme the transgene expression in human cells. An electroencephalography (EEG)-based brain–computer interface (BCI) processing mental state-specific brain waves programs an inductively linked wireless-powered optogenetic implant containing designer cells engineered for near-infrared (NIR) light-adjustable expression of the human glycoprotein SEAP (secreted alkaline phosphatase). The synthetic optogenetic signalling pathway interfacing the BCI with target gene expression consists of an engineered NIR light-activated bacterial diguanylate cyclase (DGCL) producing the orthogonal second messenger cyclic diguanosine monophosphate (c-di-GMP), which triggers the stimulator of interferon genes (STING)-dependent induction of synthetic interferon-β promoters. Humans generating different mental states (biofeedback control, concentration, meditation) can differentially control SEAP production of the designer cells in culture and of subcutaneous wireless-powered optogenetic implants in mice."
This course focuses on the exploitation of tools and concepts of SynBio for multi-scale engineering of biological systems. The program consists of practicals with two daily lectures on closely related topics.
by Noah Davidsohn , Jacob Beal , Samira Kiani , Aaron Adler , Fusun Yaman , Yinqing Li , Zhen Xie , and Ron Weiss
"A long-standing goal of synthetic biology is to rapidly engineer new regulatory circuits from simpler devices. As circuit complexity grows, it becomes increasingly important to guide design with quantitative models, but previous efforts have been hindered by lack of predictive accuracy. To address this, we developed Empirical Quantitative Incremental Prediction (EQuIP), a new method for accurate prediction of genetic regulatory network behavior from detailed characterizations of their components. In EQuIP, precisely calibrated time-series and dosage-response assays are used to construct hybrid phenotypic/mechanistic models of regulatory processes. This hybrid method ensures that model parameters match observable phenomena, using phenotypic formulation where current hypotheses about biological mechanisms do not agree closely with experimental observations. We demonstrate EQuIP’s precision at predicting distributions of cell behaviors for six transcriptional cascades and three feed-forward circuits in mammalian cells. Our cascade predictions have only 1.6-fold mean error over a 261-fold mean range of fluorescence variation, owing primarily to calibrated measurements and piecewise-linear models. Predictions for three feed-forward circuits had a 2.0-fold mean error on a 333-fold mean range, further demonstrating that EQuIP can scale to more complex systems. Such accurate predictions will foster reliable forward engineering of complex biological circuits from libraries of standardized devices."
"Genetically engineered microbes could help make manned missions to Mars, the moon and other planets more practical, according to a new analysis by UC Berkeley and NASA scientists.
In the cover story of today’s issue of the Journal of the Royal Society Interface, four bioengineers describe how synthetic biology – what some have termed “genetic engineering on steroids” – could allow space travelers to use microbes to produce their own fuel, food, medicines and building materials from raw feedstocks readily available on Mars or the moon, instead of carrying all supplies aboard the spacecraft or making them at the destination with conventional non-biological methods...."
by Konrad Müller , Raphael Engesser , Jens Timmer , Matias D. Zurbriggen , and Wilfried Weber
"Optogenetic gene switches allow gene expression control at an unprecedented spatiotemporal resolution. Recently, light-responsive transgene expression systems that are activated by UV-B, blue or red light have been developed. These systems perform well on their own, but their integration into genetic networks has been hampered by the overlapping absorbance spectra of the photoreceptors. We identified a lack of orthogonality between UV-B and blue light-controlled gene expression as the bottleneck and employed a model-based approach that identified the need for a blue light-responsive gene switch that is insensitive to low-intensity light. Based on this prediction we developed a blue light-responsive and rapidly-reversible expression system. Finally, we employed this expression system to demonstrate orthogonality between UV-B, blue and red/far-red light-responsive gene switches in a single mammalian cell culture. We expect this approach to enable the spatiotemporal control of gene networks and to expand the applications of optogenetics in synthetic biology."