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Complex cellular logic computation using ribocomputing devices

机译：使用核糖计算设备进行复杂的细胞逻辑计算

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摘要

Synthetic biology aims to develop engineering-driven approaches to the programming of cellular functions that could yield transformative technologies(1). Synthetic gene circuits that combine DNA, protein, and RNA components have demonstrated a range of functions such as bistability(2), oscillation(3,4), feedback(5,6), and logic capabilities(7-15). However, it remains challenging to scale up these circuits owing to the limited number of designable, orthogonal, high-performance parts, the empirical and often tedious composition rules, and the requirements for substantial resources for encoding and operation. Here, we report a strategy for constructing RNA-only nanodevices to evaluate complex logic in living cells. Our 'ribocomputing' systems are composed of de-novo-designed parts and operate through predictable and designable base-pairing rules, allowing the effective in silico design of computing devices with prescribed configurations and functions in complex cellular environments. These devices operate at the post-transcriptional level and use an extended RNA transcript to co-localize all circuit sensing, computation, signal transduction, and output elements in the same self-assembled molecular complex, which reduces diffusion-mediated signal losses, lowers metabolic cost, and improves circuit reliability. We demonstrate that ribocomputing devices in Escherichia coli can evaluate two-input logic with a dynamic range up to 900-fold and scale them to four-input AND, six-input OR, and a complex 12-input expression (A1 AND A2 AND NOT A1*) OR (B1 AND B2 AND NOT B2*) OR (C1 AND C2) OR (D1 AND D2) OR (E1 AND E2). Successful operation of ribocomputing devices based on programmable RNA interactions suggests that systems employing the same design principles could be implemented in other host organisms or in extracellular settings.
机译：合成生物学旨在开发工程驱动的方法来编程可产生转化技术的细胞功能（1）。结合了DNA，蛋白质和RNA成分的合成基因电路展示了一系列功能，例如双稳态（2），振荡（3,4），反馈（5,6）和逻辑功能（7-15）。然而，由于有限数量的可设计的，正交的，高性能的部件，经验的和通常乏味的组成规则以及对用于编码和操作的大量资源的要求，仍然难以按比例放大这些电路。在这里，我们报告了一种构建仅RNA的纳米器件以评估活细胞中复杂逻辑的策略。我们的“核计算”系统由创新设计的部件组成，并通过可预测和可设计的碱基配对规则进行操作，从而可以在复杂的蜂窝环境中对具有指定配置和功能的计算设备进行有效的计算机设计。这些设备在转录后水平运行，并使用扩展的RNA转录本将所有电路感测，计算，信号转导和输出元件共定位在同一自组装分子复合物中，从而减少了扩散介导的信号损失，降低了代谢成本，并提高了电路的可靠性。我们证明了大肠杆菌中的核糖计算设备可以评估动态范围高达900倍的两输入逻辑并将其缩放为四输入AND，六输入OR和复杂的12输入表达式（A1 AND A2 AND NOT A1 *）或（B1和B2而非B2 *）或（C1和C2）或（D1和D2）或（E1和E2）。基于可编程RNA相互作用的核糖计算设备的成功运行表明，采用相同设计原理的系统可以在其他宿主生物或细胞外环境中实施。

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  • 来源
    《Nature》 |2017年第7665期|117-121|共5页
  • 作者

    Green Alexander A.; Kim Jongmin; Ma Duo; Ilver Pamela A. S.; Collins James J.; Yin Peng;

  • 作者单位

    Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA|Arizona State Univ, Biodesign Inst, Biodesign Ctr Mol Design & Biomimet, Tempe, AZ 85287 USA|Arizona State Univ, Sch Mol Sci, Tempe, AZ 85287 USA;

    Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA|Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA;

    Arizona State Univ, Biodesign Inst, Biodesign Ctr Mol Design & Biomimet, Tempe, AZ 85287 USA|Arizona State Univ, Sch Mol Sci, Tempe, AZ 85287 USA;

    Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA|Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA;

    Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA|MIT, Dept Biol Engn, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA|MIT, Synthet Biol Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA|Broad Inst & Harvard, Cambridge, MA 02142 USA;

    Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA|Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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