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  1. Article: Complexity from Simple Building Blocks: Engineering Large-scale Information-processing Networks from Molecules.

    Benenson, Yaakov

    Chimia

    2016  Volume 70, Issue 6, Page(s) 392–394

    Abstract: Complexity in molecular systems can manifest itself either structurally or functionally. One of the more complex functions encountered in the natural world is that of information processing, or computation. Similarly, artificial cells will require this ... ...

    Abstract Complexity in molecular systems can manifest itself either structurally or functionally. One of the more complex functions encountered in the natural world is that of information processing, or computation. Similarly, artificial cells will require this capacity to fully exploit their potential. Here I review the state of the art in the field, describe our contribution to this challenge in the framework of NCCR Molecular Systems Engineering, and propose an outlook for future efforts.
    MeSH term(s) Chemistry ; Drug Discovery ; Macromolecular Substances
    Chemical Substances Macromolecular Substances
    Language English
    Publishing date 2016
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1516-7
    ISSN 0009-4293
    ISSN 0009-4293
    DOI 10.2533/chimia.2016.392
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  2. Article ; Online: Complexity from Simple Building Blocks

    Yaakov Benenson

    CHIMIA, Vol 70, Iss

    Engineering Large-scale Information-processing Networks from Molecules

    2016  Volume 6

    Abstract: Complexity in molecular systems can manifest itself either structurally or functionally. One of the more complex functions encountered in the natural world is that of information processing, or computation. Similarly, artificial cells will require this ... ...

    Abstract Complexity in molecular systems can manifest itself either structurally or functionally. One of the more complex functions encountered in the natural world is that of information processing, or computation. Similarly, artificial cells will require this capacity to fully exploit their potential. Here I review the state of the art in the field, describe our contribution to this challenge in the framework of NCCR Molecular Systems Engineering, and propose an outlook for future efforts.
    Keywords Complexity ; Computation ; Engineering ; Gene circuits ; Information processing ; Chemistry ; QD1-999
    Language German
    Publishing date 2016-06-01T00:00:00Z
    Publisher Swiss Chemical Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Precise determination of input-output mapping for multimodal gene circuits using data from transient transfection.

    Stelzer, Christoph / Benenson, Yaakov

    PLoS computational biology

    2020  Volume 16, Issue 11, Page(s) e1008389

    Abstract: The mapping of molecular inputs to their molecular outputs (input/output, I/O mapping) is an important characteristic of gene circuits, both natural and synthetic. Experimental determination of such mappings for synthetic circuits is best performed using ...

    Abstract The mapping of molecular inputs to their molecular outputs (input/output, I/O mapping) is an important characteristic of gene circuits, both natural and synthetic. Experimental determination of such mappings for synthetic circuits is best performed using stably integrated genetic constructs. In mammalian cells, stable integration of complex circuits is a time-consuming process that hampers rapid characterization of multiple circuit variants. On the other hand, transient transfection is quick. However, it is an extremely noisy process and it is unclear whether the obtained data have any relevance to the input/output mapping of a circuit obtained in the case of a stable integration. Here we describe a data processing workflow, Peakfinder algorithm for flow cytometry data (PFAFF), that allows extracting precise input/output mapping from single-cell protein expression data gathered by flow cytometry after a transient transfection. The workflow builds on the numerically-proven observation that the multivariate modes of input and output expression of multi-channel flow cytometry datasets, pre-binned by the expression level of an independent transfection reporter gene, harbor cells with circuit gene copy numbers distributions that depend deterministically on the properties of a bin. We validate our method by simulating flow cytometry data for seven multi-node circuit architectures, including a complex bi-modal circuit, under stable integration and transient transfection scenarios. The workflow applied to the simulated transient transfection data results in similar conclusions to those reached with simulated stable integration data. This indicates that the input/output mapping derived from transient transfection data using our method is an excellent approximation of the ground truth. Thus, the method allows to determine input/output mapping of complex gene network using noisy transient transfection data.
    MeSH term(s) Algorithms ; Animals ; DNA Copy Number Variations ; Gene Regulatory Networks ; Genes, Reporter ; Humans ; Probability ; Synthetic Biology/methods ; Transfection/methods
    Language English
    Publishing date 2020-11-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1008389
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  4. Article ; Online: Engineering. Recombinatorial logic.

    Benenson, Yaakov

    Science (New York, N.Y.)

    2013  Volume 340, Issue 6132, Page(s) 554–555

    MeSH term(s) Gene Regulatory Networks ; Genetic Engineering ; Transcription, Genetic
    Language English
    Publishing date 2013-05-03
    Publishing country United States
    Document type Comment ; Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1237738
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 27: Show issues Location:
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  5. Article ; Online: Precise determination of input-output mapping for multimodal gene circuits using data from transient transfection.

    Christoph Stelzer / Yaakov Benenson

    PLoS Computational Biology, Vol 16, Iss 11, p e

    2020  Volume 1008389

    Abstract: The mapping of molecular inputs to their molecular outputs (input/output, I/O mapping) is an important characteristic of gene circuits, both natural and synthetic. Experimental determination of such mappings for synthetic circuits is best performed using ...

    Abstract The mapping of molecular inputs to their molecular outputs (input/output, I/O mapping) is an important characteristic of gene circuits, both natural and synthetic. Experimental determination of such mappings for synthetic circuits is best performed using stably integrated genetic constructs. In mammalian cells, stable integration of complex circuits is a time-consuming process that hampers rapid characterization of multiple circuit variants. On the other hand, transient transfection is quick. However, it is an extremely noisy process and it is unclear whether the obtained data have any relevance to the input/output mapping of a circuit obtained in the case of a stable integration. Here we describe a data processing workflow, Peakfinder algorithm for flow cytometry data (PFAFF), that allows extracting precise input/output mapping from single-cell protein expression data gathered by flow cytometry after a transient transfection. The workflow builds on the numerically-proven observation that the multivariate modes of input and output expression of multi-channel flow cytometry datasets, pre-binned by the expression level of an independent transfection reporter gene, harbor cells with circuit gene copy numbers distributions that depend deterministically on the properties of a bin. We validate our method by simulating flow cytometry data for seven multi-node circuit architectures, including a complex bi-modal circuit, under stable integration and transient transfection scenarios. The workflow applied to the simulated transient transfection data results in similar conclusions to those reached with simulated stable integration data. This indicates that the input/output mapping derived from transient transfection data using our method is an excellent approximation of the ground truth. Thus, the method allows to determine input/output mapping of complex gene network using noisy transient transfection data.
    Keywords Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Rational design and construction of multi-copy biomanufacturing islands in mammalian cells.

    Altamura, Raffaele / Doshi, Jiten / Benenson, Yaakov

    Nucleic acids research

    2021  Volume 50, Issue 1, Page(s) 561–578

    Abstract: Cell line development is a critical step in the establishment of a biopharmaceutical manufacturing process. Current protocols rely on random transgene integration and amplification. Due to considerable variability in transgene integration profiles, this ... ...

    Abstract Cell line development is a critical step in the establishment of a biopharmaceutical manufacturing process. Current protocols rely on random transgene integration and amplification. Due to considerable variability in transgene integration profiles, this workflow results in laborious screening campaigns before stable producers can be identified. Alternative approaches for transgene dosage increase and integration are therefore highly desirable. In this study, we present a novel strategy for the rapid design, construction, and genomic integration of engineered multiple-copy gene constructs consisting of up to 10 gene expression cassettes. Key to this strategy is the diversification, at the sequence level, of the individual gene cassettes without altering their protein products. We show a computational workflow for coding and regulatory sequence diversification and optimization followed by experimental assembly of up to nine gene copies and a sentinel reporter on a contiguous scaffold. Transient transfections in CHO cells indicates that protein expression increases with the gene copy number on the scaffold. Further, we stably integrate these cassettes into a pre-validated genomic locus. Altogether, our findings point to the feasibility of engineering a fully mapped multi-copy recombinant protein 'production island' in a mammalian cell line with greatly reduced screening effort, improved stability, and predictable product titers.
    MeSH term(s) Animals ; CHO Cells ; Cricetulus ; Gene Targeting/methods ; Genetic Vectors ; Humans ; Mice ; Recombinant Proteins/genetics ; Transgenes
    Chemical Substances Recombinant Proteins
    Language English
    Publishing date 2021-12-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkab1214
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
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  7. Book ; Online: Precise determination of input-output mapping for multimodal gene circuits using data from transient transfection

    Stelzer, Christoph / Benenson, Yaakov

    2020  

    Keywords info:eu-repo/classification/ddc/570 ; Life sciences
    Language English
    Publishing country ch
    Document type Book ; Online
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  8. Article ; Online: Artificial signaling in mammalian cells enabled by prokaryotic two-component system.

    Mazé, Alain / Benenson, Yaakov

    Nature chemical biology

    2019  Volume 16, Issue 2, Page(s) 179–187

    Abstract: Augmenting live cells with new signal transduction capabilities is a key objective in genetic engineering and synthetic biology. We showed earlier that two-component signaling pathways could function in mammalian cells, albeit while losing their ligand ... ...

    Abstract Augmenting live cells with new signal transduction capabilities is a key objective in genetic engineering and synthetic biology. We showed earlier that two-component signaling pathways could function in mammalian cells, albeit while losing their ligand sensitivity. Here, we show how to transduce small-molecule ligands in a dose-dependent fashion into gene expression in mammalian cells using two-component signaling machinery. First, we engineer mutually complementing truncated mutants of a histidine kinase unable to dimerize and phosphorylate the response regulator. Next, we fuse these mutants to protein domains capable of ligand-induced dimerization, which restores the phosphoryl transfer in a ligand-dependent manner. Cytoplasmic ligands are transduced by facilitating mutant dimerization in the cytoplasm, while extracellular ligands trigger dimerization at the inner side of a plasma membrane. These findings point to the potential of two-component regulatory systems as enabling tools for orthogonal signaling pathways in mammalian cells.
    MeSH term(s) Bacterial Outer Membrane Proteins/genetics ; Bacterial Outer Membrane Proteins/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Gene Expression Regulation ; HEK293 Cells ; Histidine Kinase/genetics ; Histidine Kinase/metabolism ; Humans ; Multienzyme Complexes/genetics ; Multienzyme Complexes/metabolism ; Mutation ; Phosphorylation/genetics ; Protein Domains ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Protein Multimerization/genetics ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Signal Transduction/physiology ; Synthetic Biology/methods ; Tacrolimus Binding Protein 1A/genetics ; Tacrolimus Binding Protein 1A/metabolism ; beta-Arrestins/genetics ; beta-Arrestins/metabolism
    Chemical Substances Bacterial Outer Membrane Proteins ; DNA-Binding Proteins ; Escherichia coli Proteins ; Multienzyme Complexes ; Receptors, G-Protein-Coupled ; Recombinant Fusion Proteins ; beta-Arrestins ; NarL protein, E coli (123940-13-6) ; Protein Kinases (EC 2.7.-) ; Histidine Kinase (EC 2.7.13.1) ; envZ protein, E coli (EC 2.7.3.-) ; narX protein, E coli (EC 2.7.3.-) ; Tacrolimus Binding Protein 1A (EC 5.2.1.-)
    Language English
    Publishing date 2019-12-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-019-0429-9
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  9. Article ; Online: Editorial overview: Tissue, cell and pathway engineering: The advent of complexity.

    Benenson, Yaakov / Lutolf, Matthias P

    Current opinion in biotechnology

    2017  Volume 47, Page(s) iv–vi

    Language English
    Publishing date 2017-10
    Publishing country England
    Document type Editorial
    ZDB-ID 1052045-4
    ISSN 1879-0429 ; 0958-1669
    ISSN (online) 1879-0429
    ISSN 0958-1669
    DOI 10.1016/j.copbio.2017.08.015
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  10. Article ; Online: Biocomputing: DNA computes a square root.

    Benenson, Yaakov

    Nature nanotechnology

    2011  Volume 6, Issue 8, Page(s) 465–467

    MeSH term(s) Computers, Molecular ; DNA, Single-Stranded ; Information Science ; Logic ; Models, Molecular ; Nanotechnology
    Chemical Substances DNA, Single-Stranded
    Language English
    Publishing date 2011-08-04
    Publishing country England
    Document type News
    ZDB-ID 2254964-X
    ISSN 1748-3395 ; 1748-3387
    ISSN (online) 1748-3395
    ISSN 1748-3387
    DOI 10.1038/nnano.2011.128
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