Collaborative Research: Synthetic and Systems Biology Approaches to Semi-synthetic Cells with Expanded DNA Alphabets

合作研究：具有扩展 DNA 字母表的半合成细胞的合成和系统生物学方法

• 批准号: 2123995
• 负责人: Steven Benner
• 金额: $ 120万
• 依托单位: Foundation for Applied Molecular Evolution, Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2123995&HistoricalAwards=false
• 关键词: Collaborative; Research; Synthetic; Systems; Biology

This project focuses on novel forms of DNA that are not built only from the standard four nucleotides found in natural DNA, but with two or four additional nucleotides, to form an "Artificially Expanded Genetic Information System" (AEGIS). Expanded DNA has already seen widespread use in human diagnostics and environmental surveillance for pathogens. This project will break new ground in developing our understanding of DNA, and develop new technology for business, defense, and health. It will do so by studying the interaction of AEGIS DNA and its components with living microbial cells. As AEGIS can support Darwinian evolution, seen by many as the essence of life, this project will drive a deeper understanding of life. Further, it will allow laboratory evolution of new functional materials, adding evolution and adaptation to points in biotechnology where description and design are inadequate. Finally, this project emphasizes public outreach efforts and the training of early career scientists. This project will complete engineering of bacterial strains that replicate, evolve, and use DNA built not from 4 different nucleotides, but from 6 or 8, DNA in an Artificially Expanded Genetic Information System (AEGIS). These strains, "Second Examples of Genetics Undergoing Evolution" (SEGUE) will use one (or both) of two 6-letter genetic alphabets, GACTKX and GACTZP. A multidisciplinary team of chemists, molecular biologists, philosophers, and bioengineers will exploit comprehensive preliminary data. Here, critical points are integrated to yield results beneficial across multiple platforms:• Broader Impacts in training, outreach, and risk analysis by having direct contact between experiments and those who study the history of and "science of" science.• Work to develop polymerases that replicate AEGIS DNA in vitro and in vivo SEGUE. These will themselves have value in environmental pathogen surveillance, diagnostics, and therapeutic development, as well as the creation of new materials for biotechnology.• Protein engineering to build a metabolic pathway to biosynthesize, inside of living cells, AEGIS triphosphates, allowing AEGIS to be used inexpensively.• Study of interactions between AEGIS and living cells, specifically to identify "third party" genes and regulatory systems that improve the performance and lower the cost of AEGIS in SEGUE.• Broader impacts include the training of experimental scientists in philosophical and ethical features of synthetic biology, iGEM projects, and training for undergraduate and graduate students. The implications throughout science are enormous, and touch on concepts of shadow biospheres, life on Mars and elsewhere in the Solar System, and how life in general is conceived and understood by scientists and the general public alike. Two updated books will provide a framework for thinking about these and other issues, Cleland's "The Quest for a Universal Theory of Life" and Benner's "Life, the Universe, and the Scientific Method." Other outreach materials will include the blog: "Primordial Scoop", which discusses science and technology from philosophical and ethical perspectives. Educational materials will be internationally available, including in classrooms, museums, and planetariums.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目重点关注新形式的 DNA，这些 DNA 不仅由天然 DNA 中发现的标准四个核苷酸构建而成，而且还包含两个或四个额外的核苷酸，以形成“人工扩展遗传信息系统”(AEGIS)。扩展 DNA 已广泛应用于人类诊断和病原体环境监测。 该项目将在加深我们对 DNA 的理解方面开辟新天地，并为商业、国防和健康开发新技术。它将通过研究 AEGIS DNA 及其成分与活微生物细胞的相互作用来实现这一目标。由于 AEGIS 可以支持达尔文进化论，被许多人视为生命的本质，因此该项目将推动对生命的更深入理解。此外，它将允许新功能材料的实验室进化，为生物技术中描述和设计不充分的点添加进化和适应。最后，该项目强调公共宣传工作和对早期职业科学家的培训。该项目将完成细菌菌株的工程设计，这些菌株能够在人工扩展遗传信息系统（AEGIS）中复制、进化并使用不是由 4 种不同核苷酸构建的 DNA，而是由 6 或 8 个 DNA 构建的 DNA。这些菌株“遗传进化的第二个例子”(SEGUE) 将使用两个 6 字母遗传字母 GACTKX 和 GACTZP 之一（或两者）。由化学家、分子生物学家、哲学家和生物工程师组成的多学科团队将利用全面的初步数据。在此，整合关键点以在多个平台上产生有益的结果：• 通过实验与研究科学史和科学“科学”的人员之间的直接联系，对培训、推广和风险分析产生更广泛的影响。• 致力于开发在体外和体内复制 AEGIS DNA 的聚合酶 SEGUE。这些本身在环境病原体监测、诊断和治疗开发以及生物技术新材料的创造方面具有价值。• 蛋白质工程，用于在活细胞内部建立生物合成 AEGIS 三磷酸盐的代谢途径，从而使 AEGIS 的使用成本低廉。• 研究 AEGIS 和活细胞之间的相互作用，特别是识别“第三方”基因和调控系统 提高SEGUE 中AEGIS 的性能并降低其成本。• 更广泛的影响包括对实验科学家进行合成生物学哲学和伦理特征方面的培训、iGEM 项目以及对本科生和研究生的培训。对整个科学的影响是巨大的，涉及影子生物圈、火星和太阳系其他地方的生命的概念，以及科学家和公众如何构思和理解一般生命。两本更新的书将为思考这些问题和其他问题提供一个框架：克莱兰的《生命的普遍理论的探索》和本纳的《生命、宇宙和科学方法》。其他宣传材料将包括博客：“Primordial Scoop”，该博客从哲学和伦理角度讨论科学和技术。教育材料将在全球范围内提供，包括在教室、博物馆和天文馆。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。