Biomolecular computing systems principles, progress and pote(2)

自治计算在缓冲液和偶尔的体外提取物中，通过核酸和蛋白质模块实现重组。这些生化方法面对复杂度和概念验证实验的不断增加，飞速发展，验证了分子进行信息处理的潜力。另一个探究的方向是，利用重组DNA技术和合成生物学，试图将基因编码的生物计算体系嵌入活体对象，主要是单细胞。这两种方法相辅相成，构成了统一的科学奋进号。

Molecular computers could in principle perform diverse monitoring, manipulation and control tasks. A common task is generating a certain physiological effect in a cell conditioned on specific intra- and extracellular cues. The simplest case would reflect the cues’ state at a given time: for example, ‘when gene A is active AND gene B is inactive AND gene C is mutated → generate the effect’ (FIG. 1b).

分子计算机在原则上可以执行多种监控，操作和控制任务。一个常见的工作是在特定的细胞内部或外部的诱因下产生一定的生理效应。最简单的例子是，在给定的时间内反映诱因的状态：例如，当基因A是积极的,基因B是消极的，基因C产生突变→生成效应（图1b）

图1-b

The mapping from the inputs to the effect could be made increasingly elaborate by allowing different sets of conditions to generate the same out-

come or by explicitly considering time, such as ‘gene C got mutated after gene B became inactive and gene A became active’. Furthermore, the mapping could include quantitative thresholds for ‘active’ or ‘inactive’ states, or it could integrate activities gradually. Depending on the application, the effect itself could be ‘all or none’ or gradual. Numerous areas will benefit from these tools, including cell reprogramming, disease diagnosis and treatment, environmental monitoring, tissue engineering and real-time measurements in live cells. A recent example includes a prototype gene circuit that integrates six disease markers to identify and to destroy human cancer cells in culture.

从输入到输出的映射可以通过不同的条件产生相同的输出，或者通过明确的考察时间来逐步精细，如基因C的突变发生在基因B转为消极和A转为积极之后。此外，映射可能包括“积极”态或“消极”态的量化阈值，或者逐步整合活性。根据不同的应用，输出本身可以实现“all”“none”或渐变。许多领域将受益于这些工具，包括细胞重编程，疾病诊断治疗，环境监测，组织工程学和活细胞实时监测。一个最近的例子是一个原型基因电路，集成了六个疾病标签，来识别和消灭培养皿中的癌细胞。

More complex tasks can also be envisaged. For example, a computer could receive a biopolymer such as DNA or RNA as its input and, depending on certain intracellular conditions, could modify or generate a new polymer whose sequence reflects these conditions in complex ways (FIG. 1c). It could be a DNA sequence that records the number of cell divisions, the cell’s history of exposure to toxins or a protein-coding sequence that is altered in response to environmental stress to encode a polypeptide that best copes with this stress. 可以设想更复杂的任务。例如，一个计算机可以接收生物聚合物，如DNA或RNA

作为它的输入，根据细胞内固定的条件，修改或生成一个新的聚合物，其序列以一种复杂的方式反映了这些条件（图1C）。它可能是一个DNA序列，记录细胞分裂的数量，细胞暴露毒素的历史，或者是一个蛋白质编码序列，通过变异来应对环境压力, 通过编码形成一个多肽是应对这种压力最好的处理。

图 1-c

Similar programmed alteration could also occur in regulatory DNA to change gene regulatory programs. These examples constitute a drastic intervention, leading to irreversible genomic modification. Apart from application potential, the capacity to do so is of basic importance because, in the extreme case, this is tantamount to programmable genome alteration by the cell itself. The move from replicating to ‘computing’ the genetic code would greatly enrich our understanding of life.

类似的程序化变更也可以发生在调控DNA中，来改变基因调控程序。这些例子构成一个强烈的干预，导致了不可逆的基因组修饰。除了应用方面的潜力，实现这种做法的能力十分重要，因为在极端情况下，这相当于基于细胞自身的可编程的基因组变更。从复制到“计算”，基因编码将大大丰富我们对生命的理解。 With these examples in mind, I now consider the details of molecular computer design.

通过这些例子,我们现在来细细分析分子计算的细节设计。

The theory of molecular computing 分子计算的理论

Molecular computing theory incorporates elements of systems biology, chemical reaction networks and control theory in order to derive molecular-based solutions of information-processing tasks in a systematic fashion. The derivation (FIG. 1d) can be done at different resolutions: an abstract network diagram; a coarse functional description for individual network nodes (for example, ‘repressor’); a detailed structural assignment; and, ultimately, an experimental setup comprising the species, their amounts and the laboratory protocols.

分子计算理论结合了生物学体系、化学反应网络及控制理论的元素，以获得一个系统的以分子为基础的信息处理的解决方案。这个词源（图1d）可以由不同的决议得到：一个抽象的网络图；对于单个网络节点的一个粗糙的功能性描述（例如，“抑制剂”）；一个详细的结构分配；或者，最终实现一个由物种及相应数量和实验室协议构成的实验装置。

图 1-d

Computer science is instrumental in this process because it deals with systematic problem solving by means of models of computation. Thus, recognizing that a specific task naturally falls under a particular model helps to generate coarse-grained network diagrams. (Their successful translation into biochemical processes, however, depends on ingenuity more than anything else.) A number of biologically relevant models are described below.

计算机科学是在这个过程中是有帮助的，因为它通过计算模型的方式处理系统的问题。因此，我们自然的认识到一个特定的任务是设计一个特定的模型，来产生粗略的网络图。（能够成功转化到生化过程，然而，相比于其他的，能够实现更多的是取决于独创性。）。下面介绍了一些生物方面的模型。

Logic circuits 逻辑电路

Many objectives can be expressed as logic functions. For example, a reporter system that is capable of producing GFP if the cell is in mitosis under osmotic stress needs to compute the logic function ‘GFP = [mitotic marker] AND [osmotic stress marker]’. Logic circuits — a model for computing logic functions — are therefore a useful inspiration for building such reporters. Because any mapping of ‘all or none’ cues to an ‘all or none’ outcome is a logic function, diverse monitoring and control applications in cells can be enabled by systematic approaches to constructing molecular logic circuits.

许多目标可以表示为逻辑功能。例如，一个reporter系统，如果细胞在渗透应力下进行有丝分裂能够产生GFP，需要计算逻辑函数GFP = [有丝分裂标记]AND[渗透应力标记]”。逻辑电路，用于计算逻辑函数的一个模型，是建立一个这样的reporter的有用灵感。因为任何“all 或者 none”的映射对应于一个“all 或

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