I-Corps: Identifying mutational failure modes of cells

I-Corps：识别细胞的突变失效模式

• 批准号: 1744677
• 负责人: Jeffrey Barrick
• 金额: $ 5万
• 依托单位: University of Texas at Austin
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1744677&HistoricalAwards=false
• 关键词: Corps; Identifying; mutational; failure; modes

The broader impact/commercial potential of this I-Corps project is to lower costs and increase the diversity of biofuels, chemicals, and therapeutics that can be produced by engineered cells that are used as 'living factories' in the biomanufacturing industry. Because cells are alive, they accumulate mutations as they grow. These mutations often reduce or even eliminate a cell's ability to make the product it was designed to manufacture. This project aims to commercialize technology for diagnosing what 'failure' mutations accumulate in these cells during production in large bioreactors. This capability will provide biotech companies with valuable information that they can use to re-engineer cells to prevent mutations from leading to losses of product yield. Thus, it has the potential to speed the progress of many new, renewable biomanufacturing processes from early R&D test stages to economically viable commercial production at scale.This I-Corps project centers on technology that provides diagnostic reports on the genetic stability of cells used in biomanufacturing through a combination of advanced next-generation sequencing and software workflows. This process can identify mutations that lead to a loss of production in a cell population while they are thousands of times rarer than can be detected by standard methods. Mutations that are rare when cells are grown at small scale will become dominant when cells are grown at larger production scales. Many such potential future failure mutations can be profiled in one small bioreactor using this technology. Comprehensively identifying failure mutations earlier in a R&D pipeline in this way such that they can re-engineer cells to prevent these problems before scale-up will save companies developing these processes time and money. This project explores the commercial viability of a service that provides these 'stability reports' to biomanufacturing companies in order to allow them to more rapidly overcome research and development obstacles related to mutations.

这个I-Corps项目的更广泛的影响/商业潜力是降低成本，增加生物燃料，化学品和治疗剂的多样性，这些生物燃料，化学品和治疗剂可以由在生物制造业中用作“活工厂”的工程细胞生产。因为细胞是活的，它们在生长过程中积累突变。这些突变通常会降低甚至消除细胞制造其设计制造的产品的能力。该项目旨在商业化技术，用于诊断在大型生物反应器中生产期间这些细胞中积累的“失败”突变。这种能力将为生物技术公司提供有价值的信息，他们可以使用这些信息来重新设计细胞，以防止突变导致产品产量的损失。因此，它有可能加速许多新的，可再生的生物制造过程的进展，从早期的研发测试阶段到经济上可行的商业化生产。这个I-Corps项目的技术中心，通过先进的下一代测序和软件工作流程的组合，提供生物制造中使用的细胞的遗传稳定性的诊断报告。这个过程可以识别导致细胞群体中生产损失的突变，而这些突变比标准方法检测到的要罕见数千倍。当细胞以小规模生长时罕见的突变将在细胞以更大的生产规模生长时成为显性。许多这种潜在的未来失败突变可以在一个小的生物反应器中使用这种技术进行分析。通过这种方式，在研发管道中更早地全面识别故障突变，以便他们可以在扩大规模之前重新设计细胞以防止这些问题，这将节省公司开发这些工艺的时间和金钱。该项目探讨了向生物制造公司提供这些“稳定性报告”的服务的商业可行性，以便使他们能够更快地克服与突变相关的研发障碍。