Beal Jacob, Weiss Ron, Densmore Douglas, Adler Aaron, Appleton Evan, Babb Jonathan, Bhatia Swapnil, Davidsohn Noah, Haddock Traci, Loyall Joseph, Schantz Richard, Vasilev Viktor, Yaman Fusun
Raytheon BBN Technologies, 10 Moulton St., Cambridge, MA, USA.
ACS Synth Biol. 2012 Aug 17;1(8):317-31. doi: 10.1021/sb300030d. Epub 2012 Jul 17.
We present a workflow for the design and production of biological networks from high-level program specifications. The workflow is based on a sequence of intermediate models that incrementally translate high-level specifications into DNA samples that implement them. We identify algorithms for translating between adjacent models and implement them as a set of software tools, organized into a four-stage toolchain: Specification, Compilation, Part Assignment, and Assembly. The specification stage begins with a Boolean logic computation specified in the Proto programming language. The compilation stage uses a library of network motifs and cellular platforms, also specified in Proto, to transform the program into an optimized Abstract Genetic Regulatory Network (AGRN) that implements the programmed behavior. The part assignment stage assigns DNA parts to the AGRN, drawing the parts from a database for the target cellular platform, to create a DNA sequence implementing the AGRN. Finally, the assembly stage computes an optimized assembly plan to create the DNA sequence from available part samples, yielding a protocol for producing a sample of engineered plasmids with robotics assistance. Our workflow is the first to automate the production of biological networks from a high-level program specification. Furthermore, the workflow's modular design allows the same program to be realized on different cellular platforms simply by swapping workflow configurations. We validated our workflow by specifying a small-molecule sensor-reporter program and verifying the resulting plasmids in both HEK 293 mammalian cells and in E. coli bacterial cells.
我们提出了一种从高级程序规范设计和生产生物网络的工作流程。该工作流程基于一系列中间模型，这些模型逐步将高级规范转化为实现它们的DNA样本。我们确定了在相邻模型之间进行转换的算法，并将其实现为一组软件工具，这些工具被组织成一个四阶段的工具链：规范、编译、部件分配和组装。规范阶段从用Proto编程语言指定的布尔逻辑计算开始。编译阶段使用同样用Proto指定的网络基序库和细胞平台，将程序转换为实现编程行为的优化抽象遗传调控网络（AGRN）。部件分配阶段将DNA部件分配给AGRN，从目标细胞平台的数据库中提取部件，以创建实现AGRN的DNA序列。最后，组装阶段计算出一个优化的组装计划，以从可用的部件样本中创建DNA序列，从而产生一个在机器人辅助下生产工程质粒样本的方案。我们的工作流程是第一个从高级程序规范自动生产生物网络的流程。此外，该工作流程的模块化设计允许通过简单地交换工作流程配置，在不同的细胞平台上实现相同的程序。我们通过指定一个小分子传感器-报告程序并在HEK 293哺乳动物细胞和大肠杆菌细菌细胞中验证所得质粒，验证了我们的工作流程。
