Cellular Signaling Circuits Interfaced with Synthetic, Post-Translational, Negating Boolean Logic Devices

A negating functionality is fundamental to information processing of logic circuits within cells and computers. Aiming to adapt unutilized electronic concepts to the interrogation of signaling circuits in cells, we first took a bottom-up strategy whereby we created protein-based devices that perform negating Boolean logic operations such as NOT, NOR, NAND, and N-IMPLY. These devices function in living cells within a minute by precisely commanding the localization of an activator molecule among three subcellular spaces. We networked these synthetic gates to an endogenous signaling circuit and devised a physiological output. In search of logic functions in signal transduction, we next took a top–down approach and computationally screened 108 signaling pathways to identify commonalities and differences between these biological pathways and electronic circuits. This combination of synthetic and systems approaches will guide us in developing foundations for deconstruction of intricate cell signaling, as well as construction of biomolecular computers.否定运算功能是细胞与计算机内部逻辑电路信息处理的核心基础。为了将尚未得到应用的电子学概念适配于细胞信号通路的研究，我们首先采用了自下而上的研究策略：构建了基于蛋白质的器件，可执行NOT、NOR、NAND及N-IMPLY等否定型布尔逻辑运算。这类器件可通过精准调控激活分子在三种亚细胞空间中的定位，在一分钟内于活细胞中完成运算。我们将这些合成逻辑门与内源信号通路相连，并设计出了生理输出信号。为了探究信号转导过程中的逻辑功能，我们随后采用了自上而下的研究策略，通过计算筛选了108条信号通路，以厘清这些生物通路与电子电路之间的异同。这种合成与系统研究方法的结合，将为解析复杂的细胞信号通路以及构建生物分子计算机奠定理论基础。