哺乳动物合成生物学在生物医学领域的研究进展

虽然合成生物学还处于早期研究阶段,但最近十年,该领域取得了非常显著的研究进展。合成生物学是以工程学思想为基础,通过人工设计、改造基因线路,从而赋予细胞或生物体新的功能,现已广泛应用于各个领域。随着人们对基因线路设计的深入研究,使得合成生物学研究走向临床应用成为可能。本文将围绕哺乳动物合成生物学在疾病治疗方面的研究进展,介绍基因线路的设计思路和方法、不同诱导因子调控的开环式基因线路以及用于疾病诊疗的闭环式基因环路在生物医学领域的应用。最后对合成生物学走向临床治疗的应用前景和挑战进行展望。     

合成生物学技术在材料科学中的应用

材料是人类赖以生存与发展的物质基础,科技和社会的进步都离不开材料技术的发展,未来先进材料的合成和制备必然朝着绿色可持续、低耗高产出、精细可调控、高效多功能的方向发展。以"基因调控·工程设计"为核心的合成生物学技术从分子、细胞层面极大地推动了生命科学的发展,也已经并继续为材料科学的发展注入新的思路和活力。本文将围绕合成生物学技术在材料科学中的应用,以基因回路设计为核心,概念应用为线索,重点介绍合成生物学技术在高分子生物材料和无机纳米材料领域的开发和生产,细胞展示和蛋白定向进化战略对分子材料的筛选和优化,"活体"功能材料、工程菌调节的人工光合系统功能材料体系以及基因回路在材料科学中的应用。     

The emerging age of cell-free synthetic biology

The engineering of and mastery over biological parts has catalyzed the emergence of synthetic biology. This field has grown exponentially in the past decade. As increasingly more applications of synthetic biology are pursued, more challenges are encountered, such as delivering genetic material into cells and optimizing genetic circuits in vivo. An in vitro or cell-free approach to synthetic biology simplifies and avoids many of the pitfalls of in vivo synthetic biology. In this review, we describe some of the innate features that make cell-free systems compelling platforms for synthetic biology and discuss emerging improvements of cell-free technologies. We also select and highlight recent and emerging applications of cell-free synthetic biology.     

Therapeutic cell engineering: designing programmable synthetic genetic circuits in mammalian cells

Cell therapy approaches that employ engineered mammalian cells for on-demand production of therapeutic agents in the patient’s body are moving beyond proof-of-concept in translational medicine. The therapeutic cells can be customized to sense user-defined signals, process them, and respond in a programmable and predictable way. In this paper, we introduce the available tools and strategies employed to design therapeutic cells. Then, various approaches to control cell behaviors, including open-loop and closed-loop systems, are discussed. We also highlight therapeutic applications of engineered cells for early diagnosis and treatment of various diseases in the clinic and in experimental disease models. Finally, we consider emerging technologies such as digital devices and their potential for incorporation into future cell-based therapies.     

A day of systems and synthetic biology for non‐experts

From understanding ageing to the creation of artificial membrane‐bounded ‘organisms’, systems biology and synthetic biology are seen as the latest revolutions in the life sciences. They certainly represent a major change of gear, but paradigm shifts? This is open to debate, to say the least. For scientists they open up exciting ways of studying living systems, of formulating the ‘laws of life’, and the relationship between the origin of life, evolution and artificial biological systems. However, the ethical and societal considerations are probably indistinguishable from those of human genetics and genetically modified organisms. There are some tangible developments just around the corner for society, and as ever, our ability to understand the consequences of, and manage, our own progress lags far behind our technological abilities. Furthermore our educational systems are doing a bad job of preparing the next generation of scientists and non‐scientists.     

合成生物学中的DNA组装技术

合成生物学旨在应用工程学的研究思路及手段去设计或改造生物系统,是一个综合了科学与工程的拥有发展潜力的新兴学科,在生物医药、农业、能源、环保等方面发挥着巨大作用。DNA组装技术是合成生物学中的关键技术,也是合成生物学快速发展的限制性技术。综述了众多DNA组装技术的发展及其在合成生物学研究中的意义和应用。     

基因组装技术在合成生物学中的应用

基因组装技术是合成生物学领域近年来发展起来的新型技术。它基于大规模基因组数据分析,发现新型的或隐藏的生物活性物质合成基因簇。利用基因组装技术,可提高或激活沉默的生物合成基因簇在微生物中的表达,从而合成潜在的、有价值的生物活性物质。本文旨在阐明最新的体内和体外基因组装技术的设计原理、关键策略及其应用。基因组装技术是合成生物学、代谢工程和功能基因组学研究的重要工具,对生物活性物质的高效生产及合成具有重要意义。     

Synthetic mammalian signaling circuits for robust cell population control

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基于合成基因线路的智能药物

合成生物学自诞生以来对生物学领域的研究产生了重要的影响。利用工程学思维与方法,合成生物学揭开了生命系统许多调控机制,改造并扩展了一系列生物元件,同时带来了广泛的生物医学应用,为疾病诊断与治疗提供了新的思路。本文综述了适用于哺乳动物细胞或者细菌的合成基因线路并用于疾病诊断与治疗领域的最新进展,为未来智能药物设计提供新的思路。     

从DNA合成技术角度阐述合成生物学

合成生物学是一个拥有巨大潜力的新兴学科,合成生物学技术的发展将会对未来生物、医药、农业、能源、材料和环保等方面产生巨大的推进作用。基因合成是合成生物学中最基本和使用最多的一种技术手段,合成生物学的快速发展对基因合成能力提出了空前需求。综述基因合成技术的发展历史、现状和未来趋势,探讨基因合成技术存合成生物学以及整个生命科学研究中的应用和重要意义。     

2017合成生物学专刊序言

近10年来,合成生物学的发展受到广泛关注。为了集中报道本领域的最新研究进展,特组织出版了此合成生物学专刊。本专刊分3个栏目:科学意义、新技术新方法和应用领域,重点介绍了合成生物学的科学内涵、技术方法进步及合成生物学在医学、药物、农业、材料、环境和能源等领域的应用前景。     

Orthogonal control of endogenous gene expression in mammalian cells using synthetic ligands

Gene switches have wide utility in synthetic biology, gene therapy, and developmental biology, and multiple orthogonal gene switches are needed to construct advanced circuitry or to control complex phenotypes. Endogenous vascular endothelial growth factor (VEGF‐A) is crucial to angiogenesis, and it has been shown that multiple alternately spliced VEGF‐A isoforms are necessary for proper blood vessel formation. Such a necessity limits the utility of direct transgene delivery, which can provide only one splice variant. To overcome this limitation, we constructed a gene switch that can regulate the (VEGF‐A) locus in mammalian cells by combining an engineered estrogen receptor (ER) ligand‐binding domain (LBD), a p65 activation domain, and an artificial zinc‐finger DNA binding domain (DBD). Our gene switch is specifically and reversibly controlled by 4,4′‐dyhydroxybenzil (DHB), a small molecule, non‐steroid synthetic ligand, which acts orthogonally in a mammalian system. After optimization of the gene switch architecture, an endogenous VEGF‐A induction ratio of >100‐fold can be achieved in HEK293 cells at 1 µM DHB, which is the highest endogenous induction reported to date. In addition, induction has been shown to be reversible, repeatable, and sustainable. Another advantage is that the ligand response is tunable by varying the clonal composition of a stably integrated cell line. The integration of our findings with the technology to change ligand specificity and DNA binding specificity will provide the framework for generating a wide array of orthogonal gene switches that can control multiple genes with multiple orthogonal ligands. Biotechnol. Bioeng. 2013; 110: 1419–1429. © 2012 Wiley Periodicals, Inc.     

匹诺塞林合成生物学研究进展

匹诺塞林是一种广泛存在于植物中的黄酮类化合物,具有很好的生物活性,如神经保护、抗菌、抗氧化等。2009年,匹诺塞林被CFDA批准为Ⅰ类注射新药,主要用于治疗急性脑卒中,现已经进入Ⅱ期临床试验阶段。匹诺塞林的良好成药性使其合成方法备受关注。匹诺塞林可以通过化学合成、植物提取和合成生物学技术制备。合成生物学技术是一种环境友好的工程化生物技术,代表未来匹诺塞林的合成发展方向。文中总结了利用合成生物学技术制备匹诺塞林的研究现状,并从选择酶的物种来源、提高丙二酰Co A含量、选择经济的底物及减弱中间产物的抑制作用等角度系统地总结了提高微生物合成匹诺塞林的策略。     

Identification of line‐specific strategies for improving carotenoid production in synthetic maize through data‐driven mathematical modeling

Plant synthetic biology is still in its infancy. However, synthetic biology approaches have been used to manipulate and improve the nutritional and health value of staple food crops such as rice, potato and maize. With current technologies, production yields of the synthetic nutrients are a result of trial and error, and systematic rational strategies to optimize those yields are still lacking. Here, we present a workflow that combines gene expression and quantitative metabolomics with mathematical modeling to identify strategies for increasing production yields of nutritionally important carotenoids in the seed endosperm synthesized through alternative biosynthetic pathways in synthetic lines of white maize, which is normally devoid of carotenoids. Quantitative metabolomics and gene expression data are used to create and fit parameters of mathematical models that are specific to four independent maize lines. Sensitivity analysis and simulation of each model is used to predict which gene activities should be further engineered in order to increase production yields for carotenoid accumulation in each line. Some of these predictions (e.g. increasing Zmlycb/Gllycb will increase accumulated β‐carotenes) are valid across the four maize lines and consistent with experimental observations in other systems. Other predictions are line specific. The workflow is adaptable to any other biological system for which appropriate quantitative information is available. Furthermore, we validate some of the predictions using experimental data from additional synthetic maize lines for which no models were developed.     

利用合成生物学生产药物和燃料

合成生物学是一个快速发展的研究领域,其重要性体现在科学研究和应用开发两方面。它不但加深了我们对复杂的生物过程与机理的理解,而且使得基础生物研究向实际应用的快速转化成为可能。将介绍一些新型高效的合成生物学工具以及如何利用它们开发能从可再生原料生产药物和燃料的上程菌株。     

利用合成生物学原理提高光合作用效率的研究进展

我国人口增多与耕地面积减少的矛盾日益突出,粮食安全已成为我国国民经济可持续发展的重要保障。光合作用是作物产量形成的物质基础,提高作物光能利用效率是提高作物产量的重要途径之一。本文从光合作用过程中光能高效吸收、传递与转化,光能高效利用和碳同化等三大模块综述了近期科学家利用合成生物学对光合作用改造的最新进展。最后我们对其在农业中的应用前景进行了展望,通过合成生物学原理提高光合作用效率可能将为增加粮食产量提供重要理论支撑和关键生物技术。     

合成功能菌群的构建及其工程化应用

自然界中存在着大量的天然微生物群落,不同种群的微生物通过通信及分工拓展了单菌的性能边界,降低了整体的代谢负担并增加了对环境的适应性。合成生物学依据工程设计原理构建或改造基本功能元件、基因线路和底盘细胞,从而对生命的运行过程进行具有目的性的重新编程,获得丰富及可控的生物学功能。将这种工程设计的原理引入菌群,获得结构明确及功能可调的合成群落,可以为合成功能菌群的理论研究到应用提供思路及方法。本文回顾了近年来合成功能菌群领域的相关工作,对合成功能菌群的设计原则、构建方法以及应用进行详细介绍,并对未来的发展进行了展望。     

The simulation approach in synthetic biology

Synthetic biology and systems biology are often highlighted as antagonistic strategies for dealing with the overwhelming complexity of biology (engineering versus understanding; tinkering in the lab versus modelling in the computer). However, a closer view of contemporary engineering methods (inextricably interwoven with mathematical modelling and simulation) and of the situation in biology (inextricably confronted with the intrinsic complexity of biomolecular environments) demonstrates that tinkering in the lab is increasingly supported by rational design methods. In other words: Synthetic biology and systems biology are merged by the use of computational techniques. These computational techniques are needed because the intrinsic complexity of biomolecular environments (stochasticity, non-linearities, system-level organization, evolution, independence, etc.) require advanced concepts of bio bricks and devices. A philosophical investigation of the history and nature of bio parts and devices reveals that these objects are imitating generic objects of engineering (switches, gates, oscillators, sensors, etc.), but the well-known design principles of generic objects are not sufficient for complex environments like cells. Therefore, the rational design methods have to be used to create more advanced generic objects, which are not only generic in their use, but also adaptive in their behavior. Case studies will show how simulation-based rational design methods are used to identify adequate parameters for synthesized designs (stability analyses), to improve lab experiments by ‘looking through noise’ (estimation of hidden variables and parameters), and to replace laborious and time-consuming post hoc tweaking in the lab by in-silico guidance (in-silico variation of bio brick properties). The overall aim of these developments, as will be argued in the discussion, is to achieve adaptive-generic instrumentality for bio parts and devices and thus increasingly merging systems and synthetic biology.     

系统生物学和合成生物学研究在生物燃料生产菌株改造中的应用

基于生物质资源生产环境友好的生物燃料,对经济和社会的可持续发展具有重要意义,但其生产成本高的问题十分突出,而高效生产菌株的获得是解决这一问题的根本出路。以下综述了利用系统生物学研究所获得的信息进行菌种改造的过程,重点论述了生产菌株胁迫耐受性方面的研究进展,并讨论了系统生物学、合成生物学和代谢工程技术在改造生物燃料生产菌株中的应用,展望了合成生物学在构建高效生物能源生产菌株方面应用的前景。