Automatic design of digital synthetic gene circuits.
Automatic design of digital synthetic gene circuits.
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DOI：
10.1371/journal.pcbi.1001083
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发表时间：
2011-02
影响因子：
4.3
通讯作者：
Stelling J
中科院分区：
文献类型：
--
作者：
Marchisio MA;Stelling J
实现明确目标功能的合成基因电路的从头计算设计是一项艰巨的任务。现有的强力方法对网络的结构和动力学参数值运行优化算法。然而，目前还缺乏更为直接、合理的自动电路设计方法。围绕数字合成基因电路，我们开发了一种在线自动设计的方法和相应的工具。对于指定电路输入输出关系的给定真值表，我们的算法无需任何优化即可生成并排序多个可能的电路方案。逻辑行为是通过调节因子和化学物质对启动子和生物布尔门的核糖体结合位点的作用而复制的。对具有多达四个输入的电路的仿真表明，即使在参数扰动和随机噪声的情况下，也能真实且毫不含糊地表示真实表。此外，与已经实现的电路进行比较，揭示了具有相同功能的更简单设计的潜力。因此，我们希望该方法有助于设计新的电路和简化现有的解决方案。合成生物学是一门新的学科，旨在构建能够执行特定任务的新的生物系统。按照电子工程的例子，迄今为止实现的大多数合成系统看起来都像电路，其中较小的DNA编码组件通过不同类型的分子交换而相互连接。根据这种模块化的方法，我们在之前的工作中开发了一种工具，用于可视化设计新的遗传电路，其组件显示在计算机屏幕上，并通过假设的分子流动的电线连接起来。在这里，我们提出了这个工具的一个扩展，它通过将电子工程中常用的程序应用于生物学，自动计算数字基因电路的结构-其中输入和输出只取0/1的值。通过这种方式，我们的方法推广和简化了比迄今所实现的复杂得多的遗传电路的设计。此外，与目前使用的其他方法不同，我们的方法限制了优化过程的使用，并大大减少了推导电路结构所需的计算时间。未来的改进可以通过利用更多能够模拟布尔行为的生物机制来实现，而不会大幅增加算法的复杂性。
De novo computational design of synthetic gene circuits that achieve well-defined target functions is a hard task. Existing, brute-force approaches run optimization algorithms on the structure and on the kinetic parameter values of the network. However, more direct rational methods for automatic circuit design are lacking. Focusing on digital synthetic gene circuits, we developed a methodology and a corresponding tool for in silico automatic design. For a given truth table that specifies a circuit's input–output relations, our algorithm generates and ranks several possible circuit schemes without the need for any optimization. Logic behavior is reproduced by the action of regulatory factors and chemicals on the promoters and on the ribosome binding sites of biological Boolean gates. Simulations of circuits with up to four inputs show a faithful and unequivocal truth table representation, even under parametric perturbations and stochastic noise. A comparison with already implemented circuits, in addition, reveals the potential for simpler designs with the same function. Therefore, we expect the method to help both in devising new circuits and in simplifying existing solutions. Synthetic Biology is a novel discipline that aims at the construction of new biological systems able to perform specific tasks. Following the example of electrical engineering, most of the synthetic systems so far realized look like circuits where smaller DNA-encoded components are interconnected by the exchange of different kinds of molecules. According to this modular approach, we developed, in a previous work, a tool for the visual design of new genetic circuits whose components are displayed on the computer screen and connected through hypothetical wires where molecules flow. Here, we present an extension of this tool that automatically computes the structure of a digital gene circuit–where the inputs and the output take only 0/1 values–by applying procedures commonly used in electrical engineering to biology. In this way, our method generalizes and simplifies the design of genetic circuits far more complex than the ones so far realized. Moreover, different from other currently used methods, our approach limits the use of optimization procedures and drastically reduces the computational time necessary to derive the circuit structure. Future improvements can be achieved by exploiting some more biological mechanisms able to mimic Boolean behavior, without a substantial growth of the algorithmic complexity.
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