INSPIRE: Modeling and optimization of DNA manufacturing processes

INSPIRE：DNA 制造过程的建模和优化

• 批准号: 1241328
• 负责人: Jean Peccoud
• 金额: $ 99.95万
• 依托单位: Virginia Polytechnic Institute and State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1241328&HistoricalAwards=false
• 关键词: INSPIRE; Modeling; optimization; DNA; manufacturing

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.

该INSPIRE奖的部分资金来自生物科学局生物基础设施部的生物信息学进步计划、工程局民用、机械和制造创新部的制造企业系统计划以及生物科学局分子细胞生物学部的网络和调控集群。弗吉尼亚理工大学获得了一笔赠款，用于评估使用工业和系统工程(ISE)的技术分析DNA制造过程的可行性和好处。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。采用其他行业使用的方法将导致新的工艺规划、监测和控制策略，以满足DNA制造的需要。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，以产生不同类型的结构，说明广泛的制造问题和生物学领域；(3)评估算法，以估计小批量过程中的高错误率，实施监测策略，并比较适用于特定DNA制造问题的不同制造策略的性能；以及(4)为本科生、研究生和博士后提供分子生物学和ISE的交叉培训机会。DNA制造是将天然和化学合成的DNA片段组合在一起，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，即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，如开发突变集合、质粒库和重构基因组。在这种广阔的视角下，大多数生物学家都在实践DNA制造，尽管他们更有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获得的低成本仪器和实验室基础设施。不幸的是，缺乏合适的框架来分析DNA制造正在限制其有效性，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流。没有证据表明以前的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重现了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，生物过程太复杂，不能像物理系统那样用数学模型建模。物理学家和工程师对这一假设的挑战，重新引发了人们对使用ISE工具分析实验室过程的生物学兴趣。这个项目的目标是预测和准备未来15年，届时生物学家将使用工程方法进行比今天可能的数量级更大的实验。提高质量，避免延误和错误，并大幅减少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制造过程代表了许多生命科学专业的过程，这些过程将从该项目的结果中受益。这个项目的回报是生命科学研究企业亟需的生产率提高。在预算紧张的时代，国家研发基础设施需要在财务上更负责任；为了增强美国的竞争力，有必要找到方法，在资源稳定或萎缩的情况下生产更多数据、更多发现和更多应用程序。