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      Emerging biomedical applications of synthetic biology

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          Key Points

          • A decade after the report of the first devices, synthetic biology has developed into an engineering science that provides novel opportunities to understand, diagnose, prevent and treat diseases.

          • Chemical synthesis and reconstruction of extinct or difficult-to-propagate viral genomes improves our understanding of virulence factors.

          • The de novo synthesis of deoptimized viral genomes enables the production of safe life vaccines.

          • Engineering environmentally responsive dominant-lethal genetic circuits into disease-transmitting insects provides a highly specific approach for controlling disease propagation.

          • The reconstruction of bacterial resistance circuits in mammalian cells enables the integrated discovery of agents to overcome resistance.

          • Engineered bacteria and synthetic genetic circuits that specifically detect and destroy neoplastic cells will provide momentum to future cancer therapies.

          • Molecular prostheses that detect disease states and autonomously trigger a therapeutic response in a closed-loop control configuration provide novel opportunities in the treatment of genetic and acquired diseases.

          • Synthetic gene circuits will provide novel opportunities for future gene and cell-based therapies.

          Abstract

          Synthetic biological devices can be engineered to achieve high levels of precision and specificity, which makes them ideally suited for use in clinical settings. Devices are being developed to meet a range of biomedical needs, including specific cancer therapies and metabolic control.

          Abstract

          Synthetic biology aims to create functional devices, systems and organisms with novel and useful functions on the basis of catalogued and standardized biological building blocks. Although they were initially constructed to elucidate the dynamics of simple processes, designed devices now contribute to the understanding of disease mechanisms, provide novel diagnostic tools, enable economic production of therapeutics and allow the design of novel strategies for the treatment of cancer, immune diseases and metabolic disorders, such as diabetes and gout, as well as a range of infectious diseases. In this Review, we cover the impact and potential of synthetic biology for biomedical applications.

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          Most cited references132

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          A common mechanism of cellular death induced by bactericidal antibiotics.

          Antibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.
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            Production of the antimalarial drug precursor artemisinic acid in engineered yeast.

            Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l(-1)) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.
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              Identification of functional elements and regulatory circuits by Drosophila modENCODE.

              To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
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                Author and article information

                Contributors
                fussenegger@bsse.ethz.ch
                Journal
                Nat Rev Genet
                Nat. Rev. Genet
                Nature Reviews. Genetics
                Nature Publishing Group UK (London )
                1471-0056
                1471-0064
                29 November 2011
                2012
                : 13
                : 1
                : 21-35
                Affiliations
                [1 ]GRID grid.5963.9, Faculty of Biology, University of Freiburg, ; Schänzlestrasse 1, Freiburg, D-79104 Germany
                [2 ]GRID grid.5963.9, BIOSS Centre for Biological Signalling Studies, University of Freiburg, ; Hebelstrasse 25, Freiburg, D-79104 Germany
                [3 ]GRID grid.5801.c, ISNI 0000 0001 2156 2780, Department of Biosystems Science and Engineering, , ETH Zurich, ; Mattenstrasse 26, Basel, CH-4058 Switzerland
                [4 ]GRID grid.6612.3, ISNI 0000 0004 1937 0642, Faculty of Science, University of Basel, ; Mattenstrasse 26, Basel, CH-4058 Switzerland
                Article
                BFnrg3094
                10.1038/nrg3094
                7097403
                22124480
                e6d84f0b-6bf3-4f5f-a3fd-65563c39974a
                © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2011

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2012

                technology,gene expression,systems biology,synthetic biology,health sciences

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