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综合技术平台，以在基因组量表上有效，安全地设计生物学。我建议通过三个补充工作包来解决这个雄心勃勃的目标。工作套餐很大且重要，但彼此互补。该愿景的成功交付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师，能够将基于高级的基于语义的功能纳入更高的真核生物基因组设计。 CAD软件将提供序列筛选功能，以识别潜在的有害序列。该序列筛查的发展将与一个由核威胁倡议（NTI），联合国（UN）和世界经济论坛（WEF）支持的国际财团协调，以提高基因组合成和组装的功效，我将应用最先进的机器人技术来监控基因组合成和使用过程工程的自动化，以监视基因组和计划基因组的基因组和计划基因组。我还将开发一种新的并发基因组组装方法来并行结构。从酵母到其他生物的移植合成基因组是一个重大挑战。我将通过开发一个新的标准化模块化装配套件来有效地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，以跨越王国的这些合成染色体穿梭。为了追踪潜在危险的合成基因组，我们将开发基因组隐志，以嵌入可追溯的水印，这些水印是抗侵害的，不会在合成的基因组中干扰正常的细胞生理学，从而最大程度地减少生物恐怖主义的风险，并从生物恐怖量和生物遗传学技术中最小化。转录，推荐和蛋白质稳定性开关以包含合成菌株。我将在允许和限制性条件下表征他们各自的表演。总而言之，我为基因组设计，制造，转移和保护的高度创新和集成的工程平台提供了建议。

项目成果

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

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