中国合成生物学2035发展战略
  合成生物学因其所具有的革命式、颠覆式创新潜力,已经成为世界各国必争的科技战略高地,正在引发新一轮科技与产业国际竞争。《中国合成生物学 2035 发展战略》力求综合性回顾合成生物学的发展历程并探讨其学科定义,界定学科内涵;多方位反映合成生物学的发展现状及其促进“会聚”研究的科学意义与提升人类“能力”的战略价值;深入分析该新兴学科自 21世纪初创立到今天逐步厘清的关键科学问题、技术瓶颈及社会核心需求,寻求升级发展所面临的严峻挑战,以及抓住“大数据 + 人工智能”和“互联网 +”开源共享平台蓬勃发展的机遇,实现突破,在科技、经济、政治、社会一并进入“百年未有之大变局”的背景下,“不负韶华”承担历史使命的战略思考与策略布局;为进一步强化合成生物技术战略科技工程力量,推动我国合成生物学高质量发展,推动合成生物学及“会聚”研究的生态建设,高效率服务科技与社会发展,提供政策建议的参考。
  本书为相关领域战略与管理专家、科技工作者、企业研发人员及高校师生提供了研究指引,为科研管理部门提供了决策参考,也是社会公众了解合成生物学发展现状及趋势的重要读本。
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总序

  党的二十大胜利召开,吹响了以中国式现代化全面推进中华民族伟大复兴的前进号角。习近平总书记强调“教育、科技、人才是全面建设社会主义现代化国家的基础性、战略性支撑”,明确要求到 2035 年要建成教育强国、科技强国、人才强国。新时代新征程对科技界提出了更高的要求。当前,世界科学技术发展日新月异,不断开辟新的认知疆域,并成为带动经济社会发展的核心变量,新一轮科技革命和产业变革正处于蓄势跃迁、快速迭代的关键阶段。开展面向 2035 年的中国学科及前沿领域发展战略研究,紧扣国家战略需求,研判科技发展大势,擘画战略、锚定方向,找准学科发展路径与方向,找准科技创新的主攻方向和突破口,对于实现全面建成社会主义现代化“两步走”战略目标具有重要意义。

  当前,应对全球性重大挑战和转变科学研究范式是当代科学的时代特征之一。为此,各国政府不断调整和完善科技创新战略与政策,强化战略科技力量部署,支持科技前沿态势研判,加强重点领域研发投入,并积极培育战略新兴产业,从而保证国际竞争实力。

  擘画战略、锚定方向是抢抓科技革命先机的必然之策。当前,新一轮科技革命蓬勃兴起,科学发展呈现相互渗透和重新会聚的趋势,在科学逐渐分化与系统持续整合的反复过程中,新的学科增长点不断产生,并且衍生出一系列新兴交叉学科和前沿领域。随着知识生产的不断积累和新兴交叉学科的相继涌现,学科体系和布局也在动态调整,构建符合知识体系逻辑结构并促进知识与应用融通的协调可持续发展的学科体系尤为重要。

  擘画战略、锚定方向是我国科技事业不断取得历史性成就的成功经验。科技创新一直是党和国家治国理政的核心内容。特别是党的十八大以来,以习近平同志为核心的党中央明确了我国建成世界科技强国的“三步走”路线图,实施了《国家创新驱动发展战略纲要》,持续加强原始创新,并将着力点放在解决关键核心技术背后的科学问题上。习近平总书记深刻指出:“基础研究是整个科学体系的源头。要瞄准世界科技前沿,抓住大趋势,下好‘先手棋’,打好基础、储备长远,甘于坐冷板凳,勇于做栽树人、挖井人,实现前瞻性基础研究、引领性原创成果重大突破,夯实世界科技强国建设的根基。”

  作为国家在科学技术方面最高咨询机构的中国科学院和国家支持基础研究主渠道的国家自然科学基金委员会(简称自然科学基金委),在夯实学科基础、加强学科建设、引领科学研究发展方面担负着重要的责任。早在新中国成立初期,中国科学院学部即组织全国有关专家研究编制了《1956—1967 年科学技术发展远景规划》。该规划的实施,实现了“两弹一星”研制等一系列重大突破,为新中国逐步形成科学技术研究体系奠定了基础。自然科学基金委自成立以来,通过学科发展战略研究,服务于科学基金的资助与管理,不断夯实国家知识基础,增进基础研究面向国家需求的能力。2009 年,自然科学基金委和中国科学院联合启动了“2011—2020 年中国学科发展战略研究”。2012 年,双方形成联合开展学科发展战略研究的常态化机制,持续研判科技发展态势,为我国科技创新领域的方向选择提供科学思想、路径选择和跨越的蓝图。

  联合开展“中国学科及前沿领域发展战略研究(2021—2035)”,是中国科学院和自然科学基金委落实新时代“两步走”战略的具体实践。我们面向 2035 年国家发展目标,结合科技发展新特征,进行了系统设计,从三个方面组织研究工作:一是总论研究,对面向2035 年的中国学科及前沿领域发展进行了概括和论述,内容包括学科的历史演进及其发展的驱动力、前沿领域的发展特征及其与社会的关联、学科与前沿领域的区别和联系、世界科学发展的整体态势,并汇总了各个学科及前沿领域的发展趋势、关键科学问题和重点方向;二是自然科学基础学科研究,主要针对科学基金资助体系中的重点学科开展战略研究,内容包括学科的科学意义与战略价值、发展规律与研究特点、发展现状与发展态势、发展思路与发展方向、资助机制与政策建议等;三是前沿领域研究,针对尚未形成学科规模、不具备明确学科属性的前沿交叉、新兴和关键核心技术领域开展战略研究,内容包括相关领域的战略价值、关键科学问题与核心技术问题、我国在相关领域的研究基础与条件、我国在相关领域的发展思路与政策建议等。

  三年多来,400 多位院士、3000 多位专家,围绕总论、数学等18 个学科和量子物质与应用等 19 个前沿领域问题,坚持突出前瞻布局、补齐发展短板、坚定创新自信、统筹分工协作的原则,开展了深入全面的战略研究工作,取得了一批重要成果,也形成了共识性结论。一是国家战略需求和技术要素成为当前学科及前沿领域发展的主要驱动力之一。有组织的科学研究及源于技术的广泛带动效应,实质化地推动了学科前沿的演进,夯实了科技发展的基础,促进了人才的培养,并衍生出更多新的学科生长点。二是学科及前沿领域的发展促进深层次交叉融通。学科及前沿领域的发展越来越呈现出多学科相互渗透的发展态势。某一类学科领域采用的研究策略和技术体系所产生的基础理论与方法论成果,可以作为共同的知识基础适用于不同学科领域的多个研究方向。三是科研范式正在经历深刻变革。解决系统性复杂问题成为当前科学发展的主要目标,导致相应的研究内容、方法和范畴等的改变,形成科学研究的多层次、多尺度、动态化的基本特征。数据驱动的科研模式有力地推动了新时代科研范式的变革。四是科学与社会的互动更加密切。发展学科及前沿领域愈加重要,与此同时,“互联网 +”正在改变科学交流生态,并且重塑了科学的边界,开放获取、开放科学、公众科学等都使得越来越多的非专业人士有机会参与到科学活动中来。

  “中国学科及前沿领域发展战略研究(2021—2035)”系列成果以“中国学科及前沿领域 2035 发展战略丛书”的形式出版,纳入“国家科学思想库 - 学术引领系列”陆续出版。希望本丛书的出版,能够为科技界、产业界的专家学者和技术人员提供研究指引,为科研管理部门提供决策参考,为科学基金深化改革、“十四五”发展规划实施、国家科学政策制定提供有力支撑。

  在本丛书即将付梓之际,我们衷心感谢为学科及前沿领域发展战略研究付出心血的院士专家,感谢在咨询、审读和管理支撑服务方面付出辛劳的同志,感谢参与项目组织和管理工作的中国科学院学部的丁仲礼、秦大河、王恩哥、朱道本、陈宜瑜、傅伯杰、李树深、李婷、苏荣辉、石兵、李鹏飞、钱莹洁、薛淮、冯霞,自然科学基金委的王长锐、韩智勇、邹立尧、冯雪莲、黎明、张兆田、杨列勋、高阵雨。学科及前沿领域发展战略研究是一项长期、系统的工作,对学科及前沿领域发展趋势的研判,对关键科学问题的凝练,对发展思路及方向的把握,对战略布局的谋划等,都需要一个不断深化、积累、完善的过程。我们由衷地希望更多院士专家参与到未来的学科及前沿领域发展战略研究中来,汇聚专家智慧,不断提升凝练科学问题的能力,为推动科研范式变革,促进基础研究高质量发展,把科技的命脉牢牢掌握在自己手中,服务支撑我国高水平科技自立自强和建设世界科技强国夯实根基做出更大贡献。

“中国学科及前沿领域发展战略研究(2021—2035)”

联合领导小组            

2023 年 3 月            

前言
  合成生物学在合成化学理念基础上被“隐喻”而问世,距今已有超过百年的历史。20世纪70~80年代,在DNA双螺旋模型和“中心法则”理论的指引下,DNA重组、DNA测序、DNA扩增和DNA定点突变等技术的突破和迅速拓展,形成了生命科学的第一次革命,即分子生物学及基因工程革命,“人工合成生命”应势成为合成生物学的“愿景”。20世纪末,人类基因组研究给生命科学带来了第二次革命,实现了对基因组编码的全面“解读”,系统生物学和定量生物学对生物体组成和生命规律的认识达到了前所未有的深度和精度。
  21世纪初,一系列利用生物元件在微生物细胞底盘内构建逻辑线路的成功案例,将工程科学的研究理念引入生命科学;合成生物学被赋予崭新的内涵,并吸引了一批从事工程科学研究的中青年科学家投入到生命科学的研究中来。在习惯于“单兵作战”的生物学研究领域里,形成了多学科交叉、团队协作的工程学研究文化氛围和理念,将生命科学的研究推向“建物致知”的新高度。与此同时,科学家于2006年成功将哺乳动物的成体细胞“重编程”为诱导多能干细胞(induced pluripotent stem cell,iPSC);2010年,全人工合成的约100万碱基对的支原体基因组,成功取代另一支原体细胞基因组,获得可正常生长和分裂的“人造生命”,实现了“撰写”基因组的梦想;而2012年CRISPR/Cas技术的高效利用,颠覆性地实现了对哺乳动物基因组的精准“编辑”。至此,由合成科学、系统科学与工程科学“会聚”而孕育的交叉前沿学科—合成生物学基本成型,迅速发展,并获得广泛关注。
  今天的合成生物学,不仅逐步将对生命系统的研究提升到“可定量、可预测、可合成”的新高度,而且深刻影响物理与化学的发展,引发了一场从根本上提升生命世界(包括人类自身)“能力”的“会聚研究”革命。同时,一系列使能技术(enabling technology)的突破加快了合成生物学的工程化应用,开创了以构建分子机器(体外催化)和细胞工厂(体内催化)为代表的合成生物制造的新兴生物工程领域,揭开了合成生物学“建物致用”的产业前景的“帷幕”。合成生物学的应用迅速向材料、能源等社会经济重要领域和医药、农业、食品等人民健康相关领域拓展,正在形成一个新兴的“产业方向”。
  经过十余年来不同学科与领域专家的合作攻关以及国际合作,我国奠定了较好的合成生物学研究基础,实现了“创造”世界首例单条染色体真核细胞、实现二氧化碳(CO2)到淀粉的人工合成等重大突破,但在底层创新、成果转化和科研生态等方面仍然面临严峻的挑战。从开创新格局的战略思考出发,总结合成生物学发展过程中积累的经验教训,“倒逼”认识合成生物学发展战略布局中的问题,认识实现其核心理论与关键技术工程突破的“瓶颈”,思考实现的方向与途径,探索推进突破所应采用的战略布局、思路方法,乃至文化和政策生态,这就是中国科学院和国家自然科学基金委员会第二次联合启动合成生物学的学科战略研究的“初心”。
  我们组建了由合成生物学领域专家以及文献情报研究人员共同组成的战略研究组。在追溯合成生物学发展历史的基础上,对“合成生物学”的定义做了系统梳理,强调了工程学的“目的导向”以及其特有的理论架构与技术(工程)平台;全面厘清了合成生物学区别于其他生命科学学科的工程科学、生命科学和生物技术内涵;既反映出合成生物学对生命科学研究战略和文化的革命性影响,又阐明了合成生物学技术在工业、农业、健康、能源、环境、材料等领域创新应用所带来的潜在价值和战略意义。我们邀请了国内活跃在合成生物学领域的90多位中青年科学家,开展多轮研讨,回顾各具体领域、方向的发展历史,分析研究与应用的现状和面临的瓶颈问题,进一步明确合成生物学的核心科学问题和“设计生命”的关键理论与技术瓶颈,探讨了我国合成生物学的发展思路、发展目标、优先发展领域及重要研究方向;在此基础上,提出面向2035年,我国合成生物学在基本科学问题、重点技术和应用领域的重点发展方向及政策建议,包括加强顶层设计和基础研究投入支持;利用定量合成生物学的手段,结合基于“大数据”的人工智能,推动生命科学理论研究;聚焦更高效、更精准、更智能的“理性设计”等使能技术以及先进的分析技术;重视合成生物学的工程应用以及与此相关的监管科学发展;夯实多学科专业基础的学科教育和人才培养体系;关注促进“会聚”的生态系统与治理体系的建设等,以保障并促进合成生物学的健康、快速发展。
  当然,面对“合成生物学”这一源自高度会聚(远超越“交叉”)各学科与技术前沿的新兴学科,又具有深度赋能(远超越“转化”)各研究和应用领域的巨大潜力,我们种种努力所能企及的“精准性”、“全面性”和“深刻性”都是有限的。诚盼读者在翻阅之余,拨冗指正。无论是批评意见,还是修改建议,不仅是作者所“渴求”的,也应对我国合成生物学今后的发展大有裨益。
  赵国屏 赵进东
  《中国合成生物学2035发展战略》战略研究组组长
  2022年2月
摘要
  《中国合成生物学2035发展战略》包括“合成生物学的学科起源与发展历程”“合成生物学的科学意义与战略价值”“合成生物学的发展现状”“合成生物学的未来发展”,以及“对我国合成生物学发展的政策建议”五个部分。报告力求综合性回顾合成生物学的发展历程并探讨其学科定义,界定学科内涵;多方位反映合成生物学的发展现状及其促进“会聚”研究的科学意义与提升人类“能力”的战略价值;深入分析该新兴学科自21世纪初创立到今天逐步厘清的关键科学问题、技术瓶颈及社会核心需求,寻求升级发展所面临的严峻挑战,以及抓住“大数据+人工智能”和“互联网+”开源共享平台蓬勃发展的机遇,实现突破,在科技、经济、政治、社会一并进入“百年未有之大变局”的背景下,“不负韶华”,承担历史使命的战略思考与策略布局;为进一步强化合成生物技术战略科技工程力量,推动我国合成生物学高质量发展,合成生物学及“会聚”研究的生态建设,以及高效率服务科技与社会发展,提供政策建议的参考。
  一、合成生物学的学科起源与发展历程
  第一章第一节阐述合成生物学的定义与内涵。2000年,E. 库尔(E. Kool)基于利用细菌基因元件构建逻辑线路的工程科学研究突破,给予了“合成生物学”—这一在19世纪末由合成化学“隐喻”而首创的名词,在20世纪中因“基因克隆”支撑而被赋予“人工合成生命”“愿景”的新兴交叉学科—以工程科学理念研究生命科学的新定义。此后,合成生物学发展迅速,领域日益拓宽,而对这个学科的认识,却依然是“见智见仁”,极难统一。我们在系统梳理各种定义的基础上,对2014年尤恩 卡梅伦(Ewen Cameron)等提出的合成生物学定义进行了调整与补充,强调了工程学对生命体系“自下而上”认识的基本理念,以及在生命科学中采用以工程的“以目的为导向”的迭代研究范式的原理;归纳出了既强调合成生物学本质又反映现阶段合成生物学全貌的一个定义,为进一步的分析奠定基础。
  这个定义是:合成生物学是在工程科学“自下而上”理念的指导下,以创建特定结构功能的工程化生命或实现生命过程的工程化为导向,综合系统、合成、定量、计算与理论科学的手段,以“设计—构建—测试—学习”的迭代研究原理认识生命的理论架构与方法体系。
  该节进一步全面梳理了合成生物学既联系于又区别于其他生命科学与生物技术学科的内涵。合成生物学的核心科学基础,是它的工程科学内涵;但在一定意义上,它又是生命科学与生物技术在基因组学和系统生物学基础上的延伸以及质的飞跃。一方面,合成生物学将原有的以“模拟自然过程”和“遗传工程改造”为基础的生物技术上升到“定量理性设计”和“标准化构建测试”的新高度,把生物工程、代谢工程推向对生命过程的高效率、普适性的工程化研究的新高度,实现“建物致用”,即合成生物学的生物技术内涵。另一方面,在全基因组学和系统生物学基础上创建工程化新生命体系,如人造生命(artifcial life)、正交生命(orthogonal life)等,将为生命科学从整体到局部的“格物致知”“还原论”传统研究策略,提供通过“从创造到理解”的崭新的研究策略,开启“建物致知”理解生命本质的新思路,建立生命科学研究新范式,这就是合成生物学的生命科学内涵。
  上述三个内涵的表述,综合阐明了决定合成生物学核心的“会聚特性”。也就是说,合成生物学会聚了自然科学的“发现能力”,工程科学的“建造能力”,以及技术研发的“发明能力”;从而全面提升社会在科学、技术、工程乃至经济、文化、产业与生态的“创新能力”。由此已经催生并将不断推进生命科学领域正在发生的“会聚研究”的新一轮革命。
  第一章第二节,在追溯合成生物学的“合成科学”、“系统生物学”和“工程科学”等三大起源殊途同归发展史的同时,首先回顾了生物科学对“生命是什么?”这一人类每个文明体系都必须回答的哲学问题,与全人类健康生存繁衍、社会和谐发展密切相关的科学问题,以及与此关联的现代社会和自然相互关系的经济与工程发展的技术问题—经千年而不懈的探索历程。然后,以19世纪自然科学革命实现了从以系统观察、描述、分类研究为基础的动物学、植物学和微生物学为基础的生物科学,向以假说驱动的实验与分析为基础的细胞学、生物化学和遗传学为基础的生命科学的革命性转型;引出20世纪中期生命科学迎来的“分子生物学革命”,与分子生物学共同发展起来的“基因克隆”“DNA测序”“定向突变”等技术,赋予了人类对基因“写”“读”“编”的操控能力,也由此促进了以“基因工程技术”为核心的新一代生物技术与生物工程的蓬勃发展。20 世纪后叶,人类对生命运动本质的研究,由于“基因组学革命”而拓展到计算生物学、定量生物学和系统生物学等领域,最终迎来21 世纪初“合成生物学”的产生—革命性突破的曙光。至此,读者通过第一节关于合成生物学定义与内涵的阐述,可以有一个更为清晰的历史性认识,也为第二章阐述合成生物学的科学意义与战略价值提供了铺垫。同时,在第二节第二部分的阅读中,读者更能感受到2000年以来的二十多年中,这一新兴学科历经四个阶段的强劲发展势头,以及今天所面临的新的挑战和机遇。
  二、合成生物学的科学意义与战略价值
  第二章第一节从合成生物学“催生生命科学的‘会聚研究’范式”,“推动生物技术革命”,以及“提升人类自身能力”三个层次,阐述了合成生物学的科学意义,核心是强调其“革命性”。合成生物学是会聚研究的典型代表;在多学科会聚和“大数据-人工智能”技术的大力推动下,合成生物学在应用“设计—构建—测试—学习”反复迭代的工程科学研究策略中不断强化系统定量的理念,驱动了“假设驱动”与“数据驱动”研究的结合,带来了生命科学研究范式的转变,推动了生物技术的革命;也为开发式研究和新知识体系的建立创造了条件,由此可能提升人类自身的能力,影响人类社会的发展。在此基础上,第二节强调分析合成生物学加速生物学向工程科学转化,有可能为改善人类健康,解决资源、能源、环境等重大问题提供全新解决方案所带来的潜在社会经济价值和战略意义。在简要阐述合成生物学成为世界各国必争的科技战略高地的背景情况后,着重分析了合成生物学将成为我国社会各行各业新的增长点的战略价值,囊括合成生物技术在工业(含材料、能源)、医疗健康、农业食品、环境保护乃至国家安全(国防)领域的创新应用,并将为上述产业带来跨越性乃至颠覆性发展的机遇。
  三、合成生物学的发展现状
  合成生物学因其所具有的革命式、颠覆式创新潜力,已经成为世界各国必争的科技战略高地,正在引发新一轮科技与产业国际竞争。第三章试图针对这个背景情况,从国际与国内两个视角出发,在战略规划、研究平台与机构设置、科技产出、产业发展及人才培养等层次上,综合阐述合成生物学发展的现状。
  美国、英国、澳大利亚、欧盟等国家和组织不断更新和发布相关的研究和技术路线图,加大经费投入并持续支持新的研究项目,建立合成生物学/工程生物学研究中心和平台设施等。在巨大的研发及产业转化的背景下,合成生物学的应用迅速向材料、能源等社会经济重要领域和医药、农业、食品等人民健康相关领域拓展,正在形成一个新兴的“产业方向”,甚至有可能形成新兴的“投资生态圈”。2021年全球全年总共完成近180亿美元的融资,几乎相当于2009~2020年所有融资额的总和;而由于新冠疫情的全球大流行,合成生物学在医疗健康领域、食品营养领域的应用也更加受资本青睐。
  在我国,中央政府部门和科技界高度重视合成生物学的研究。“十二五”期间,国家重点基础研究发展计划(973计划)、国家高技术研究发展计划(863计划)中战略布局了合成生物学的系统发展,并于2018年启动首个国家重点研发计划“合成生物学”重点专项。经过多年发展,我国在合成生物学领域的科学研究、平台设施建设、国际交流合作等方面都取得了长足进步,不仅出现了“创造”世界首例单条染色体真核细胞、CO2到淀粉的从头合成等重大科技进展和突破,而且2020年以来我国的合成生物学初创公司更是迅速发展,投融资高度活跃。在取得显著成绩的同时,应该看到,我国在合成生物学领域的底层创新、成果转化和科研生态等方面与国际领先水平还存在差距,尤其是核心基础理论的突破和关键工程技术的创新有待提高,资源平台及工具的研发及共享有待加强,促进“会聚”和“转化”的激励及评价等政策有待建立和完善。
  四、合成生物学的未来发展
  为充分把握合成生物学领域的国际发展态势和国家战略需求,进一步明晰我国合成生物学领域的发展思路、发展目标、优先发展领域及重要研究方向,第四章从基础科学问题、重点技术主题和应用领域三个方面,回顾了合成生物学细分领域的研究和发展历史,分析了研究现状和水平、面临的瓶颈问题,探讨了未来突破与拓展的主要挑战,冀以凝练我国合成生物学未来中期重点发展方向。
  (一)基础科学问题
  合成生物学的基础科学问题,一方面是解答生命体系结构相变加功能涌现的原理,另一方面是基于上述原理解决生命系统的理性设计与构建的瓶颈问题。在合成生物学研究过程中,通过功能涌现原理已知或未知情形下的不同研究范式总结,讨论合成生物学的定量研究方法,包括基于“定量表征+数理建模”的白箱模型与基于“自动化+人工智能”的黑箱模型;结合“自上而下”的工程研究范式与定量化、理论化研究方法的讨论,提出了定量合成生物学有望推动基础生命科学与合成生物学的双重变革。
  (二)重点技术主题
  重点技术主题分为基因编辑、合成与组装,设计技术,细胞工程,合成生物学先进分析技术,以及合成生物数据库、大数据智能分析与自动化实验五个方向。
  1.基因编辑、合成与组装
  基因组编辑技术是合成生物学的一项核心使能技术。CRISPR 基因组编辑技术在生命科学领域掀起了一场全新的技术革命,但目前CRISPR基因组编辑技术的性能尚有欠缺;智能设计、表达和递送系统等技术还不能满足医疗等应用需求。未来基因组编辑技术的发展,一方面亟待开发更精准、高效、全面和智能的CRISPR基因组编辑技术;另一方面,需利用大数据分析和人工智能技术,不断开发全新的颠覆性基因组编辑技术。
  DNA组装技术是合成生物学的重要基础。随着对DNA序列长度需求的增加,对DNA组装技术也提出更高要求,尤其是快速发展的基因组设计合成领域,需要超大DNA片段的组装技术的支撑。体外拼装的片段大小虽然已可达几百kb,但所得的量依然不足以进行后续实验,在未来的研究过程中,需要开发更加高效的组装方法。大尺度DNA分子组装未来需要不断提高组装效率,降低组装成本并且拓展组装能力,开发新的分子生物学工具,突破长度更大、复杂程度更高的大DNA组装技术等。
  DNA信息存储提供了一种新的存储模式,但其在应用方面仍面临很多挑战。未来发展需要从高效率高质量直接“编”码、低成本高通量信息“写”入、稳定高兼容性分子信息“存”储、实时永久性信息稳定“读”取等方向实现突破。随着DNA信息存储各个问题的逐步解决,或将打开全球海量数据存储的新纪元。
  2.设计技术
  蛋白质结构预测和功能设计致力于解决根据结构设计序列以及根据功能设计结构两个重大问题,其终极目标是利用计算机算法,设计具有所需功能且能够折叠成特定结构的蛋白质。未来一段时间,需要着重发展恰当描述主链运动和更加精确描述侧链构象的表示方法,提高能量函数的准确性和通用性,构建高质量蛋白质标注数据集,推进蛋白质计算设计软件的国产化,摆脱长期以来对国外软件的依赖,构建自主可控的蛋白质计算设计平台。
  人工基因线路设计与构建促进了人们对生命调控基本规律的认识,丰富了对天然生物系统改造、从头设计的手段。然而,人工基因线路与底盘细胞的各种相互作用,却阻碍了人工设计生命系统复杂度的进一步提升。未来研究应重点关注:拓展更加多样的调控元件,开发基于转录组、蛋白质组等多层次的高通量技术,开发新型的全细胞模型,研发元件-宿主隔离技术和策略,开发植物和哺乳动物细胞等高等生物的基因线路移植和定量表征技术等。
  生物合成途径设计的发展,极大提升了生物合成途径的挖掘效率以及微生物细胞工厂的优化效率。随着人工智能与机器学习等技术的进步,未来的生物合成途径设计中需要构建智能化信息更新、可共享的细胞代谢和酶催化数据资源库,研究适用于生物逆合成预测的化合物结构数字化描述方法,解析微生物细胞工厂在不同发酵环境下的组学规律,挖掘并整理与细胞相关的化合物毒性和转运数据库,优化完善细胞模型和代谢数据库,开发高版本数字细胞模型与生物逆合成途径算法等。
  3.细胞工程
  无细胞系统未来发展中,需进一步优化以提高效率、降低成本,同时提高生物大分子合成的个性化、多样化、普适性和稳定性;使用寿命需进一步延长,朝着能够实现自我复制的无细胞合成系统迈进。单细胞工厂未来需要开发通用性底盘细胞,以及高通量、自动化实验技术,实现对细胞工厂的理性设计。微生物组工程应重点发展微生物群落的原位编辑工具,开发微生物群落的精准调控方法,理解合成微生物群落的设计原则,指导构建可控、稳定的微生物互作网络,探索复杂微生物群落的基本科学规律,同时致力于解决人类健康、农业生产等领域的重要问题。非天然系统目前普遍存在翻译效率低、正交性和兼容性差等核心瓶颈。未来研究的重点和难点应针对翻译系统中多种翻译元件的系统性优化改造乃至从头设计,构建具有多个空白密码子的底盘细胞;针对翻译工具和底盘细胞的相互适配原则的探索与优化改造,以及结合这些研究内容实现多种非天然氨基酸在基因组上同时编码。
  4.合成生物学先进分析技术
  多组学技术中,蛋白质组学的发展将主要围绕蛋白质解析技术、新型蛋白质修饰解析技术、定量蛋白质组鉴定分析、超高分辨率解析技术等展开;代谢组学优先发展的方向包括创新发展分析方法、拓展代谢研究的空间维度、建立代谢计算平台等。单细胞技术作为一种细胞功能测试的新手段,需要重点拓展单细胞代谢表型组的应用,开发“靶标分子特异性”与“全景式表型测量”兼顾的单细胞光谱成像,实现单细胞“成像—分选—测序—培养—大数据”全流程的标准化、装备化与智能化。传感技术则需开发代谢物荧光传感普适性技术、多参数单细胞代谢传感技术、生物正交细胞代谢光遗传学控制技术,以及全光型大规模多参数单细胞代谢表型分析技术。活体成像技术未来发展主要包括打破超分辨率成像的时空分辨率极限、实现多模态全景超分辨率成像、发展高通量超分辨率成像、攻关成像核心材料器件、深化深度学习显微成像以及设计更好的新型成像探针。类器官芯片技术需构建典型的类器官芯片系统,促进与多组学技术的深度融合,未来实现“类人”的生命模拟系统构建,以及针对个体化的疾病风险预测、药物药效评价、毒理评估和预后分析。
  5.合成生物数据库、大数据智能分析与自动化实验
  现有合成生物数据库/知识图谱分散、内容完整度差、缺乏统一标准,如何构建标准化合成生物数据库,构建全面、准确的合成生物知识图谱,是亟待解决的关键技术问题。未来,在合成生物数据库和知识图谱方面,需要建立适应大数据时代的新技术和资源体系,建设面向合成生物研究的数据仓库、数据库和知识图谱等,用于合成生物大数据的标准化存储、共享和挖掘分析等;在数据智能分析方面,需要深度集成传统生物信息技术与新型人工智能方法,实现数据驱动的“设计—构建—测试—学习”智能闭环,在系统建模、异构数据集成、智能设计与功能预测等方面实现关键技术突破。
  (三)应用领域
  应用领域主要包括低碳生物合成、合成生物能源、生物活性分子的人工合成及创新应用、健康与医药、农业与食品、纳米与材料、环境等七个方向。
  1.低碳生物合成
  面向“双碳”目标与产业变革的重大需求,提高生物对能量的利用效率,需要在低碳生物合成的基础研究、关键技术、产业应用等方面开展系统研究。面向2035年,需要围绕两个重大突破方面开展深入研究:①推动工业原料路线的代替,以CO2为工业原料,利用可再生能源,形成生物制造路线,实现工业绿色化;②推动农业生产方式的转变,创造利用太阳能将CO2合成为有机物的“非高等植物”新途径,推动“农业工业化”。此外,应尝试建立以太阳能发电为主要能源输入,以CO2为原料的有机物人工合成为主体,形成封闭空间高效物质循环供给模式。
  2.合成生物能源
  合成生物能源面临高昂生产成本和低廉产品价值之间的矛盾、巨大市场需求和较低技术成熟度之间的矛盾,这两种矛盾是当前合成生物能源技术发展及产业应用的关键瓶颈。因此,需要研究生物发酵工艺优化、智能发酵控制、发酵产品分离纯化等,实现合成生物能源的高效低成本生产,从而在与化石能源的竞争中取得优势。未来需要优先发展以下5个方向:纤维素生物燃料整合生物炼制系统设计构建、利用含碳气体人工生物转化系统制备生物燃料、生物甲烷高效转化的多细胞体系设计构建、高效生物产氢体系的设计组装、便携式与植入式生物燃料电池系统创制等。
  3.生物活性分子的人工合成及创新应用
  合成生物学在天然产物研究领域的应用,面临着植物天然产物合成基因元件挖掘困难、工程化微生物的发酵产物市场准入受限、新型天然产物实体库的建立问题。在未来的发展中,需要开发从未知的基因簇出发,逐步建模蛋白质结构、推定蛋白质功能、预测产物结构,最后通过结构上的药效官能团来预测新产物可能的生物活性的生物信息学算法或工具;同时,搭建统一的新型天然产物结构文库,对化合物进行系统且全面的生物活性或靶点的评估。
  4.健康与医药
  在应对传染病方面,病毒性疾病新型研究体系、新型疫苗开发、治疗性抗体设计等领域都取得了一定进展。未来的发展方向包括建立重要新发烈性病毒的研究体系,建立和完善针对病毒大类的基因组信息专用数据库,从头设计抗体分子,开发具有广谱保护活性的T细胞多肽疫苗、包括RNA疫苗的新型核酸疫苗,开发个体生物反应器、蛋白质化学工厂等新技术。
  在应对重大慢性疾病方面,基于人工基因线路的定制细胞疗法和基因治疗推动了重大慢性疾病创新治疗策略的发展。然而,目前基因线路定制细胞的设计与构建主要依靠假设-试错循环的经验性方法。如何设计与构建智能化、自动化的定制细胞和基因线路以满足不同实际应用场景需求是目前亟待解决的瓶颈问题。未来的发展,将利用蛋白质定向进化技术、人工智能化技术在解析底盘细胞生命活动分子机制的基础上,设计动态化感知的智能化基因线路,有效保证癌症、代谢疾病等治疗的安全性、高效性和特异性。
  5. 农业与食品
  农业合成生物技术将为光合作用、生物固氮、生物抗逆、生物转化和未来合成食品等世界性农业生产难题提供革命性解决方案。未来将以人工高效光合、固氮和抗逆等领域为重点突破口,提出三个发展阶段的战略目标。5年近期目标:创制新一代高效根际固氮微生物产品,在田间示范条件下替代化学氮肥25%;光合效率提升30%,生物量提升20%;模式植物耐受2%盐浓度,农作物耐受中度盐碱化、耐旱节水15%。10年中期目标:扩大根瘤菌宿主范围,构建非豆科作物结瘤固氮的新体系,减少化学氮肥用量50%;光合效率提升30%,产量提升10%;农作物耐受中度盐碱化并增产5%~10%、耐旱节水20%。20年远期目标:在逆境条件下大幅度减少化学氮肥,光合效率提升50%,产量提升10%~20%。
  合成生物学在食品领域的应用分为开发非主要营养成分和主要营养成分。非主要营养成分的生产方面,利用合成生物技术生产维生素方面需要进一步提高产量、突破发酵工艺瓶颈,透明质酸、母乳寡糖等的生产需要创建适合于食品工业的细胞工厂,动植物来源的功能性天然产物的生产亟待解决的问题是合成效率低下。主要营养成分方面,功能蛋白需要在质构仿真、营养优化、风味调节等方面实现突破,新植物资源食品的开发目前亟待研究的重点是营养、风味和口感等多个方面的问题,此外,利用CO2,依靠光能或电能生产油脂也是重要的研究方向。
  6. 纳米与材料
  合成生物学工程化的生物源纳米材料已有诸多进展,但在临床转化方面还有很多亟待解决的难题。“仿生命体”虽然原料源充足,但其中一些纳米材料的获取方式还不具有工业生产的普适性,需要增强靶向效率、提高转染率;“半生命体”材料能够在体内实现药效,但在一定程度上也会引起机体的不适或引发新的毒副作用,未来需要监控并纠正药物在体内的不正确状态、提高药物靶向性等;“类生命体”只模仿了生命体的一部分功能,投入到临床使用的最大困难还是技术成熟度的问题。此外,未来不同生物源纳米材料的量产模式和标准化获取路线的建立,以及工程化优化体系的建立等,都将推动该领域的广泛临床应用。
  合成生物技术在推进天然生物组分的异源表达生产、仿生功能材料的模块化设计和功能“活”材料发展方面取得了重要进展。未来需要重点发展的方向主要包括在合成材料中重现天然生物材料的结构和性能、新材料或模块的发现、材料性能的定向进化、工程“活”材料的性能优化、新材料的规模化生产,以及生物合成材料的生物安全问题等。
  7. 环境
  基于合成生物学的环境检测与生物修复技术仍存在一些直接制约大规模实际应用的瓶颈性问题,如应用广泛性、空间适应性、生物安全性等问题。未来优先发展方向包括生物传感与环境检测、污染物多靶点和细胞毒性评价、微生物改造和污染物生物降解、人工多细胞系统构建和生物修复等。
  五、对我国合成生物学发展的政策建议
  为了实现我国合成生物学未来中长期发展目标,充分发挥合成生物学的“赋能”潜质,推动“生物技术革命”和“提升人类自身能力”,不仅需要重新审视现有的研究和开发体系,还迫切要求组织管理模式的变革以及创新生态的建设,从而保证资助机制和管理政策能够与合成生物学的“会聚”特点及“赋能”潜质相匹配。基于系统的调研并整合多方观点,第五章主要从研究开发体系与能力建设、综合治理与科学传播体系、教育与人才培养三方面提出了具体的建议。
  (一)研究开发体系与能力建设
  未来应围绕国家重大战略需求,着眼未来国家竞争力,结合领域发展规律与趋势,加强战略谋划和前瞻布局,通过制定国家中长期发展路线图,有计划、有步骤地开展科学研究和技术开发,既考虑全面、多层次的布局,也突出“高精尖缺”技术;重点支持能力建设,特别是支持合成生物学元件库、数据库,以及专业性、集成性、开放共享的工程技术平台(包括基础设施)建设和核心工具的研发。从我国合成生物学产业发展的需求和目标出发,建立和完善从工程平台到产品开发、产业转化的研发体系与资助保障机制,打通科技成果转化的通道。同时,建立政产学研等多层次、综合性的协作网络,跨领域、跨部门合作的组织模式,以及开放与包容的文化,形成有利于“会聚”的生态系统。
  (二)综合治理与科学传播体系
  合成生物学技术的快速发展,直接带来涉及开源共享与知识产权、市场准入,以及伦理、生物安全(安保)等问题,挑战了传统的管理模式和治理体系。首先,应针对现有管理政策中存在的问题、漏洞和空白,开展长期的监管科学和政策研究,明确相应的主管部门,厘清责权,建立科学、理性、有效、可行的管理原则,制定研发、生产、上市等各环节的配套政策和规范体系,并明确政策衔接、调整、突破或创新的重点。其次,需要从合成生物学的颠覆性特点出发,评估和研判其带来的伦理、生物安全等方面的新风险与新挑战,建立风险防范治理体系。最后,应针对合成生物学科学传播与公众认知/参与的影响因素和有效途径等问题,建立合成生物学各级科普教育基地与科学传播平台,培养专业的合成生物学科普人才和传播队伍,促进合成生物学科技及其产业的健康发展。
  (三)教育与人才培养
  合成生物学的会聚发展,需要创新的教育和人才培养模式。一方面,要进一步加强合成生物学的学科建设,夯实多学科专业基础;通过实施相关的教育计划,逐步建立合成生物学的学科教育体系。另一方面,通过基地(平台)建设与队伍建设相结合,国家及地方的系列人才工程相结合,培养具备跨学科研发能力的人才队伍。

 

  Abstract
  The “2035 Development Strategy of Synthetic Biology in China”includes the following fve parts: the origin and development of synthetic biology, the scientifc signifcance and strategic value of synthetic biology, the development status of synthetic biology, the future development of synthetic biology, as well as the policy suggestions for the development of synthetic biology in China. The report aims to comprehensively review the development process of synthetic biology, explore its disciplinary definitions, and calrify its connotation; reflect its current development status and the scientific significance of promoting “convergence” research, as well as the strategic value of enhancing human “capabilities” from multiple aspects; perform in-depth analysis of the key scientific issues, technological bottlenecks and core social needs that have been gradually clarified since the establishment of this emerging discipline in the early 21st century, the serious challenges facing upgrading and development, seize opportunities to achieve breakthroughs for the vigorous progress of “big data + artifcial intelligence” and “internet+” open-source sharing platform, and undertake the strategic thinking and blueprint of the historical mission, “live it to the fullest”, as the world’s science and technology, economy, politics and society undergo “the greatest changes in a century”; provide reference for policy suggestions in order to further strengthen the strategic science and technological engineering power of synthetic biotechnology; promote the high-quality development of synthetic biology in China and the “convergence” research ecosystem construction of synthetic biology to efectively serve the scientifc and technological and social development. 
  1. The origin and development of synthetic biology
  The first section of Chapter 1 elaborates on the definition and connotations of synthetic biology. Asignifcant breakthrough was made by E. Kool in 2000 using bacterial genetic components to construct logical circuits, and gave a new defnition of “synthetic biology”, which was invented as synthetic chemistry “metaphor” at the end of the 19th century, and later became an interdisciplinary discipline that was given a “vision” of “synthetic life” with the support of “gene cloning” in the 20th century, redefining the study of life sciences with the concept of engineering science. Since then, synthetic biology has developed and expanded rapidly. However, the understanding of this discipline remains controversial, and is extremely difficult to unify. Based on the systematical analysis of various kind of definitions, we adjusted and supplemented the definition of “synthetic biology” proposed by Ewen Cameron et al. in 2014, emphasizing “bottom-up” concept of understanding the life systems, and the engineering science principle of purpose-orientation and iterative research paradigm.The definition emphasizes the essence of synthetic biology and reflects the overall landscape of the feld at current stage, laying the foundation for further analysis. 
  This definition is: synthetic biology is a theoretical framework and methodology for This definition is: synthetic biology is a theoretical framework and methodology for constructing the engineered life with specific structure and functionor for the engineered biological process based on modulization of bio-parts and chassis, under the guidance of engineering science concept. It integrates system science, synthetic science, as well as quantitative research, computational and theoretical scientific approaches to study and understand life systems and process via the “design-build-test-learn” (DBTL) engineering science principle of iterative research paradigm.
  In this section, we further comprehensively sort out the connotations of synthetic biology that are both related to and diferent from other life sciences and biotechnology disciplines. The core scientific foundation of synthetic biology is its engineering science connotation; but to some extent, it is also an extension and qualitative leap of biotechnology in the era of genomics and systems biology. On one hand, synthetic biology has raised the original biological technology based on “simulating natural processes” and “genetic engineering and modifcation” in biotechnology to a new level of “quantitative rational design” and “standardized construction tests”, and push biological engineering and metabolic engineering to a new level of efcient and universal engineering on life processes. This is the biotechnology connotation of synthetic biology. On the other hand, synthetic biology enables technology revolution of creating engineered new life systems(such as artifcial life “protocell”, orthogonal life, etc.) on the basis of whole genomics and systems biology, that will have the potential to revolutionize the traditional life sciences research from the whole to the local “reductionism” strategy of acquiring knowledge to a certain extent, and initiate science research through the “from creation to understanding” research strategy, launching a new way for “building knowledge” to understand the essence of life, establishing a new paradigm of life sciences research. This is the life sciences connotation of synthetic biology.
  The statement of the above three connotations comprehensively clarifies the “convergence characteristics” that determine the core of synthetic biology. That is, synthetic biology brings together the “discovery capability” of natural science, the “building capability” of engineering science, and the “inventive capability” of revolutionary technologies; thus, it comprehensively improves the “innovation capability” of society in science, technology, engineering and even culture, industry, and ecology. This has spawned and will continue to advance a new revolution in the “convergence research” that is taking place in the field of life sciences.
  In the second section of Chapter 1, while tracing the history of the three major origins of synthetic biology—synthetic science, systems biology and engineering science, this report first reviews the question of “What is life?”, a philosophical question that every civilization must answer as well as the scientific question that is closely related to the survival and reproduction of all mankind and the harmonious development of society, and the economic and engineering development within the interrelationship between modern society and nature which has been explored unremittingly for thousands of years. The natural science revolution in the 19th century has brought the revolutionary transition from zoology, botany, and microbiology based on systematic observation, description, and taxonomic research to hypothesis-driven experimentation, analysis-based cytology, biochemistry, and genetics-based life sciences. Based on that, in the middle of the 20th century, the “molecular biology revolution” ushered in by life sciences, together with molecular biology developed “gene cloning”, “DNA sequencing” and “directional mutation” and other technologies enabling humans to control genes “writing”, “reading” and “editing”, and thus forming a new generation of biotechnology and biological engineering with “genetic engineering technology” as the core. In the late 20th century, due to the “genomics revolution”, human research on the nature of the movement of life rose to the research paradigm of computational biology, quantitative biology and systems biology, and finally inaugurated the emergence of “synthetic biology” at the beginning of 21st century, the dawn of a revolutionary breakthrough. At this point, the reader would have a clearer historical understanding of the defnition and connotation of synthetic biology in the first section, also providing a prelude for Chapter 2 to expound the scientific significance and strategic value of synthetic biology. At the same time, the reader will experience the strong momentum of this emerging discipline, in the second part of the second section, through four stages since 2000, as well as the new challenges and opportunities it faces today. 
  2. The scientific significance and strategic value of synthetic biology
  The frst section of Chapter 2 expounds the scientifc signifcance of synthetic biology from three levels—initiating the “convergence research” paradigm in life sciences, promoting the biotechnology revolution, and enhancing human capabilities, the core of which is to emphasize its “revolution”. Synthetic biology is a typical example of convergence research; under the strong impetus of multidisciplinary convergence and “big data-artificial intelligence” technology, synthetic biology not only makes cross-generation “design-build-test-learn” the repeated cycle of iteration with optimization and improvement, but also drives the combination of “hypothesis-driven” and “data-driven” research, bringing a paradigm shift in life sciences research, and promoting the revolution of biotechnology; it also creates platforms for the development-orientated research and the new knowledge system establishment, which might enhance human capabilities and afect the development of human society. On this basis, the second section highlights the major strategic needs of the national economy, human health and national security, and analyzes the potential socio-economic value and strategic signifcance of synthetic biology to accelerate the transformation of biology into engineering science, which may provide new solutions to improve human health and solve major problems on resources, energy and the environment. This section briefly expounds the background that synthetic biology has become a scientific and technological strategic highland that must be contested by all countries; the strategic value of synthetic biology will become a new growth point for all kinds of occupations in China, including the innovative application of synthetic biotechnology in the felds of industry (including materials and energy), medical health, agri-food, environmental protection, and even national security (national defense), which will bring a leap forward and even revolutionary development opportunities for these industries. 
  3. The development status of synthetic biology
  The revolutionary and subversive innovation potential of synthetic biology has become a strategic highland of science and technology that must be contested by all countries in the world, and is triggering a new round of international competition in science, technology and industry. Chapter 3 comprehensively elaborates the status of synthetic biology development at the levels of strategic planning, research platform and institutional setting, scientific and technological output, industrial development and specialist training from international and domestic perspectives.
  The United States, the United Kingdom, Australia, the European Union, and other countries and organizations continue to update and release relevant research and technology roadmaps, increase funding, support new research projects, and establish synthetic biology/engineering biology research center and platform facilities, etc. in a consistent manner. With thremendous research and development and industrial transformation, the application of synthetic biology to materials, energy and other important socio-economic felds and medicine, agriculture, food and other areas related to human health is forming an emerging “industrial direction”, and may even form an emerging “investment ecosystem”. The total number of investment and financing in the field of synthetic biology reached 18 billion dollars in 2021, almost equivalent to the total fnancing from 2009 to 2020. Due to the global COVID-19 pandemic, the application of synthetic biology in the feld of medical health and food nutrition is also more favored by capital.
  In China, the central government departments and the scientifc and technological community put a high premium on the synthetic biology research. During the “Twelfth Five-Year Plan” period, China strategically blueprinted the systematic development of synthetic biology in the 973 plan and the 863 plan, and launched the frst national key research and development plan of “synthetic biology” key special project in 2018. After years of development, China has made great progress in scientifc research, platform facilities construction, international exchanges and cooperation in the field of synthetic biology. Scientists in China have “created” the world’s frst single chromosome eukaryotic cells, achieved de novo synthesis of starch from carbon dioxide and other major scientifc and technological progress and breakthroughs; China’s synthetic biology startups are also developing rapidly, along with highly active investment and financing since 2020. While making remarkable achievements, we should realize the gap between China and the international leading level in terms of underlying innovation, achievement transformation and scientifc research ecosystem in the feld of synthetic biology. Especially the innovation ability of core technologies would need to be improved, the development and sharing of resource platforms and tools need to be strengthened, and the incentive and evaluation policies to promote “convergence” and “transformation” need to be improved. 
  4. The future development of synthetic biology
  In order to fully grasp the international development trend and national strategic needs in the field of synthetic biology, and further clarify the development ideas, development goals, priority development areas and important research directions in the feld of synthetic biology in China, in Chapter 4, we review the research and development history of the subdivision field of synthetic biology from three aspects—basic scientific questions, key technical topics and application fields; and then analyze the current status and level of research, the encountered bottlenecks, and discuss the main challenges of future breakthroughs and expansion,so as to condense the future medium-term key development direction of synthetic biology in China.
  4.1 Basicscientifcquestions
  The basic scientifc questions of synthetic biology are, on one hand, to solve the principle of cross-level emergence of life functions, and on the other hand, to solve the bottleneck problem of rational design and construction of living systems based on the principle of emergence. In the process of synthetic biology research, through the summary of diferent research paradigms under the known or unknown functional emergence principle, the quantitative research methods of synthetic biology are discussed, including the white-box model based on “quantitative characterization + mathematical modeling” and the black-box model based on “automation + artificial intelligence”; combined with the discussion of top-down engineering research paradigms and quantitative and theoretical research methods, quantitative synthetic biology is expected to promote the dual changes of basic life science and synthetic biology.
  4.2 Keytechnicaltopics
  The key technical topics are divided into five parts: gene editing, synthesis and assembly; design technology; cell engineering; advanced analytical techniques of synthetic biology; and synthetic biological database and big data, intelligent analysis of big data and automatic experiment.
  (1)Gene editing, synthesis and assembly
  Genome editing technology is a core enabling technology in synthetic biology. CRISPR genome editing technology has set of a new technological revolution in the feld of life sciences, but the performance of CRISPR genome editing technology is still lacking; technologies such as intelligent design, expression and delivery systems still could not meet the needs of medical applications. In the future, the development of genome editing technology, on the one hand, needs to develop more accurate, efficient, comprehensive and intelligent CRISPR genome editing technology; on the other hand, big data analysis and artificial intelligence technology should be used to continuously develop new and revolutionary genome editing technologies.
  DNA assembly technology is an important foundation of synthetic biology. With the increase in the demand for DNAlength, there are also higher requirements for DNA assembly technology, especially in the rapidly developing feld of genome design and synthesis, which requires the support of assembly technology for ultra-large DNA fragments. Although the size of the fragments assembled in vitro has reached several hundred kb, the amount obtained is still not enough for follow-up experiments,and more efcient assembly methods need to be developed from future research. The future of large-scale DNAmolecular assembly needs to continuously improve assembly efciency, reduce assembly cost and expand assembly capabilities, develop new molecular biology tools, and break through larger DNAassembly technologies with larger length and greater complexity.
  DNA information storage provides a new storage model, but it still faces many challenges in terms of application. The future development needs to achieve breakthroughs from high-efficiency and high-quality direct “code”, low-cost and high-throughput information “write”, stable high-compatibility molecular information “storage”, real-time permanent information stabilization “read”. With the gradual solution of DNA information storage problems, it may open a new era of global massive data storage. 
  (2)Design technology
  Protein structure prediction and functional design are committed to solving the two major problems—designing sequences according to structure and designing structures according to function, and the ultimate goal is to use computer algorithms to design proteins with the required functions and the ability to fold into specific structures. In the future, it is necessary to focus on the development of a representation method that appropriately describes the movement of the main chain and more accurately describes the conformation of the side chain, improve the accuracy and versatility of the energy function, build a high-quality protein labeling dataset, promote the localization of protein computing design software, get rid of the chronic dependence on foreign software, and build an independent and controllable protein computing design platform.
  The design and construction of artifcial gene circuits has promoted people’s understanding on the basic laws of life regulation and enriched the methods of transforming and de novo designing natural biological systems. However, the various interactions between artificial gene circuits and chassis cells hinder the further complexity of artificially designed living systems. Future research should focus on expanding more diverse regulatory elements, developing high-throughput technologies based on multiple levels such as transcriptome and proteome, developing new whole-cell models, developing part-host isolation technologies and strategies, and developing gene route transplantation and quantitative characterization technologies for higher organisms such as plant and mammalian cells. 
  The development of biosynthetic pathway design has greatly improved the mining efficiency of biosynthetic pathways and the optimization efciency of microbial cell factories. With the advancement of artifcial intelligence, machine learning and other technologies, the future design of biosynthetic pathways needs to build intelligent information update, build shareable cell metabolism and enzyme catalytic data resource library, study the digital description method of compound structure suitable for bio-retrosynthesis prediction, analyze the omics rules of microbial cell factories under different fermentation environments, excavate and sort out cell-related compound toxicity and transport databases, optimize and improve cell models and metabolic databases, and develop with higher version digital cell model and bio-resynthetic pathway algorithm, etc.
  (3)Cell engineering
  In the future, the cell-free system needs to be further optimized to improve efficiency, reduce costs, and improve the individualization, diversification, universality and stability of biological macromolecule synthesis; the lifespan of the system needs to be further extended, towards a cell-free synthesis system that can achieve self-replication. In the future, single-cell factories will need to develop universal chassis cells, as well as high-throughput, automated experimental techniques to achieve rational design of cell factories. Microbiome engineering should focus on the development of in situ editing tools for microbial communities, the development of precise regulation methods of microbial communities, the understanding of the design principles of synthetic microbial communities, the guidance of the construction of controllable and stable microbial interaction networks, and the exploration of the basic scientifc laws of complex microbial communities. At the same time, it should also commit to solving important problems in the felds of human health and agricultural production. At present, there are core bottlenecks such as low translation efciency, orthogonality and poor compatibility in non-natural systems. The systematic optimization, transformation and even denovo design of multiple translation elements in the translation system, the construction of chassis cells with multiple blank codons, the exploration and optimization of the principle of mutual adaptation of translation tools and chassis cells, and the realization of simultaneous genetic coding of multiple non-natural amino acids in combination with these research contents will be the focuses and difculties of future research. 
  (4)Advanced analytical techniques of synthetic biology
  In the multi-omics technology, the development of proteomics will mainly focus on techniques for protein identification, new protein modifcation analysis, quantitative proteomic identifcation and analysis, ultra-high resolution determination, etc.; the priority development direction of metabolomics includes innovative development of analytical methods, expanding the spatial dimension of metabolic research, and establishing metabolic computing platforms. As a new method of cell function testing, single-cell technology needs to focus on expanding the application of single-cell metabolic phenotype groups, developing single-cell spectral imaging that takes account of both “target molecular specificity” and “panoramic phenotypic measurement”, and achieving the standardization, equipment and intelligence of the whole process of single-cell “imaging-sorting-sequencing-culturing-big data”. Sensing technology requires the development of metabolite fuorescence sensing universal technology, multi-parameter single-cell metabolic sensing technology, optogenetics control technology of biological orthogonal cell metabolism, and full-optical large-scale multi-parameter single-cell metabolic phenotypic analysis technology. The future development trend of in vivo imaging technology includes breaking the spatio-temporal resolution limit of super-resolution imaging, achieving multimodal panoramic super-resolution imaging, developing high-throughput super-resolution imaging, tackling imaging core material devices, deepening deep learning microscopic imaging, and designing better new imaging probes. Organoid chip technology needs to build a typical organoid on-chip system, promote deep integration with multi-omics technology, and achieve the construction of a “human-like” life simulation system, as well as personalized disease risk prediction, drug efcacy evaluation, toxicological assessment and prognosis analysis in the future. 
  (5)Synthetic biological database, intelligent analysis of big data and automatic experiment 
  The existing synthetic biological databases are scattered, whose content integrity is poor, and lack of unified standards. How to build a standardized synthetic biological database, and a comprehensive and accurate synthetic biological knowledge base is the key technical problem that needs to be solved urgently. In the future, in terms of synthetic biological databases and knowledge graphs, it is necessary to establish new technologies and resource systems adapted to the age of big data, build data warehouses, databases and knowledge graphs for standardized storage, sharing and mining analysis of synthetic biological big data, etc.; in terms of data intelligent analysis, it is necessary to deeply integrate traditional bioinformatic technology and new artificial intelligence methods to achieve data-driven “design-build-test-learn” intelligent closed-loop, and key technological breakthroughs in system modeling, heterogeneous data integration, intelligent design and functional prediction.
  4.3 Areasofapplication
  The application areas of synthetic biology mainly include the following 7 parts: low-carbon biosynthesis, synthetic bioenergy, artifcial synthesis and innovative application of bioactive molecules, health and medicine, agriculture and food, nanometer and materials, and environment. 
  (1)Low-carbon biosynthesis
  To meet the major needs of the “double carbon” goal and industrial transformation, and the need of improving the efficiency of biological energy utilization, it is necessary to carry out systematic research in basic research, key technologies, and industrial applications of low-carbon biosynthesis. Facing 2035, it is necessary to carry out in-depth research around two major breakthroughs: 1)promote the replacement of industrial raw material routes, using CO2 as industrial raw materials, using renewable energy and forming biomanufacturing routes to achieve industrial greening; 2)promote the transformation of agricultural production methods, creating artificial synthetic organisms using solar energy to synthesize CO2 into organic matter according to the principle of photosynthesis, and to achieve “agricultural industrialization”. In addition, the industry should establish an efficient model, with solar power generation as the main energy input and CO2 as the main raw material, to form a material circulation supply in a closed space.
  (2)Synthetic bioenergy
  Synthetic bioenergy faces the contradiction between high production cost and low product value, and that between huge market demand and low technological maturity, which are the key bottlenecks in the development of synthetic bioenergy technology and industrial application. Therefore, it is necessary to study the optimization of biological fermentation process, intelligent fermentation control, separation and purifcation of fermentation products, etc., and to achieve efcient and low-cost production of synthetic bioenergy, thus gaining an advantage in the competition with petrochemical energy. In the future, the following five directions need to be prioritized: the design and construction of integrated biorefning systems for cellulosic biofuels, the preparation of biofuels by artifcial biotransformation systems for carbon-containing gases, the design and construction of multicellular systems for efcient conversion of biomethane, the design and assembly of efcient bio-hydrogen production systems, and the creation of portable and implantable biofuel cell systems.
  (3)Artificial synthesis and innovative application of bioactive molecules
  The application of synthetic biology in the field of natural product research faces the difficulty of mining the synthetic gene elements of plant natural products, the limited market access of fermented products of engineered microorganisms, and the establishment of new natural product entity libraries. In the future, it is necessary to develop bioinformatics algorithms or tools that start from unknown gene clusters, and then gradually model protein structure, infer protein function and predict product structure, and finally predict the possible bioactivity of new products through the pharmacodynamic functional groups on the structure; at the same time, establishing a unifed library of new natural product structures to systematically and comprehensively evaluate the bioactivity or targets of compounds is also necessary.
  (4)Health and medicine
  In terms of dealing with infectious diseases, certain progress has been made in the felds of new research systems for viral diseases, new vaccine development, and therapeutic antibody engineering. The future development direction includes the establishment of a research system for important emerging virulent viruses, the establishment and improvement of a special database for genomic information for virus categories, and the development of new nucleic acid vaccines based on synthetic biology methods, including T cell polypeptide vaccines with broad-spectrum protective activity, mRNAvaccines, antibody molecule de novo engineering, individual bioreactors, and protein chemical factory, etc.
  As for dealing with major chronic diseases, customized cell therapies and gene therapies based on artifcial gene circuits are driving innovative treatment strategies for major chronic diseases. However, the current design and construction of gene loop custom cells relies heavily on empirical approaches to hypothesis-trial-error cycles. Designing and building intelligent and automated customized cells and gene circuits to meet the needs of different practical application scenarios is a bottleneck that needs to be solved urgently. In the future, protein-oriented evolution technology and artifcial intelligence technology will be used to design intelligent gene routes for dynamic perception on the basis of analyzing the molecular mechanism of life activity of chassis cells, that will effectively ensure the safety, efficiency and specificity of cancer, metabolic diseases and other treatments.
  (5)Agriculture and food
  Agricultural synthetic biotechnology will provide revolutionary solutions to worldwide agricultural production difficulties such as photosynthesis, biological nitrogen fxation, biological stress resistance, biotransformation and future synthetic food. In the future, we will focus on the fields of artificial high-efficiency photosynthesis, nitrogen fxation and stress resistance, and put forward strategic goals for 3 stages of development. 5-year short-term goals: to create a new generation of high-efficiency rhizosphere nitrogen-fixing microbial products, to replace chemical nitrogen fertilizers by 25% under field demonstration conditions; to increase photosynthetic efficiency by 30%, to increase biomass by 20%; to tolerate 2% salt concentration of model plants, and to tolerate moderate salinization of crops, and to make drought tolerance and water saving by 15%. 10-year mid-term goals are to expand the host range of rhizobia, to build a new system for nodule nitrogen fixation in non-leguminous crops, to reduce the amount of chemical nitrogen fertilizer by 50%, to increase photosynthetic efficiency by 30%, to increase yield by 10%, to tolerate moderate salinization and increase yield by 5%-10%, and to make drought tolerance and water saving by 20%. 20-year long-term goals: to signifcantly reduce chemical nitrogen fertilizer under adverse conditions, to increase photosynthetic efciency by 50%, and to increase yield by 10% to 20%. 
  Applications of synthetic biology in the food field are divided into the production of non-major nutrients and major nutrients. In terms of the production of non-major application components, the production of vitamins by synthetic biotechnology needs to further improve the yield and break through the bottleneck of the fermentation process; the production of hyaluronic acid, breast milk oligosaccharides, etc. needs to create a cell factory suitable for the food industry, and the production of functional natural products of animal and plant sources needs to be solved urgently. In terms of major nutrient components, functional proteins need to make breakthroughs in texture simulation, nutrition optimization, flavor regulation, etc. The development of new plant resources and foods is currently requiring focusing on nutrition, favor and texture. In addition, the use of carbon dioxide, relying on light energy or electrical energy to produce oils and fats is also an important research direction. 
  (6)Nanometer and materials
  There have been many advances in bio-derived nanomaterials engineered by synthetic biology, but there are still many urgent problems that need to be solved in clinical translation. Although the raw materials of “imitation organisms” are sufficient, some nanomaterials are not yet available in a way that is universally applicable to industrial production, and it is necessary to enhance the targeting and transfection efficiency; “semi-living organisms” materials can achieve efficacy in vivo, but to a certain extent, they would cause discomfort to the body or cause new toxic side effects. Therefore, in the future, it is necessary to monitor and correct the incorrect state of drugs in the body, and to improve drug targeting; “life-like organisms” only imitate part of the functions of living organisms, and the biggest difculty in putting it into clinical use is the question of technological maturity. In addition, the establishment of mass production models and standardized acquisition routes for nanomaterials of diferent biological sources, as well as the establishment of engineering optimization systems, will promote the general clinical application in the future. 
  Synthetic biotechnology has made important progress in promoting the production of heterologous expressions of natural biological components, the modular design of biomimetic functional materials and the development of functional “living” materials. In the future, the key development will be reproducing the structure and properties of natural biomaterials in synthetic materials, the discovery of new materials or modules and the directed evolution of material properties, the optimization of the performance of engineered “living” materials, achieving large-scale production of new materials, and having high-level biosafety of biosynthetic materials, etc.
  (7)Environment
  Environmental monitoring and bioremediation technology based on synthetic biology still have some bottlenecks that directly restrict largescale practical applications, such as application universality, spatial adaptability, biosafety and other issues. Future priority development directions include biosensing and environmental monitoring, multi-target and cytotoxic evaluation of pollutants, microbial modifcation and biodegradation of pollutants, artifcial multicellular system construction and bioremediation, etc.
  5. Policy suggestions for the development of synthetic biology in China
  In order to achieve the future medium- to long-term prospective development goal of synthetic biology in China, to bring the “enabling” potential of synthetic biology into full play,and to promote the “biotechnology revolution” and “human capabilities enhancement”, it is not only necessary to re-examine the existing scientifc and technological research and development framework, but also urgently require the reform of organizational management mode and the construction of innovative ecosystems, so as to ensure the funding mechanism and management framework could match the “convergence” characteristics and “empowerment” potential of synthetic biology. Based on systematic research and integration of multiple perspectives, Chapter 5 mainly puts forward specific suggestions from three aspects—research and development framework and capacity building, comprehensive management and science communication system, and education and specialist training. 
  5.1 Researchanddevelopmentframeworkandcapacitybuilding
  In the future, we should incorporate the major strategic needs of the country, focus on enhancing the nation strength, combine the rules and trends of regional development, strengthen strategic planning and prospective blueprint, and carry out scientifc research and technological development in a planned and systematic manner through the formulation of the national medium- to long-term development roadmap, consider both a comprehensive and multilevel layout and highlight the “high-grade, precise, frontier, and scarce” technology; focus on supporting capacity building, especially support synthetic biology cell library, databases, and professional, integrated, open and shared engineering technology platforms (including infrastructure) construction and development of core utilities. Starting from the needs and goals of the development of China’s synthetic biology industry, we should establish and improve the research and development system and funding guarantee mechanism for engineering platform construction to product development and industrial transformation, and open up the channel for the transformation of scientific and technological achievements. At the same time, we need to establish a multilevel and comprehensive “government-industry-university-research” collaboration network, and to establish an organizational model of cross-feld and cross-departmental cooperation, as well as an open inclusive culture to form an ecosystem conducive to “convergence”. 
  5.2 Comprehensivemanagementandsciencecommunication system
  The rapid development of synthetic biology technology has directly brought concerns involving open-source sharing and intellectual property rights, market access, as well as ethics, bio-safety (security), etc., challenging the traditional management model and governance system. First of all, we should carry out long-term regulatory science and policy research in view of the current management policies, loopholes and gaps; clarify the corresponding competent departments, responsibilities, and rights; establish the scientifc, rational, efective and feasible management principles; formulate supporting policies and normative systems for research and development, production, and product launching; and clarify the focus of policy connection, adjustment, breakthrough, or innovation. Secondly, it is necessary to start from the revolutionary characteristics of synthetic biology, evaluate and assess the new risks and challenges in ethics and biosafety, and establish a risk prevention and governance system. Finally, in view of the influencing factors and efective channels of synthetic biology science communication and public awareness/participation, we should establish synthetic biology science popularization education bases and science communication platforms at all levels, foster professional synthetic biology science popularization specialists and communication teams, and promote prosperity and development of synthetic biology research and its industry. 
  5.3 Educationandspecialisttraining
  The convergence development of synthetic biology requires innovative educational and specialist training models. On the one hand, it is necessary to further strengthen the discipline construction of synthetic biology and consolidate the foundation of multidisciplinary majors. Through the implementation of relevant education programs, the discipline education system of synthetic biology will be gradually established. On the other hand, through the combination of base (platform) construction and team building, and the combination of national and local specialists projects, a specialist team with interdisciplinary research and development capabilities will be fostered.
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