Engineering and safeguarding synthetic genomes

工程和保护合成基因组

• 批准号: EP/V05967X/1
• 负责人: Yizhi Cai
• 金额: $ 171.46万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV05967X%2F1
• 关键词: Engineering; safeguarding; synthetic; genomes

The overarching goal of this proposal is the development of an integrated technological platform for efficiently and safely engineering biology at the genome scale. I propose tackling this ambitious goal with three complementary work packages. Work packages are substantial and significant, but complementary to each other. The successful delivery of this vision will require the coordinated co-developments of all three work packages.First, I will develop a next-generation computer- assisted designer, capable of incorporating high- level, semantics-based features within higher eukaryotic genome design. The CAD software will provide sequence screening functionality to identify potentially harmful sequences. This sequence screening development will be coordinated with an international consortium backed by the Nuclear Threat Initiative (NTI), United Nations (UN) and World Economic Forum (WEF).To improve the efficacy of genome synthesis and assembly, I will apply state-of-the-art robotics for the automation of genome synthesis and use process engineering principles to monitor and schedule genome assembly pipelines. I will also develop a new concurrent genome assembly method to parallelise construction. Transplanting synthetic genomes from yeast to other organisms is a significant challenge. I will tackle this obstacle by developing a new standardised modular assembly kit to efficiently assemble large synthetic chromosomes. I will then exploring and optimising three distinct genome transfer methods to shuttle these synthetic chromosomes across kingdoms. To trace potentially dangerous synthetic genomes, we will develop genomic steganography to embed traceable watermarks, which are tamper-resistant and do not interfere with normal cellular physiology, across synthesised genomes.Finally, to minimise the risk of bioterrorism and bio-error arising from synthetic genome technology, I will develop SafeGuard technologies incorparating genetic code alterations and transcriptional, recom- binational, and protein stability switches to contain synthetic strains. I will characterise their respective performances under permissible and restrictive conditions. In summary, I propose a highly innovative and integrated engineering platform for genome design, manufacture, transfer and safeguarding.

该提案的总体目标是开发一个集成技术平台，以在基因组规模上高效、安全地工程生物学。我建议通过三个互补的工作包来实现这一雄心勃勃的目标。工作包内容丰富、意义重大，但又相互补充。这一愿景的成功实现将需要所有三个工作包的协调共同开发。首先，我将开发下一代计算机辅助设计器，能够将高级的、基于语义的特征纳入高等真核基因组设计中。 CAD 软件将提供序列筛选功能，以识别潜在有害的序列。该序列筛选开发将与由核威胁倡议 (NTI)、联合国 (UN) 和世界经济论坛 (WEF) 支持的国际联盟协调。为了提高基因组合成和组装的效率，我将应用现状-用于基因组合成自动化的最先进的机器人技术，并使用过程工程原理来监控和安排基因组组装管道。我还将开发一种新的并发基因组组装方法来并行构建。将酵母的合成基因组移植到其他生物体是一项重大挑战。我将通过开发一种新的标准化模块化组装套件来有效组装大型合成染色体来解决这一障碍。然后，我将探索和优化三种不同的基因组转移方法，以将这些合成染色体穿梭于各个王国之间。为了追踪潜在危险的合成基因组，我们将开发基因组隐写术，在合成基因组中嵌入可追踪的水印，这些水印是防篡改的，不会干扰正常的细胞生理学。最后，最大限度地减少合成基因组引起的生物恐怖主义和生物错误的风险在基因组技术方面，我将开发包含遗传密码改变和转录、重组和蛋白质稳定性开关的 SafeGuard 技术，以包含合成菌株。我将描述他们各自在允许和限制条件下的表现。总之，我提出了一个用于基因组设计、制造、转移和保护的高度创新和集成的工程平台。

项目成果

Cellular Surveillance: DNA-Based Recording to Monitor and Memorize Biological Events

• DOI: 10.1089/genbio.2023.0018
• 发表时间: 2023-06-01
• 期刊: GEN BIOTECHNOLOGY
• 作者: David，Gabrielle;O'Keefe，Raymond T.;Cai，Yizhi
• 通讯作者: Cai，Yizhi

Engineering stringent genetic biocontainment of yeast with a protein stability switch

• DOI: 10.1101/2022.11.24.517818
• 发表时间: 2023-02
• 期刊: Nature Communications
• 影响因子: 16.6
• 作者: Stefan A. Hoffmann;Yizhi Cai