Personal Information

Principal Investigator
Researcher
Email:syang@sibs.ac.cn
Personal Web: http://people.ucas.edu.cn/~yangsheng


Research Direction

 


Research Unit

Key Laboratory of Synthetic Biology, CAS

Sheng Yang

Personal Profile

Education  

1995-2000 Ph.D., Biochemistry and Molecular Biology, Shanghai Institute of Biochemistry, Chinese Academy of Sciences.  

1991-1995 B.E., Chemical Engineering, Zhejiang University, Hangzhou, China.  

Academic Experience 

2006-present Professor, Institute of Plant Physiology & Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 

2002-2006 Associate Professor, Institute of Plant Physiology & Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences           

2000-2002 Research Associate, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 


Research Work

Green chemistry is the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances (Anne E. Marteel et al., 2003). The US Environmental Protection Agency presented five projects each year as Presidential Green Chemistry Challenge Awards since 1996. Biocatalysis has won more than a quarter of 114 awards [https://www.epa.gov/greenchemistry]. However, application of biocatalysis in chemical industry is still quite limited partially because the development and implementation of biocatalysts is rather slow compared to chemical synthesis (Keasling et al., 2012).  

Key advances in DNA sequencing and gene synthesis provide tremendous resource and possibility for building biocatalysts by functional expression and reorganization of enzymes into new biosynthetic pathways (Bornscheuer et al., 2012). Our overall research goal is the development of synthetic biology-based biocatalysts for industrial use by providing new enabling technologies and novel designs. Our scientific objectives include 1) a more efficient enzyme production protocol and facility for synthetic chemistry, 2) more efficient microbial genome editing tools for faster construction of designer cells, and 3) building genetically defined cells to understand the mechanism behind the efficient catalytic performance of evolved biocatalysts.  

A consensus biocatalysts enzymes production process was established on Escherichia coli T7 expression system with 2000 L fermentation capability. More than 200 biocatalysts enzymes have been made upon requests from synthetic chemistry. 19 enzymes have been used for producing 13 fine chemicals commercially in recent 5 years. CRISPR-Cas based genome editing tools have been setup for 10 microorganisms and are under adaptation in more microbial species with a diversified CRISPR-Cas nucleases collection. A rational designed and adaptive evolved xylose fermenting yeast has been used for commercially production of cellulosic ethanol in the United States and Brazil. The molecular mechanism behind its outstanding performance is currently under investigation through genotype reconstruction, as well as others evolved cells, such as an L-arginine hyperproducer Corynebacterium glutamicum strain. 

  

Cost-effective sustainable biomanufacturing systems are needed to enable the continued availability of products at low cost such as biopharmaceutical, nutraceutical, feed additive, bulk chemical and fuel. High-risk, high-reward research is necessary to achieve innovations for new biomanufacturing technologies. However, company fiduciary responsibilities often limit the levels of risk in research that companies can undertake on their own, with acceptable risk levels varying by different sectors. As a result, a critical need to support biomanufacturing is increasingly evident. Advanced DNA technologies, including next-generation DNA sequencing and low-cost DNA synthesis, provide massive genetic resources and fast access to genes, providing near-infinite possibilities for designing and creating novel biocatalysts (Bornscheuer et al., 2012). However, it is still in the early stage to predict the biocatalytic performance of synthetic biocatalysts (Mak et al., 2015). Therefore, a more powerful synthetic biology tool kit for faster building of designer biocatalysts is needed to provide the infrastructure necessary for translating laboratory prototypes into commercial products. Our laboratory is interested in the continuous expanding and improving the tool kit and uses it as a platform to develop biocatalysts together with industrial partners. The particular interests are biocatalysts for conversion of renewable resources to chemicals and biofuels with conventional chassis microorganisms, such as Escherichia coli, Corynebacterium glutamicum and Saccharomyces cerevisiae as well as non-conventional microbial hosts such as clostridia and Yarrowia lipolytica. 


Main Achievements

1 磷酸甲基赤藓糖醇途径与甲羟戊酸途径的协同效应
所有萜类物质均需通过磷酸甲基赤藓糖醇(methylerythritol phosphate, MEP)途径或甲羟戊酸(mevalonate, MVA)途径合成,以往的萜类代谢工程均只优化其中一条途径。申请人在大肠杆菌进行了数十轮十余靶点的基因工程操作,同时优化两条途径,双途径较单途径菌株的异戊二烯得率高3倍以上,突破单途径得率的理论上限,较之前报道最高的发酵单位还要提高一个数量级。同位素流量分析与途径特异性抑制剂及甲羟戊酸添加实验证明还原力和ATP互补在双途径协同中起到了关键作用。并且这一协同效应亦能提高其他萜类如番茄红素的生产强度,表明这一策略在提高微生物萜类合成能力上具普适性。相关研究结果发表于Metabolic Engineering上。

2 梭菌戊糖代谢工程
我们将CRISPR/Cas系统首次适配到丙酮丁醇梭菌中,实现了无痕敲除及表达抑制功能,并做微调后用于拜氏梭菌和嗜纤梭菌。秸秆糖液尚需由预处理生物质添加纤维素酶糖化后才能作为发酵原料。统合生物工艺(Consolidated Bioprocessing , CBP)的策略是将糖化和发酵整合到一个生物过程中,从而省去外源添加纤维素酶带来的较高成本。课题组选取,运用TargeTron和以上CRISPR/Cas技术,将嗜纤梭菌与拜氏梭菌人工双梭菌系统分产酸、酸回用、木糖利用和还原力供应4个模块进行代谢工程改造(图1)。第一步中断了嗜纤梭菌的乙酸激酶和乳酸脱氢酶并过表达丁酸激酶,将其代谢流推向丁酸;第二步用CRISPRi抑制了嗜纤梭菌的氢酶转录,以减少释放氢气损失的还原力,用于产醇;第三步过表达拜氏梭菌的辅酶A转移酶加强回用嗜纤梭菌所产丁酸;第四步中断拜氏梭菌的木糖阻遏子和过表达木糖转运体增强木糖内运和代谢。这四步改造将人工双梭菌转化玉米芯产溶剂的速度大为提升,通过中间补加玉米芯的方法,可将溶剂终浓度提升到22 g/L,达到用淀粉糖培养基同样的水平。相关研究结果发表于Metabolic Engineering上。

获奖情况:
DuPont Young Professor Award (杜邦青年教授奖 2006)
国务院政府特殊津贴 (2010)
中国科学院院地合作奖 科技类先进个人一等奖 (2010)
《载体固定化酶---原理、应用和设计》(与袁中一研究员共同主译) 中国石油和化学工业优秀出版物奖(图书奖) 一等奖 (2010)
上海市优秀学科带头人 (2014)
中国产学研合作创新成果奖 (2014)
中国专利优秀奖(2015)
Novozymes Innovation Award (诺维信创新奖 2015)
上海市科技进步一等奖 (2015)
伦世仪教育基金杰出青年(2016)
中国科学院科技促进发展奖(2016)


Publications