合成生物学在疾病诊疗中的应用

doi:10.12211/2096-8280.2022-059

合成生物学 ›› 2023, Vol. 4 ›› Issue (2): 244-262.DOI: 10.12211/2096-8280.2022-059

合成生物学在疾病诊疗中的应用

吴晓昊¹, 廖荣东², 李飞云¹, 欧阳中天¹, 冉怡¹, 公维远¹, 曲明灏¹, 陈明珏¹, 林荔军², 肖国芝¹

^1.南方科技大学医学院，广东深圳 518055
^2.南方医科大学珠江医院关节骨病外科，广东广州 510280

收稿日期:2022-10-31 修回日期:2023-02-01 出版日期:2023-04-30 发布日期:2023-04-27
通讯作者: 林荔军,肖国芝
作者简介:吴晓昊（1991—），男，博士研究生。研究方向为骨关节稳态和疾病发生的分子机制。E-mail：wxho0606@163.com
廖荣东（1996—），男，博士研究生。研究方向为骨科疾病的发病机制。E-mail：lrdyxs12138@163.com
林荔军（1976—），男，博士，主任医师，博士生导师。主要从事合成生物学与骨科疾病诊治领域方面的研究，利用合成生物学方法构建新型材料用于骨关节炎、骨折不愈合等骨科多发疾病的治疗，研究方向为骨关节炎发病分子机制研究、骨肉瘤侵袭和转移的分子机制研究、骨组织3D打印和生物力学研究学。E-mail：gost1@smu.edu.cn
肖国芝（1963—），男，教授，乌克兰国家工程院外籍院士。主要研究方向是骨骼发育和疾病的相关分子基础。E-mail：xiaogz@sustech.edu.cn
基金资助:
国家重点研发计划(2019YFA0906004);国家自然科学基金(82230081)

Applications of synthetic biology in disease diagnosis and treatment

WU Xiaohao¹, LIAO Rongdong², LI Feiyun¹, OUYANG Zhongtian¹, RAN Yi¹, GONG Weiyuan¹, QU Minghao¹, CHEN Mingjue¹, LIN Lijun², XIAO Guozhi¹

^1.School of Medicine，Southern University of Science and Technology，Shenzhen 518055，Guangdong，China
^2.Department of Orthopedics，Zhujiang Hospital，Southern Medical University，Guangzhou 510280，Guangdong，China

Received:2022-10-31 Revised:2023-02-01 Online:2023-04-30 Published:2023-04-27
Contact: LIN Lijun, XIAO Guozhi

摘要/Abstract

摘要：

合成生物学是一门新兴学科。从广义上讲，合成生物学是通过将基因工程、系统生物学、计算机工程等多学科作为工具，根据特定需求进行设计，乃至重新合成生物体系。近20年来，合成生物学领域的相关研究不断取得突破，并已在针对人类疾病的诊断、临床治疗、药物研发等诸多方面获得重要应用。合成生物学不仅为疾病的早期、精确诊断提供新的思路和技术手段，还发展出多种新型的疾病治疗手段，包括基于合成生物学原理设计的细胞疗法、细菌疗法、疫苗、生物医学材料等。利用合成生物学方法，我们可以精确诊断早期疾病、精准改造细胞或细菌、进行疾病机制研究和药物筛选、快速生产新型疫苗和生物医学材料。基于合成生物学的疾病诊疗方法将是科研领域重要的发展方向之一，并将在未来彻底改变临床疾病的诊疗方式。本文综述合成生物学原理和技术在疾病诊断和治疗中的应用，并进一步探讨合成生物学在疫苗生产、生物医学材料、新药研发等方面的应用。

关键词: 合成生物学, 疾病, 诊断, 治疗, 新药研发

Abstract:

Synthetic biology (SB) is an emerging discipline, which utilizes genetic engineering, systems biology, computer science, and other disciplines as tools to design, and even re-synthesize biological systems for specific needs. In the past 20 years, milestone breakthroughs in SB have been achieved and applied in the diagnosis and treatment of human diseases, particularly in the discovery of new drugs. SB not only provides new ideas and technical tools for the early and accurate diagnosis of diseases, but also develops a variety of new approaches for treating diseases, including cell therapy, bacteriotherapy, vaccines, and biomedical materials. Using SB-based methods, we can precisely diagnose diseases at an early stage, specifically engineer cells or bacteria, conduct mechanistic studies and drug screening, and rapidly produce vaccines and biomedical materials. SB with the "design-build-test" cycle greatly facilitates the development of new diagnostic and therapeutic approaches. Moreover, SB applies engineering principles (modularity, composability, abstraction, and standardization) to redefine biological systems in a more modular and composable way. Through this framework, the basic units of the biological system are fully characterized as standardized motifs (DNA sequences or gene-encoded products), and these motifs are mixed and matched to construct a fully functional genetic apparatus. By utilizing recently developed gene editing tools, such as the clustered regularly interspaced palindromic repeats (CRISPR/Cas9) technology, SB can integrate programmed devices into a chassis (e.g., bacteria and yeast), create new systems capable of producing target biomolecules or behaviors, and precisely manipulate the genome of cells and individuals to repair genetic defects. SB-based disease diagnosis and treatment will be one of the important development directions in the field of scientific research to completely change the way of diagnosis and clinical treatment of diseases in the future. This article reviews the applications of SB-based technologies in disease diagnosis and treatment, as well as in the production of vaccines and biomedical materials, as well as in new drug development.

Key words: synthetic biology, disease, diagnosis, treatment, drug development

中图分类号:

吴晓昊, 廖荣东, 李飞云, 欧阳中天, 冉怡, 公维远, 曲明灏, 陈明珏, 林荔军, 肖国芝. 合成生物学在疾病诊疗中的应用[J]. 合成生物学, 2023, 4(2): 244-262.

WU Xiaohao, LIAO Rongdong, LI Feiyun, OUYANG Zhongtian, RAN Yi, GONG Weiyuan, QU Minghao, CHEN Mingjue, LIN Lijun, XIAO Guozhi. Applications of synthetic biology in disease diagnosis and treatment[J]. Synthetic Biology Journal, 2023, 4(2): 244-262.

图/表 5

表1 合成生物学在癌症诊断中的生物传感器特点

Table 1 Biosensors developed through synthetic biology for cancer diagnosis

项目	酶传感器	质粒传感器	哺乳动物细胞传感器	细菌传感器
原始信号	酶活性失调	转录活性改变	转录或代谢活性改变	生化特性改变（如营养物质，pH等）
放大方式	催化放大尿液浓缩	分泌物增加	细胞增殖分泌物增加	细菌增殖催化放大尿液浓缩
信号特征	底物信号扩大	特异性转录	肿瘤微环境驱动信号激活	特异性肿瘤靶向浸润
检测方式	尿液，血液，呼吸	尿液，血液	尿液，血液	尿液，血液

图1 在CAR-T细胞中引入的“逻辑门”系统“与门”：当synthetic notch（SynNotch）受体识别并结合肿瘤抗原时，激活CAR的表达，由CAR识别另一肿瘤抗原后激活T细胞并介导其对肿瘤的杀伤功能（如图左上所示）。另一种“与门”：弱活化信号的CAR和共刺激受体（co-stimulatory receptor， CCR）均不足以单独提供激活T细胞的信号。当两个受体共同识别出对应肿瘤抗原时，才足以激活T细胞功能（如图右上所示）。“或门”：串联表达不同CAR的单链可变区片段（single-chain variable fragment， ScFv），任一ScFv片段识别到对应肿瘤抗原都可以激活T细胞功能（如图左下所示）。“非门”：当CAR识别到肿瘤抗原后激活T细胞，同时当inhibitory CAR（iCAR）识别到正常细胞抗原时，iCAR发出抑制信号抑制CAR的激活信号从而保护正常细胞（如图右下所示）

Fig. 1 Diagram for the logic gate to CAR-T cellsAND gate: When the synthetic notch (SynNotch) receptor recognizes and binds to a tumor antigen, it activates the expression of CAR to recognizes another tumor antigen for activating T cells to mediate its killing function against tumors (as shown in the upper left of the figure). Another AND gate: both CAR and CCR with weak activation signals are not sufficient to activate T cells. When the two receptors jointly recognize the corresponding tumor antigen, the combined signal is sufficient to activate T cell for function (as shown in the upper right of the figure). OR gate: any ScFv fragment expressing different CARs in tandem can activate T cell for function when it recognizes the corresponding tumor antigen (as shown in the lower left of the figure). Not gate: CAR recognizes tumor antigens to activate T cells, but when iCAR recognizes normal cell antigens, it sends out an inhibitory signal to inhibit the activation signal of CAR for the protection of normal cells (as shown in the lower right of the figure)

图2 工程细菌生物合成和细菌疗法原理示意图运用合成生物学应用工程原理，将特化和标准化的DNA序列或基因编码产物等基序混合匹配构建为功能齐全的遗传装置并将其集成到底盘细菌中，最终构建出一个能够产生纳米抗体、分泌特定蛋白或表达免疫抗原刺激免疫通路激活的工程细菌

Fig. 2 Schematic diagram for engineering bacterial biosynthesis and corresponding therapyWith the engineering principles of synthetic biology, specialized and standardized DNA sequences or gene coding products and other sequence motifs are mixed and matched to construct fully functional genetic devices for integrating them into chassis bacteria to finally develop an engineered bacteria that can produce nanobodies, secrete specific proteins or express immune antigens to stimulate the activation of the immune pathways

表2 合成生物医学材料总结

Table 2 Summary of synthetic biomedical materials

材料种类	材料名称	材料特性	参考文献
多糖材料	细菌纤维素	高物理强度和高保水能力，可生产人造血管支架	[115]
多糖材料	纤维素-几丁质共聚物	可作为静脉假体，在动物体内能被降解	[116]
核酸材料	ssDNA纳米材料	制作病原体传感器，对动物体内的病原体进行探测	[117]
核酸材料	RNA纳米材料	控制体内细胞代谢过程	[118]
蛋白质材料	弹性蛋白样多肽	用于组织工程和药物递送	[119]
蛋白质材料	弹性蛋白样重组体	制作基于ELR的水凝胶，用于传递药物和疫苗	[120]
活细胞材料	curli纳米纤维	与生物膜融合后可结合在特定表面，用于治疗小鼠胃肠道炎症	[121]
	大肠杆菌ECM材料	生产抗肿瘤药物——脱氧紫罗兰素	[122]
	E.coli Nissle材料	一种无毒性的大肠杆菌材料，对患者进行持续给药	[123]
	枯草芽孢杆菌水凝膜	具有多功能再生和可调性，可作为潜在的医疗生物材料	[124]

图3 合成生物学在新药研发中的应用（a）在药物机制研究中构建基因编辑动物模型；（b）在药物筛选与机制研究中使用类器官模型；（c）生产特异性药物，如mRNA疫苗和特异性抗体；（d）在抗体生产和筛选过程中应用广泛的酵母双杂交技术

Fig. 3 Applications of synthetic biology in drug discovery(a) Building animal models for gene-editing in drug mechanism research; (b) Building organoid models for drug screening and mechanism discovery; (c) Expressing specific drugs like mRNA vaccines or antibodies; (d) Yeast two-hybrid technology for screening and producing antibodies

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合成生物学在疾病诊疗中的应用

Applications of synthetic biology in disease diagnosis and treatment

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