Amorphous computation with transcription logic gates

要研究的基本概念是如何使生物学适应合理的可编程，以便分子和最终的生物体可以更容易地用于各种研究和商业应用。广泛的遗传可编程性将需要一种新型的生物计算机。“非晶计算机”一词是由麻省理工学院的研究人员创造的，用来描述由大量相同的计算机组成的计算系统，每台计算机都具有有限的处理能力、有限的内存、本地通信、没有先验的位置知识，也没有同步时钟。用“无定形”来形容是恰当的——在这样的计算机上执行算法的结果来自于一个没有形状、看似没有组织的群体。为了实现实际的无定形计算，我们已经建模并开始构建转录逻辑门的二维阵列。在实践中，从一个启动子转录的RNA分子扩散，结合到另一个启动子上，激活或灭活它。这种转录逻辑门的优点是地址空间基本上与核酸序列空间一样大（缩放到4n）。为非晶计算建立一个通用平台的里程碑包括：开发可重复的表面编程测试平台。2. 从固定的“拨动”开关生成模式。3. 产生一种程序化的行为：体育场波。4. 信号放大和传感器功能。通过开发依赖于可扩散的、信息丰富的分子来驱动门结构的算法，我们开始构建运行模块化遗传软件的生物计算机。我们在开发这个软件的过程中获得的原则将会产生远远超出任何单个算法或实例的影响。二维阵列和伴随的分子计算将成为复杂信息系统中反应扩散动力学建模和实验的测试平台。除了放大来自分子传感器的信号（里程碑4），这些实验还解决了纳米技术中的一个关键问题：如何对复杂设备的自组装进行编程。

The basic concept to be investigated is how to adapt biology to being rationally programmable, so that molecules and eventually organisms can be more readily engineered for a variety of research and commercial applications. Extensive genetic programmability will require a new type of biological computer. The term "amorphous computer" was coined by MIT researchers to describe computing systems comprised of very large numbers of identical computers each of which possessed limited processing power, limited memory, local communcation, no a priori knowledge of position, and no synchronizing clock. The description as "amorphous" is apropos - the results of algorithms executing on such computers emerge from a shapeless, seemingly unorganized, mass. In order to implement practical, amorphous computations, we have modeled and are beginning to build two-dimensional arrays of transcriptional logic gates. In practice, RNA molecules transcribed from one promoter diffuse, bind to another promoter, and either activate it or inactivate it. The advantages of such transcriptional logic gates is that the address space is essentially as large as nucleic acid sequence space (scaling to 4n). Milestones that will build towards a generalized platform for amorphous computation include: 1. Developing a reproducible testbed for programming on surfaces. 2. Pattern generation from immobilized 'toggle' switches. 3. Generating a programmed behavior: the stadium wave. 4. Signal amplification and sensor function. By developing algorithms that rely upon diffusible, information rich molecules to actuate gate structures we are beginning to build biological computers that run modular genetic software. The principles that we acquire in developing this software will have an impact well beyond any individual algorithms or instantiations. The 2-D arrays and accompanying molecular computations will become a testbed for both modeling and experimenting with reaction-diffusion kinetics in complex informational systems. Beyond enabling amplification of signals from molecular sensors (Milestone 4), these experiments also address one of the key problems in nanotechnology: how to program the self-assembly of complex devices. PUBLIC HEALTH RELEVANCE: We propose to develop a new type of molecular computer, an amorphous computer. This computer will operate much like organisms do: individual processors (like cells) will be programmed to carry out a limited set of operations (like eating sugar) based on diffusible signals (like the hormone, insulin). However, instead of cells we will use DNA elements as the processors. The DNA elements will make diffusible RNA molecules that will move between, and alter the state and function of, the processors. We suggest a graded approach to the construction of our new type of computer, building from a standardized testbed through a static demonstration of pattern formation to a dynamic demonstration of pattern formation to the application as a sensor for an important protein in the blood, platelet-derived growth factor. The new genetic computer that we develop will be modular and expandable, and will create a new paradigm that allows for the rational development of biological software. The results of these inquiries should help understand development, including how development sometimes goes awry during disease formation, and may assist with building nanoscale devices for therapy and diagnostics.