《生命科学》 2019, 31(5): 516-525

微生物，高智商，大产业——合成生物学助力阿维菌素的高效智能制造

刘乐诗1，谭高翼1，王为善2，李珊珊3，夏雪奎4，刘昌衡4，代焕琴2，王泽建1，张嗣良1*，张立新1*

(1 华东理工大学生物反应器工程国家重点实验室，上海 200237；2 中国科学院微生物研究所，北京 100101； 3 中国农业科学院植物保护研究所，北京 100193；4 齐鲁工业大学(山东省科学院)生物研究所，济南 250143)

摘　要：摘　要：合成生物学研究具有两种属性，即生命本质的认识提升属性与生物制造属性。以阿维菌素产生的生命过程复杂性为例，几乎可用“高智商”来形容。通过系统认知微生物的“智商”，从“格物致知”到“建物致用”，实现师法自然，让微生物更高效地为人类服务。在人工工业大规模制造时，上述生命本质的认识无疑是有帮助的，但在微生物与生物反应器组成的复杂系统中，如何从基因到代谢的细胞生理状态到胞外的环境影响中，由“格物致知”的因果关系找到可人工操作的生物智能制造( 智造)，这又是极其困难的科学问题，这就是合成生物学的生物制造属性。因此，必须开展生物过程大数据分析，克服基因、代谢、过程到生产组织中产生的大量互不联系的数据孤岛。近年来，合成生物学的蓬勃发展掀起的技术革命已经彻底颠覆了人们过去对于生物和生物技术的认识。该文以阿维菌素的研究为例，讨论在合成生物学时代如何利用微生物的“智商”来加速实现微生物药物高效智能制造的研发过程，并为其他微生物天然产物药物的智能化生产提供可借鉴的思路和方法。

Infinitely small is infinitely large——the efficient & intelligent    bio-manufacture of avermectin by synthetic biology in China

LIU Le-Shi1， TAN Gao-Yi1， WANG Wei-Shan2， LI Shan-Shan3， XIA Xue-Kui4， LIU Chang-Heng4，DAI Huan-Qin2， WANG Ze-Jian1， ZHANG Si-Liang1*， ZHANG Li-Xin1*

(1 State Key Laboratory of Bioreactor Engineering， School of Biotechnology， East China University of Science and Technology， Shanghai 200237， China; 2 State Key Laboratory of Microbial Resources and CAS Key Laboratory of Pathogenic Microbiology and Immunology， Institute of Microbiology， Chinese Academy of Sciences， Beijing 100101， China; 3 State Key Laboratory for Biology of Plant Diseases and Insect Pests， Institute of Plant Protection， Chinese Academy of Agricultural Sciences， Beijing 100193， China; 4 Key Biosensor Laboratory of Shandong Province， Biology Institute， Qilu University of Technology (Shandong Academy of Sciences)， Jinan 250013， China)

Abstract: Abstract: There are two important properties in synthetic biology， which are understanding the nature of life and the corresponding biological manufacturing. Here we choose the bio-production of avermectin as a case because its production involves the complexity of life process with the “high intelligence quotient (IQ)” of microorganisms. By understanding this IQ， we could evolve the “building to understand” to “building to apply” and finally better serve human beings. Although understanding the nature of life is helpful to the large-scale manufacturing industry， the complex system is involved in the microorganisms and bioreactor such as the relationship， the interaction between intracellular environment (gene regulation， metabolic regulation and physiological state of the cell， etc.) and extracellular environment. It is very complicate. So far， these data were not linked to each other. How to reveal such kind of black-boxes to realize the intelligent bio-manufacture process for manual manipulation is an extremely difficult scientific problem. Therefore， it is necessary for us to investigate the complete bioprocess steps by the big data analysis which integrates all kinds of massive data produced by cells (such as gene transcription， metabolic profiling， etc.)， fermentation process (parameters such as OUR， CER， RQ etc.)， and even comprehensive system management. In recent years， the technological advancement initiated by synthetic biology has completely revolutionized our understanding of biotechnology. Therefore， this article will take the latest research progress of avermectin as an example， focusing on how to use the "high intelligence quotient" of microorganisms to speed up the development of microbial drug efficient manufacturing process in the age of synthetic biology.