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China's Synthetic Biology Research
Guo-Qiang CHEN (Ph.D.)
School of Life Sciences, Tsinghua University
Beijing 100084 China
Tel: +86-10-62783844, Fax: +86-10-62794217, e-mail: chengq@tsinghua.edu.cn


Synthetic Biology has been a hot area of research since 2010 when the synthetic genome successfully activated a bacterium. So far the Ministry of Sciences and Technology (MOST) has provided around 250 million yuan to support the following Synthetic Biology National Basic Research (973) projects under the leadership of these Principle Investigators:

  1. Professor MA Yanhe, Tianjin Institute of Industrial Biotechnology (Chinese Academic of Sciences). Project entitled: "Synthetic Cell Factories". Project Financial Years 2011–2015

  2. Professor ZHAO Guoping, Shanghai Institute of Life Sciences (Chinese Academic of Sciences). Project entitled: "Artificial Biological Devices with Special Functions: Designing, Construction and Assembly". Project Financial Years 2012–2016

  3. Professor FENG Yan, Shanghai Jiaotong University. Project entitled: "Synthetic System of Microbial Medicines for Genetic and Production Innovation". Project Financial Years 2012–2016

  4. Professor CHEN Guo-Qiang, Tsinghua University. Project entitled: "Construction of New Synthetic Pathways for Bio-based Materials using Synthetic Biology Approach". Project Financial Years 2012–2016

  5. Professor LIN Zhanglin, Tsinghua University. Project entitled: "Synthetic Genetic Devices for Improving Stress Tolerance for Microbes and Plants". Project Financial Years 2013–2017

  6. Professor ZHANG Lixin, Institute of Microbiology, (Chinese Academic of Sciences). Project entitled: "Compatibility study of the synthetic microbial systems". Project Financial Years 2013–2017

  7. Professor YUAN Yingjin, Tianjin University. Project entitled: "Design and Synthesis of Microbial Multicellular Systems". Project Financial Years 2014–2018

  8. Professor CAI Zhiming, Shenzhen University. Project entitled: "Basic Research on Curing Bladder Cancer using Synthetic Biology Principles". Project Financial Years 2014–2018
In addition, MOST also supports an 863 Application Project coordinated by Tianjin University with funding of around 100 million. The project is entitled: "Synthetic Biology Technologies". Project Financial Years 2014–2018. Synthetic biology has become an area of continuous investments by MOST in China in the upcoming years, 2–3 large 973 projects will be initiated every year beginning from 2012. This has demonstrated that synthetic biology has been taken as strategy importance for the nation. So far, major Universities such as Tsinghua University, Peking University, Tianjin University, Nankai University, Jiangnan University, Beijing University Chemical Technology, Nanjing University of Technology as well as many institutes of Chinese Academy of Sciences have participated in the synthetic biology projects.

Details of Individual Projects

The following details each project together with some of their achievements.

Synthetic Cell Factories

The project is guided by Professor MA Yanhe of Tianjin Institute of Industrial Biotechnology under the Chinese Academic of Sciences. It attempts to utilize biological, chemical, physical and computational as well as engineering approaches to assemble biological systems for industrial applications. The project will focus on establishing theoretical basis for chassis and assembling of pathways for chemicals synthesis. E. coli and phototrophic cyanobacteria are the two representatives of the chassis cells. It is aimed to construct CO2 to glucose to chemicals pathways by introducing even non-nature existing pathways. The purpose of this project is to meet the increasing demand on bulk chemicals using biological approaches.

Photosynthetic cyanobacteria have attracted significant attention recently as a "microbial cell factory" to produce renewable biofuels and fine chemicals due to their capability to utilize solar energy and CO2 as the sole energy and carbon sources, respectively. Recent synthetic biology efforts have led to successful production of various biofuels in engineered cyanobacteria systems, including ethanol, 1-butanol, isobutanol, alkanes, alkenes, free fatty acids, biodiesel, and hydrogen, demonstrating that the large-scale production of biofuels from cyanobacteria could be achievable in the near future. However, the tolerance of these non-native microorganisms to toxic biofuels is naturally low, which has restricted the potentials of their application for high-efficiency biofuel production. To address the issues, Professor ZHANG Weiwen of Tianjin University, part of this project, tries to explore the biofuel tolerance mechanisms and to construct robust high-tolerance strains for biofuel-producing cyanobacteria.

Using integrated transcriptomics, proteomic and metabolomic approaches, Professor Zhang determined the metabolic profiles of cyanobacterium Synechocystis sp. PCC 6803 stressed by ethanol, butanol or hexane. The results showed that Synechocystis sp. PCC 6803 cells employed a combination of cell wall and membrane modifications, induction of multiple transporters and heat shock proteins, as well as induced common stress response, and induction of cell mobility-related proteins as major protection mechanisms against ethanol toxicity. Based on the analyses, a list of potential gene targets was identified to construct biofuel-tolerant Synechocystis strains.

Early genome-level studies have showed that microbes tend to employ multiple resistance mechanisms in dealing with stress of single biofuel product, and it is thus very challenging to achieve tolerance improvement by sequential multigene modifications. As an alternative, the manipulation of regulatory genes, such as global transcription machinery engineering (gTME) approach, could provide a route to complex phenotypes that are not readily accessible by traditional methods of targeting some number of metabolic genes. However, so far very little is known about regulatory mechanism related to biofuel tolerance in Synechocystis. To address the issue, by constructing the gene knockout mutant and conducting phenotypic analysis, Prof Zhang recently confirmed that a novel two-component response regulator Slr1037 was involved in butanol tolerance in Synechocystis, and determined the possible butanol-tolerance regulon regulated by Slr103.

Artificial Biological Devices with Special Functions: Designing, Construction and Assembly

Professor ZHAO Guoping, Shanghai Institute of Life Sciences (Chinese Academic of Sciences) is leading this project, based on the engineering-oriented technology and directed by systematic design.

The key scientific and technological problems that will be addressed include the designing theory for biological devices, the techniques for de novo synthesis of large DNA fragments and high efficiency construction and standardization of biological parts and modules, as well as the optimized fitting of the biological devices in chassis cells.

The specific aims of this project are: (1) To develop a bioinformatics-oriented platform for analyzing genomic network and structural-functional relationships of biological modules, which will lead to the theory and enabling technology for the design of pathways, modules and parts as well as optimization of the chassis cells. (2) To develop biochemical and bioengineeing platforms for high-throughput, high-fidelity synthesis and ligation of large DNA fragments, for construction of biological parts and functional modules, and for the systematic assembly and fine-tuning of device. (3) To develop a comprehensive synthetic biology registry with standardized reusable parts and modulized devices identified from different natural sources or designed/redesigned based on systematic analysis, which can be used for quick assembly of biological pathways for the heterogeneous synthesis of terpene and polyketide-based biologically active chemical products. (4) To develop in sillico and in vivo technologies to optimize metabolic network in chassis cells and to increase the biosynthetic flux towards the target compounds.

Completion of this project will lay down the scientific and technological foundation for the engineering strategies of synthetic biology. It is expected to achieve significant breakthroughs with regard to the construction and assembly of artificially designed biological devices via realizing the goal of heterogeneously production of pharmaceutically important rare phytochemicals employing the technology and registry developed by this project. Meanwhile, an active research team of young scientists and technical experts for synthetic biology will be established to ensure the future development of this emerging discipline in China.

So far, major achievements of this project include: 1) The development of a platform for genome network analysis and functional module design, construction of the genome-scale metabolic models of oleaginous yeast Yarrowia lipolytica and microalgae Nannochloropsis, and the establishment of a framework for rational design of metabolic engineering strategies; 2) Techniques for high-throughput, high-fidelty DNA synthesis and assembly of DNA fragments are estabablished, and construction of Streptomyces strains with reduced genome as candidate chassis has been completed; 3) A synthetic biology registry with standardized reusable parts and modulized devices identified from different natural sources is ready, and creation of a bio-orthogonal redox systems is completed; 4) characterization of a number of important parts involved in terpenoid biosynthesis has been done enabling the heterogeneous synthesis of ginsenoside compound K, ferruginol, and rebaudioside A in yeast or Escherichia coli.

Synthetic System of Microbial Medicines for Genetic and Production Innovation

Professor FENG Yan, Shanghai Jiaotong University, is working on this project, which comes with pragmatic goals. On one hand, with the joint efforts of top domestic research teams of multi-disciplinary backgrounds, core scientific problems in the field of microbial medicine can expect to be targeted and solved. Such core scientific problems include: (1) the molecular basis for synthesis and regulation in biosynthesis of microbial medicine with high efficiency; (2) the adaptation mechanisms in the designed biosynthesis system with an engineering concept. On the other hand, with the application of biological-component-oriented directional design, module assembly of metabolic pathway, chassis built from Actinomycetes, network optimization in organisms and other aspects, the establishment of an orderly and efficient synthetic system should be accomplished, with innovation in the structure and activity of microbial medicines, and realize highly efficient biomanufacturing, and provide theoretical and technical supports for the modern biomedical industry in its rapid development. The project is composed of deciphering, designing and optimizing of the biological components, pathways and networks. Finally, constructing a highly efficient system for production of microbial medicine.

Various goals have been reached including (1) Construction of an informaiton-oriented biosynthesis pathway design platform (RxnIP), (2) design and directed evolution of the catalytic bio-parts (enzymes), (3) Streptomyces chassis for the production of microbial medicines, (4) Validamycin producer Streptomyces hygroscopicus 5008: a potential chassis with enhanced regulatory cascade for antibiotic overproduction, (5) Partially establish the basis for Synthetic Biology of Ansamycins

Construction of New Synthetic Pathways for Bio-based Materials using Synthetic Biology Approach

This project, led by Professor CHEN Guo-Qiang, Tsinghua University (author of this article) intends to construct bacteria that can produce diverse polyhydroxyalkanoates PHA biopolymers.

Microbial polyhydroxyalkanoates (PHA) have been developed as bioplastics for the past many years. Commercial PHA are normally poly-3-hydroxybutyrate (PHB), copolyesters of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx), copolyesters of 3-hydroxybutyrate and 4-hydroxybutyrate (P3HB4HB), as well as copolyesters of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV). Synthetic biology approaches will be used to produce a series of novel PHA including homopolymers, random copolymers and block copolymers. For example, poly-3-hydroxypropionate (P3HP), poly-4-hydroxybutyrate (P4HB), poly-3-hydroxydecanoate (P3HD) and poly-3-hydroxydodecanoate (P3HDD) et al. Random copolymers containing defined monomer compositions should be produced. More importantly, block copolymerization containing various block such as diblock copolymers of PHB-b-P4HB, PHB-b-PHHHx, P3HP-b-P4HB, PHBHHx-b-PHDD et al will be produced by the synthetic bacteria. Thus, the project will allow extend the diversity of PHA structures and properties.

Now, the PHA industry will be entering a functional polymer era, which allows PHA competitiveness not by the low cost but by its functionality. This project soon will lead to microbial synthesis of ultra-strong, shape memory, gas selective permeability and other environmentally responsive PHA.

The project has succeeded in the design and construction of a PHA super production strain that is able to grow fast to high cell density (>120 g/L) utilizing low cost substrates including cellulose, starch or even kitchen wastes under a very high carbon source to PHA conversion efficiency of at least 35% (g/g). The synthetic cell is able to partially achieve oxygen limitation induced >90% PHA accumulation in cell dry weights. After completing the PHA production, the very large cells can be induced for flocculation precipitation followed by induced cell lysis to release large PHA granules. The PHA fermentation process is conducted under unsterile and continuous way using seawater to save energy and fresh water, reduce process complexity.

Synthetic Genetic Devices for Improving Stress Tolerance for Microbes and Plants

Professor LIN Zhanglin, Tsinghua University works on this project.

The tolerance of microbial cells toward different industrially relevant stresses is very important for industrial strains of microbes, but difficult to improve by the manipulation of single genes. This problem is also relevant to Chinese economy, given that China has a significant fermentation sector. Synthetic biology offers a very unique opportunity in devising and testing genetic devices for improving stress tolerance by combining different regulatory elements (such as promoters of different strengths) and different functional genes encoding either proteins or RNA. Additionally, many microbial genes have been successfully used in transgenic plants, and thus some of the microbial genes that elicit stress tolerance are also likely functional in plants.

A group of 8 PIs are working together to design and test different synthetic devices for heat and acid tolerance for microbes, and for salt and drought tolerance for plants. The team has been systematically surveying proteins or RNAs that produce stress resistance, and then will move on to synthetic design. The proteins are either structural proteins such as antiporters, heat shock proteins, or detoxification enzymes that are directly involved in providing stress protection, or regulatory proteins such as global regulators or sigma factors that operate at a higher level and activate various stress responses. RNAs under consideration are mostly small non-coding RNAs that are involved in regulating stress responses.

So far, the team has been able to identify several heat shock proteins and regulators of extremophilic or mesophilic origins that function well in E. coli and other microbes, and provide significant stress protection. Moveover, the team has found that the global regulator irrE from an extremely radiation-resistant bacterium, Deinococcus radiodurans, confer Brassica napus with a significant tolerance toward 350 mM NaCl, and a small scale field test is underway.

Compatibility Study of the Synthetic Microbial Systems

This project is headed by Professor ZHANG Lixin from Institute of Microbiology, Chinese Academic of Sciences, and aims at studying microbial evolution for an efficient cell factory which is important to transform "Made in China" to "Innovated in China". This project focuses on the design and synthesis of biological chassis, parts, device and modules from the microbial diversity on the planet to reconstruct and optimize their dynamical process, as well as predict favorable future outcomes. The implementation of this project will observe efficient microbial evolution in ways not previously possible.

In details, the project has conducted computational modeling on the biosynthesis of Polynik A and Avermectin. Avermectins are macrocyclic lactones produced by Streptomyces avermitilis, which are well known and widely used for antiparasitic therapy. Avermectin is the only biopesticide with an annual sale more than $1.2 billion. Eight different avermectins were isolated in four pairs of homologue compounds, among which B1a is the most active agent. Given the importance of this molecule and its derivatives, many efforts and strategies have been followed to improve avermectin production and generate new active analogues. Polynik A is the man-made un-natural compound with improved bioactive properties.

In order to achieve the goals of this project, Professor Zhang and his team will explore the mechanism of integration and compatibility for synthetic life systems; to clarify interaction theory for the biological chasses with exogenous components; to develop efficient strategy for synthetic microbial system; and to determine the regulatory factors and modification approaches for genetic circuits. E. coli and aerobic facultative anaerobic Streptomyces as prokaryotic hosts will be used for the development of biosynthetic genes cluster module, the key enzyme and cofactor modules and regulatory elements module. The modules will then be assembled to build synthetic biological systems. The goal is to provide a biotechnological platform for the biosynthesis of novel drugs, for synthetic biology research and for industrial applications.

Design and Synthesis of Microbial Multicellular Systems

Professor YUAN Yingjin, of Tianjin University leads this project which will focus on closed systems, especially bi-bacteria systems and their applications in pharmaceutics production, for example, symbiotic fermentation of two bacteria for vitamin C production, unsaturated fatty acids are also important for this project. The project aims at two scientific questions including 1) Constructions of multispecies microbial systems with symbiotic benefits, 2) Regulatory mechanisms for multispecies microbial systems and their interactions on metabolites, energy substrates and information sharing.

The project has been able to construct one-step vitamin C fermentation system using mixed population, the yield of vitamin C has been increased by 43.2%. At the same time, a methane mixed population system has been constructed to produce methane using kitchen waste as raw materials. The methane will be further utilized for production of energy, materials and medicines.

Basic Research on Curing Bladder Cancer using Synthetic Biology Principles

Professor CAI Zhiming, Shenzhen University leads this project, the only team working on eukaryotic cells. There is no much information available on this project. Since eukaryotic cells are much more difficult to conduct synthetic biology on, we would expect to see the results some time later.

MOST 863 Project

Finally, a MOST 863 project aims to commercialize some of the synthetic biology projects that have been initiated at the end of 2012. The project is coordinated by Tianjin University. It is intended to construct production strains for industrial pilot production of specialty biomaterials such as PHA, energy and medical products. Not only plant synthesis systems but also phototrophic bacterial systems will be employed to do the job. The project has also supported the artificial synthesis of yeast genome as part of the international efforts to make a synthetic yeast.

Photo credit: David Robert Bliwas/Flickr/CC

About the Author

CHEN Guo-Qiang (George)
Professor of Microbiology and Biomaterials
School of Life Sciences, Tsinghua University, Beijing/China
Mobile: 13901026792
e-mail: chengq@mail.tsinghua.edu.cn

Professor George Guo-Qiang CHEN received his BSc and PhD from South China University of Technology in 1985 and Graz University of Technology (Austria) in 1989. He also conducted research in 1990-1994 as a postdoc at University of Nottingham in UK and University of Alberta in Canada, respectively. He has been focusing his research on microbial metabolic engineering, synthetic biology and biomaterials since 1986. After joining Tsinghua University in 1994, he has been actively promoting the microbial Bio- and Material Industries in China. Professor Chen has more than 25 years of R&D experiences on microbial physiology, microbial production and applications including recently synthetic biology using extremophiles et al, has published over 200 international peer reviewed papers with over 8000 citations (H-Index 42). With over 25 issued patents and 39 pending patents, Prof. Chen's technologies have been provided to several companies that succeed in mass production of microbial polyhydroxyalkanoates (PHA). Recently, he focuses his research on Synthetic Biology, has become a PI of a "Synthetic Biology" project for the largest national basic research program, the 973 program. Currently, Professor Chen is associate editor for "Journal of Biotechnology", "Biotechnology Journal", "Microbial Cell factories" and "Chinese Journal of Biotechnology", he is also on the editorial board of the journals of "Current Opinions in Biotechnology", "Biomaterials" and "Biomacromolecules", "ACS Synthetic Biology" and "Applied Microbiology and Biotechnology".

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