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: 2123996
• 负责人: Andrew Ellington
• 金额: $ 129.97万
• 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: 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=2123996&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，以形成已经出现的“人工扩展遗传信息系统”（AEGIS）。该项目将通过研究 AEGIS DNA 及其成分的相互作用，在人类诊断和病原体环境监测方面取得新突破，并为商业、国防和健康开发新技术。由于 AEGIS 可以支持被许多人视为生命本质的达尔文进化论，因此该项目将推动对生命的更深入理解，此外，它将允许实验室进化新的功能材料，增加进化和适应的点。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，这些菌株的复制、进化和使用的 DNA 不是由 4 种不同的核苷酸构建的，而是由 6 种核苷酸构建的。或8，DNA在人工扩展遗传信息系统（AEGIS）。这些菌株“进化中的遗传学的第二个例子”（SEGUE）将使用两个 6 字母遗传字母表中的一个（或两个），GACTKX 和 GACTZP 一个由化学家、分子生物学家组成的多学科团队。 、哲学家和生物工程师将利用全面的初步数据，在多个平台上整合关键点以产生有益的结果：• 在培训、推广和风险分析方面产生更广泛的影响。实验与研究科学历史和“科学”的人们之间有直接联系。• 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、诊断和治疗开发中具有价值。以及用于生物技术的新材料的创建。• 蛋白质工程，用于构建在活细胞内生物合成 AEGIS 三磷酸盐的代谢途径，从而使 AEGIS 的使用成本低廉。• 研究 AEGIS 与活体之间的相互作用细胞，特别是识别“第三方”基因和调控系统，以提高 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 项目以及对对本科生和研究生的影响是巨大的，涉及影子生物圈、火星和太阳系其他地方的生命以及科学家和公众如何构思和理解生命的概念。将提供一个思考这些问题的框架其他外展材料包括克莱兰的“生命的普遍理论的探索”和本纳的“生命、宇宙和科学方法”。教育材料将在国际上提供，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。