Biomolecular computing systems principles, progress and pote

REVIEWS Yaakov Benenson

Biomolecular computing systems: principles, progress and potential 生物分子计算体系:原理、进展和潜力

Abstract 摘要

The task of information processing, or computation, can be performed by natural and man-made ‘devices’. Man-made computers are made from silicon chips, whereas natural ‘computers’, such as the brain, use cells and molecules. Computation also occurs on a much smaller scale in regulatory and signalling pathways in individual cells and even within single biomolecules.

信息处理或计算,可以通过自然的和人造的“装置”实现。人造电脑由硅芯片构成,而自然的“计算机”,如大脑,由细胞和分子构成。计算也可以在更小规模的单个细胞调控和传递信号的通路中进行,甚至可以在单个的生物分子中进行。 Indeed, much of what we recognize as life results from the remarkable capacity of biological building blocks to compute in highly sophisticated ways. Rational design and engineering of biological computing systems can greatly enhance our ability to study and to control biological systems. Potential applications include tissue engineering and regeneration and medical treatments. This Review introduces key concepts and discusses recent progress that has been made in biomolecular computing.

事实上，我们将大部分工作看作是来自于生物模块的非凡能力，能够以一种高度复杂的方式进行计算。生物计算系统的合理的设计和建造可以大大提高我们研究和控制生物系统的能力。其潜在的应用包括组织工程、组织再生和医学治疗等。

本文介绍了生物分子计算的主要概念，并讨论了生物分子计算领域最近的进展。 Any delicately structured system will have difficulty surviving in the world if it is left to its own devices, as it will be subject to malfunction of its complex internal organization and to environmental perturbations. The survival of man-made objects such as aeroplanes or natural objects such as birds crucially depends on internal control mechanisms that counter such damage. These mechanisms have the same stereotypical structure (FIG. 1a): sensors that collect information (input) from inside and outside the system; computers or processors that interpret this information to determine potential damage and to decide on the response; and actuators (output) that carry the response out. In animals, this description applies equally well to the brain, to the immune and homeostasis systems and to the regulatory pathways in individual cells. 任何微妙的结构化系统如果总是依赖于自己的装置，那么他将很难在世界上生存，因为它会受制于自己的复杂内部组织和外界环境的扰动。人造物体像飞机，或自然物体像鸟的生存的关键取决于内部控制机制对于这种扰动的应对。这些机制具有共同的典型结构（图1a）：传感器从体系内部和外部收集信息（输入）；计算机或处理器处理这些信息，确定其潜在的危害，并决定作出响应；执行器（输出）实施响应。在动物中，这样的过程同样适用于大脑、免疫系统和体内平衡系统，包括单个细胞的调控通路。

图 1-a

Beyond the control that living systems require in order to survive, humans have always striven to control and manipulate biological objects to achieve their own goals. Recently, such goals have included engineering of metabolism for bioproduction; controlling the immune system during organ transplantation; manipulating cell differentiation and spatial organization for tissue engineering; and, at the pinnacle of these efforts, controlling myriad aspects of human physiology to treat or cure disease. Here I argue that rational design of biological computation is needed to rapidly advance our ability to exercise such control.

除了生命系统为了存活所需的控制，人们一直想要控制和操纵生物对象来实现自己的目标。最近，这些目标已经包含了生物生产的代谢工程；器官移植过程中免疫系统的控制；组织工程学的细胞分化和空间结构的操纵；这些努力的巅峰，就是控制人体生理学的种种方面来治疗治愈疾病。在这里，我们认为，为了迅速推进人类行使这种控制的能力，生物计算的合理设计是很必要的。

Computation is evident even in single-input–single-output systems, such as a conditional transgene in a mouse or an inducible expression vector, because the specific way in which the inducer and the transgene expression are linked implies a certain mathematical relationship (mapping) between them. However, more intricate multiple-input–multiple-output computations that are able to address complex internal and environmental states and to trigger multiple processes in response are needed to expand the applications of biomolecular engineering.

在单输入单输出系统中的计算是显而易见的，如老鼠体内的条件转基因，或者可诱导的表达载体，因为诱导物和转基因表达之间的特定方式的联系，蕴含着一定的数学关系（映射）。然而，更复杂的多输入多输出计算，能够处理复杂的体内和环境状态，触发多个进程的响应，来扩大生物分子工程的应用。

Accordingly, this Review focuses on the efforts to engineer complex computational modules from molecular and biological building blocks and to furnish these modules with sensors and actuators. First, I introduce some of the potential applications and then explain the theory of molecular computing. I then discuss the progress in biomolecular implementation of different models of computation and highlight key challenges posed by biological settings. I emphasize generally applicable design principles that would allow quick, flexible construction of systems with functions as diverse as drug screening, environmental monitoring or disease diagnosis.

因此，本文的重点在利用分子和生物模块设计复杂的计算模型，并将这些模块和传感器、执行器进行布置。首先介绍一些潜在的应用，然后阐述分子计算理论。接着讨论不同生物分子计算模型的实现的进展如何，着重讨论生物设置构成的关

键性挑战。强调一般通用的设计原则，快速、灵活的系统结构，具备药物筛选、环境监测、疾病诊断等多种多样的功能。

What can be done? 可以做什么呢？

Historically, the concept of a molecular computer dates decades back. First experiments encoded mathematical objects, such as connected graphs, with nucleic acids. These molecules were then biochemically manipulated to generate DNA- or RNA-encoded solutions to small instances of computationally hard problems. Later on, work commenced on autonomous systems, with the explicit vision of their eventual use for biological control. 历史上，分子计算机的概念可以追溯到数十年前。第一个编码数学对象的试验，如核酸构成的连通图。这些分子通过生化操作产生DNA或RNA编码，来解决小实例的计算困难的问题。后来，开始了自治系统的工作，其最终的愿景是用于生物控制。

Autonomous computations were implemented with nucleic acids and protein building blocks reconstituted in simple buffers and occasionally in cell-free extracts. These ‘biochemical’ approaches allowed rapid progress towards increasing complexity and proof-of-concept experiments, demonstrating the potential of information processing with molecules. Parallel efforts have attempted to embed genetically encoded ‘biological’ computing systems in live objects, mainly single cells, using recombinant DNA technology and synthetic biology. Both approaches complement and cross-pollinate each other, constituting a common scientific endeavour

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