INSPIRE: Modeling and optimization of DNA manufacturing processes

该INSPIRE奖的部分资金来自于生物科学局生物基础设施部门的生物信息学进展项目，工程局土木、机械和制造创新部门的制造企业系统项目，以及生物科学局分子细胞生物学部门的网络和监管集群。弗吉尼亚理工大学获得了一笔拨款，用于评估利用工业与系统工程（ISE）的技术分析DNA制造过程的可行性和效益。前提是这些技术可以用来更好地设计、计划、执行和控制DNA制造过程，这种范式的变化将有助于确定DNA制造的首选制造策略。适应其他行业中使用的方法将导致满足DNA制造需求的过程规划、监测和控制的新策略。该项目有四个互补的目标：(1)探索过程的目标和要求，进行功能分析，并调查DNA制造的资源和工作流程策略；(2)实施实验室管道，以生成不同类型的结构，说明广泛的制造问题和生物领域；(3)评估算法以估计小批量过程中的高错误率，实施监控策略，并比较适用于特定DNA制造问题的不同制造策略的性能；(4)为本科生、研究生和博士后提供分子生物学和ISE交叉培训的机会。DNA合成是将天然和化学合成的DNA片段结合在一起，以制造符合计算机设计序列的更大的DNA分子的过程。DNA制造包括基因合成，将化学合成的寡核苷酸组装成双链DNA片段的过程。DNA制造还包括更传统的活动，如突变体收集、质粒文库和重构基因组的开发。从这个广泛的角度来看，大多数生物学家都从事DNA制造，尽管他们更可能称之为分子生物学或基因工程。DNA制造项目依赖于生命科学家通常可以使用的低成本仪器和实验室基础设施。不幸的是，缺乏一个合适的框架来分析DNA制造限制了它的有效性，需要工具来管理这些项目中通常需要的复杂的信息流和材料。以前没有证据表明ISE方法应用于DNA的制造或生命科学中的其他实验室过程。这一新的跨学科机会再现了15年前随着系统生物学的出现而冲击生命科学的革命。生物学家传统上认为，生物过程过于复杂，无法像物理系统那样用数学建模。物理学家和工程师对这一假设的挑战，催化了用ISE工具分析实验室过程的生物学兴趣的更新。该项目的目标是预测和准备，未来15年，生物学家将使用工程方法进行比今天可能的更大数量级的实验。提高质量、避免延误和错误以及大幅缩短实施生物医学发现的时间是美国国立卫生研究院医学研究路线图的主要目标。DNA制造过程是许多生命科学专业过程的代表，这些过程将受益于本项目的结果。该项目的回报是提高生命科学研究企业的生产力。在预算紧张的情况下，国家研发基础设施需要在财政上更负责任；为了提高美国的竞争力，有必要找到方法，以稳定或萎缩的资源生产更多的数据、更多的发现和更多的应用。

This INSPIRE award is partially funded by the Advances in Biological Informatics Program in the Division of Biological Infrastructure in the Directorate for Biological Sciences, the Manufacturing Enterprise Systems Program in the Division of Civil, Mechanical and Manufacturing Innovation in the Directorate for Engineering and the Networks and Regulation Cluster in the Division of Molecular Cellular Biology in the Directorate for Biological Sciences. Virginia Polytechnic University is awarded a grant to evaluate the feasibility and benefits of analyzing DNA fabrication processes by using techniques from Industrial and Systems Engineering (ISE). The premise is that these techniques can be used to better design, plan, execute, and control DNA fabrication processes and that this change of paradigm will help identify preferred manufacturing strategies for DNA fabrication. Adapting approaches used in other industries will lead to new strategies for process planning, monitoring, and control that meet the need of DNA fabrication. The project has four complementary objectives: (1) explore the goals and requirements of the process, conduct functional analysis, and investigate resource and workflow strategies for DNA fabrication; (2) implement laboratory pipelines to generate different types of constructs illustrating a broad range of fabrication problems and biological domains; (3) evaluate algorithms to estimate high-error rates in low volume processes, implement monitoring strategies, and compare the performance of different manufacturing strategies applicable to specific DNA manufacturing problems; and (4) provide cross-training opportunities in molecular biology and ISE for undergraduate students, graduate students, and post-doctoral fellows.DNA fabrication is the process of combining natural and chemically synthetized DNA fragments together in order to make larger DNA molecules that conform to computer-designed sequences. DNA fabrication includes gene synthesis, the process of assembling chemically synthesized oligonucleotides into double- stranded DNA fragments. DNA fabrication also includes more traditional activities, such as the development of mutant collections, plasmid libraries, and refactored genomes. In this broad perspective, most biologists practice DNA fabrication, although they are more likely to call it molecular biology or genetic engineering. DNA fabrication projects rely on low-cost instruments and laboratory infrastructure commonly available to life scientists. Unfortunately, the lack of a suitable framework to analyze DNA fabrication is limiting its effectiveness, requiring tools to manage the complex flows of information and materials typically needed in these projects. There is no evidence of previous application of ISE methods to the fabrication of DNA or other laboratory processes in the life sciences. This new interdisciplinary opportunity reprises the revolution that hit the life sciences 15 years ago with the emergence of systems biology. Biologists have traditionally assumed that biological processes were too complicated to be modeled mathematically like physical systems. Challenges to this assumption among physicists and engineers has catalyzed a renewal of biological interest in analyzing laboratory processes with ISE tools. The goal of this project is to anticipate, and prepare for, the next 15 years when biologists will use engineering methods to perform experiments orders of magnitude larger than is possible today.Improving quality, avoiding delays and errors, and substantially decreasing the time to implementation of biomedical discoveries are prime objectives of the National Institutes of Health Roadmap for Medical Research. DNA fabrication processes are representative of processes across many life science specialties that will benefit from the results of this project. The reward of this project is a much-needed increase in productivity of the life science research enterprise. The national R&D infrastructure needs to be more fiscally responsible in these times of constrained budgets; in order to enhance U.S competitiveness, it is necessary to find ways of producing more data, more discoveries, and more applications with stable or shrinking resources.