Abstract:Industrial biotechnology is the application of biotechnology for the large-scale processing and production of chemicals, pharmaceuticals, fuels, materials, food and other products required by human society with microorganisms or enzymes as catalysts. The development of industrial biotechnology is the key path enabling the transition from fossil economy to bioeconomy. It will bring sustainable solutions to the natural resource use, energy supply and environmental protection currently faced by mankind. Tianjin Institute of Industrial Biotechnology of the Chinese Academy of Sciences is the main representative of China’s industrial biotechnology and biomanufacturing. Based on the development of the institute in the past decade, this review summarizes the strategic plan, important technological breakthroughs and industry impacts of China’s industrial biotechnology development, and prospects future development of industrial biotechnology and biomanufacturing in China.

Abstract:Industrial biotechnology is the application of biotechnology for the large-scale processing and production of chemicals, pharmaceuticals, fuels, materials, food and other products required by human society with microorganisms or enzymes as catalysts. The development of industrial biotechnology is the key path enabling the transition from fossil economy to bioeconomy. It will bring sustainable solutions to the natural resource use, energy supply and environmental protection currently faced by mankind. Tianjin Institute of Industrial Biotechnology of the Chinese Academy of Sciences is the main representative of China’s industrial biotechnology and biomanufacturing. Based on the development of the institute in the past decade, this review summarizes the strategic plan, important technological breakthroughs and industry impacts of China’s industrial biotechnology development, and prospects future development of industrial biotechnology and biomanufacturing in China.

Abstract:The convergence of advances in chemistry, physics, mathematics, computer science, and engineering into life science research gives rise to synthetic biology. Synthetic biology adopts the concept and strategy of engineering science research, aiming at redesigning and reprogramming the existing biological systems, designing and constructing new bio-bricks such as enzymatic parts, genetic circuits, and chassis cells, or even creating non-natural functions of “artificial life”. Synthetic biology promotes the leap from understanding of life to design of life, and is revolutionizing biotechnology and sustainable development of bioeconomy. Via this retrospective review of Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, the most representative research entity focusing on “build-for-use” of synthetic biology in China, this article summarizes the important scientific and technological breakthroughs and industry impacts in the past decade, and prospects future development of synthetic biology in China.

Abstract:The mission of all institutes under Chinese Academy of Sciences focuses on frontier science and applied technology to address the challenges for country’s development and world sustainable development. Here, I summarize the founding and development of Tianjin Institute of Industrial Biotechnology of Chinese Academy of Sciences (CAS), originated from Institute of Microbiology of CAS. The journey reflects the advances of industrial biotechnology in China. By considering the relationships among science, technology and engineering, I propose that scientists involved in basic research should develop a logical thinking of “idea-hypothesis-experiment-concept-paper-technology- sample-product-commercial goods”, from which great solutions that tackle real problems can be developed. This is the logic from basic research to applied science.

Abstract:With the increasing concerns on depletion of fossil resources and climate challenges, industrial biotechnology is considered a promising alternative to address the pressing issues including energy and resource shortage as well as climate change, so as to achieve sustainable development of the society. Owning to the theoretical advances, technological breakthroughs, and multidisciplinary convergence, the past two decades have seen rapid development of industrial biotechnology driven by the disruptive advances of life sciences, the merging of multidisciplinary technologies and concepts, and the commercial and industrial demands. This article briefly illustrated the history and the recent breakthroughs of industrial biotechnology and prospected a long-term perspective for its future direction.

Abstract:The rapid development of underlying technologies such as engineering biology and gene editing has promoted disruptive innovation in the area of industrial biotechnology. Industrial biotechnology has become the core technology supporting the innovation and development in low-carbon synthesis, future food and medicine development. Industrial biotechnology is becoming an important scientific and technological support for the transformation of traditional industrial manufacturing mode and the development of a carbon-neutral industrial manufacturing route. This review systematically summarizes the overall development of industrial biotechnology driven by Chinese Academy of Sciences with regard to strategic planning, innovation institutions building, talent pool development, basic research, scientific and technological innovation and industrial promotion, followed by suggestions for accelerating the development of industrial biotechnology.

Abstract:Industrial biotechnology is an integrated technology that utilizes biochemical reactions and biofunctions to achieve substance synthesis and energy conversion. The development of industrial biotechnology supports a green, efficient, and new route for manufacturing of chemicals using renewable raw materials. It is expected to bring a fundamental shift in industrial manufacturing and a change in economic growth mode. Industrial biotechnology is an important strategic technology supporting the sustainable development of social economy and has become a focus of global competition on science and technology. Based on an elaboration of industrial biotechnology’s deep integration in bioeconomy, this paper summarized the current situation and developmental trends of industrial biotechnology and biomanufacturing industry in China. Gaps between developed countries and China as well as key areas for biotechnology development were proposed, followed by identifying tasks and directions for future development of biomanufacturing industry.

Abstract:Biotechnology is one of the most promising forefront technologies in the 21^st century. Its disruptive, cutting-edge, and systematic characteristics, together with its intelligent, convergent, and transformative features make it increasingly strategic in steering the economic and social development worldwide. This paper analyzes the fundamentals and advantages of biotechnology and bioindustry in Tianjin in-depth, summarizes the overall planning and actions of Tianjin municipal government in supporting the development of biotechnology and bioindustry as well as the landmark achievements in recent years. It demonstrates that biotechnology is a promising path toward the high quality development of Tianjin, which will greatly contribute to the sustainable development of the national and regional economy and society, and transforming Tianjin into a socialist modern metropolis.

Abstract:Repurpose of key catalytic reaction and reconstruction of metabolic pathways all depend on in-depth understanding of the relevant proteins in protein engineering, green biomanufacturing and synthetic biology. The rapid development of synthetic biotechnology calls for proteins with excellent performance to fulfill the requirement for engineering enzymes and strains. The key is to prepare large quantities of target proteins with high purity, and study the structure-function relationship quickly and accurately. In the past 10 years, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences has built a protein structure-function study platform, and studied many proteins of industrial significance. Progress has been made on the terpene synthase related to natural plant products synthesis , PET plastic degradation related enzyme, and enzymes involved in biomass conversion and utilization. The structure-function study of these proteins provided theoretical basis for further engineering. Development of protein structure-function research technologies will facilitate the research of synthetic biology and promote biomanufacturing.

Abstract:As one of the underlying core technologies in the fields of synthetic biology and green bio-manufacturing, rational protein design is able to effectively solve generic challenges, e.g., improving insufficient performance of natural enzymes, and creating high-performance artificial enzymes. On the occasion of the 10th anniversary of the founding of the Tianjin Institute of Industrial Biotechnology (TIB), Chinese Academy of Sciences, this paper reviews the important progress of TIB achieved in rational design of industrial proteins, from the development of enzyme design methodology, the design of new enzyme reactions, to the applications of biocatalysis, and prospects future trends of this field. It is hoped that this will build a bridge between academia and industry on the rational design of enzymes, promote the development and application of new technologies and strategies. This will help merging the basic research and industrial application, thereby advancing the bio-manufacturing technological innovation.

Abstract:The development of green and low-carbon renewable energy systems has become an important international consensus. It is also an essential path for China to implement the dual-carbon strategy, ensure national energy security, and achieve sustainable development. This review introduces the theory of a new energy system based on electricity-hydrogen-carbohydrate (EHC) cycle, and highlights the biotransformations of carbohydrate/water-to-hydrogen, carbohydrate-to-electricity, and CO₂-to-carbohydrate powered by hydrogen- or electric-energy based on the in vitro synthetic enzymatic biosystems (ivSEB) developed by Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences in the past decade. We elaborate the design principle and the molecular basis of ivSEB, and further expand from the EHC cycle to in vitro biomanufacturing with starch as the feedstock. Combined with the latest research advances, we analyze and discuss advantages and disadvantages of ivSEB, prospect future directions, so as to promote the green, low-carbon and sustainable development of economy and society.

Abstract:Utilization of carbon dioxide (CO₂) is a huge challenge for global sustainable development. Biological carbon fixation occurs in nature, but the low energy efficiency and slow speed hamper its commercialization. Physical-chemical carbon fixation is efficient, but relies on high energy consumption and often generates unwanted by-products. Combining the advantages of biological, physical and chemical technologies for efficient utilization of CO₂ remains to be an urgent scientific and technological challenge to be addressed. Here, based on the development of Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences in the past decade, we summarize the important progress in the design and construction of functional parts, pathways and systems for artificial bioconversion of carbon dioxide, including the breakthrough on the artificial synthesis of starch from CO₂. Moreover, we prospect how to further develop the technologies for artificial bioconversion of carbon dioxide. These progress and perspectives provide new insight for achieving the goal of “carbon peaking and carbon neutrality”.

Abstract:DNA synthesis is one of the most basic, widely-used tools in life science as well as a key enabling technology in synthetic biology. The rapid development of industrial biotechnology promoted by synthetic biology is creating an insatiable demand for large-scale DNA synthesis from more convenient, economical and safe sources. Industrial DNA synthesis platforms have remarkable advantages in terms of throughput, cost and speed. The research and development processes of industrial biotechnology benefit from these advantages, achieving a higher efficiency and lower cost. However, challenges in DNA manufacturing process remain, such as the use of large amounts of organic reagents, waste of resources and so on. With the continuous and rapid increase of DNA synthesis scale, the hazard of toxic chemicals, cost burden and environmental burden are becoming prominent. Based on our practical work on DNA synthesis, we discuss the demand and strategies for large-scale DNA synthesis in industrial biotechnology as well as the issues and potential solutions for sustainable development.

Abstract:Precise and efficient manipulation of gene expression or rewriting genome sequence is the research hotspots of genome editing, and it is also the core enabling technology contributing to the rapid development of industrial biotechnology. Genome editing technology has experienced three stages of development, from zinc finger nuclease (ZFNs), to transcription activator like effector nuclease (TALEN) and Cas nuclease. Currently, vigorous development of CRISPR/Cas has enabled researchers establish a series of first-generation and second-generation Cas-based genome editing technologies. This contributed to the establishment and optimization for prokaryotic chassis such as Escherichia coli or eukaryotic chassis such as Saccharomyces cerevisiae. This paper summarizes the current development and application of industrial biotechnology using conventional chassis cells, and prospects future development trend with the aim to facilitate researchers to optimize industrial biotechnology and its potential applications.

Abstract:Various omics technologies are changing Biology into a data-driven science subject. Development of data-driven digital cell models is key for understanding system level organization and evolution principles of life, as well as for predicting cellular function under various environmental/genetic perturbations and subsequently for the design of artificial life. Consequently, the construction, analysis and design of digital cell models have become one of the core supporting technologies in synthetic biology. This paper summarized the research progress on digital cell models in the last ten years after the foundation of Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, with a focus on the development and quality control of genome-scale metabolic network for reliable metabolic pathway design and their application in guiding strain metabolic engineering. We also introduced the latest progress on developing cellular models with multiple constraints to improve prediction accuracy. At last, we briefly discussed the current challenges and future directions in digital cell model development. We believe that digital cell technology, along with genome sequencing, genome synthesis and genome editing, will greatly improve our ability in reading, writing, modifying and creating life.

Abstract:One of the revolutionary features of synthetic biology is that the standardization and modularization of biological experimental objects, methods, technologies and processes can be combined with various software and hardware to forge into an automated high-throughput synthetic biology biofoundry. Disrupting the conventional labor-intensive research paradigm, biofoundry represents a novel research paradigm with highly enhanced technical iteration capabilities, and remarkably promotes the development and industrial applications of synthetic biology. On the occasion of the 10th anniversary of the founding of Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, this review summarized a series of important achievements in the field of automated high-throughput editing and screening of industrial strains. These achievements range from automated editing technologies such as gene cloning, genome editing, and editing sequence design, to high-throughput screening technologies such as fluorescence activated cell sorting, fluorescence activated droplet sorting, and genome-scale gene perturb sequencing. Moreover, we prospected future development of this field, hoping to provide overall support for intelligent, automated and full chain integrated creation of excellent industrial strains with intellectual property rights.

Abstract:Artificial intelligence (AI) technology is booming up a new industrial revolution, and its successful application is rapidly spreading from the information industry to many other fields. The Artificial intelligence (AI) technology is booming up a new industrial revolution, and its successful application is rapidly spreading from the information industry to many other fields. The traditional fermentation industry also faces more opportunities and great challenges for reforming. First of all, the rapid development of synthetic biotechnology has greatly enhanced the availability and efficiency for obtaining high-performance strains, which poses great opportunities to the traditional fermentation optimization and scale-up technology. It is urgent to upgrade fermentation optimization technology to cope with the requirement for high-throughput verification of strain performance. Secondly, the development of fermentation equipment technology has laid a good foundation for advancing fermentation optimization technology. The application of AI technology, especially the digital twin and knowledge graph technology, will further boost the upgrade of the traditional fermentation technology. This review summarizes the challenges of fermentation optimization technology in the era of synthetic biology, the core technology of fermentation optimization and scale-up, the equipment technology of high-throughput fermentation, data visualization technology, as well as the application of digital twin and knowledge graph in fermentation optimization and scale-up. This review also prospects future industrial fermentation technology, and the associated new requirements for personnel training.

Abstract:Fermentation is a green, low-carbon and sustainable process for the production of food, chemicals, fuels, and materials by using microbial strains as biocatalysts and renewable resources such as starch and biomass as feedstocks. China has the world’s largest fermentation industry, the scale of amino acids, vitamins, and some other fermentation products accounted for 60%–80% of the global market share. The development of fermentation industry is of great significance for the strategic goal of “carbon neutralization and carbon peak” and the development of bioeconomy. Microbial strains are the core of fermentation industry, which directly decide what kind of chemical can be produced from what kind of feedstock at what cost. Innovating industrial strains to improve the conversion efficiency of raw materials, increase the production level, and expand product portfolio is the key to the high-quality development of fermentation industry. In recent years, the development of synthetic biology and systems biology has further deepened the understanding of the physiological and metabolic mechanisms of microbial chassis and accelerated the development of gene editing and other enabling technologies for strain design and engineering. All these advances have provided new driving force for the upgrading of industrial strains. This review focused on the representative fermentation products including amino acids, B vitamins, citric acid, and bio-ethanol. The latest progress of strain development for fermentation industry was reviewed from the perspective of basic research and technology innovation for industrial microbial chassis. How the integration of artificial intelligence and automation with life science will reshape the upgrading of industrial strains was also discussed.

Abstract:The green bio-manufacturing industry, characterized with high efficiency, safety, energy-saving, and environmental-friendliness, is a national strategic emerging industry with broad market prospect. Industrial enzyme is the “chip” of green biological process. The exploitation and application of new industrial enzymes is one of the core enabling technologies of green bio-manufacturing. This review introduces the current situation of industrial enzyme industry, followed by summarizing a series of key technical breakthroughs and research progress in industrial enzymes as well as green biological technologies and processes, which were developed by Tianjin institute of industrial biotechnology, Chinese Academy of Sciences in the past 10 years. Typical cases where traditional processing industry was promoted by the development and application of enzyme and green biological technologies were also presented. It is envisioned that development of these core technologies will enable more traditional processing industries transform into green and sustainable bio-based industry.

Abstract:In nature, chirality is a common phenomenon and closely related to life, also significantly influences the properties of the substance. The chemical synthesis of chiral pharmaceutical chemicals has encountered challenges such as poor atom economy and process economy, serious environmental pollution and waste of the resource. The biosynthesis route has the advantages of high selectivity and environmental-friendliness. In recent years, the rapid developments in the accessible key enzymes, understanding of catalytic mechanism, construction of new synthetic pathways of optical pure intermediates, process development and scale-up production have made it possible to address the challenges encountered in the production of active pharmaceutical ingredients, thus promoting a green and sustainable pharmaceutical industry in China. This review summarized the achievements made in this field by researchers at Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences.

Abstract:Plant natural products are one of the main sources of small molecule drugs, nutraceuticals, cosmetics and fragrances, and play an important role in economy development. At present, the way of obtaining plant natural products mainly depends on direct extraction from plants, which is farm land occupying and time consuming. The contents of active ingredients in plants are usually low, and thus the production cost is high. By elucidating the biosynthetic pathways and reconstructing the pathways in microbial cells, plant natural products can be produced by fermentation using renewable raw materials. Microbial biosynthesis provides a new route for the supply of plant natural products. This review summarizes the research progress of microbial synthesis of terpenoids, flavonoids, phenylpropanoids and other important natural products of plants in Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences. Current research challenges and future prospects are also briefly discussed.

Abstract:Plant biomass represents a vast resource of carbon. In China, it is estimated that 1 billion tons of biomass is available each year. The conversion of these biomass resources into bioethanol or other bio-based chemicals, if fully commercialized, may reduce at least 200 million tons of crude oil import. Therefore, bioethanol and bulk chemicals are the core components of the biomanufacturing using plant biomass as carbon sources. Since the foundation of Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (TIB, CAS), we have proposed a strategy of “two replacements and one upgrade”. Utilizing renewable carbon resources instead of non-renewable petrochemical resources to produce bulk chemicals is included in our strategy. It is a long-term effort for TIB to develop plant biomass biomanufacturing to produce renewable chemicals. Continuous and systematic research was carried out in these two fields, and significant progress has been made in the past 10 years since the foundation of TIB. Here we review the progress of TIB in this field, mainly focusing on fungal system, including the mechanism of cellulose degradation by filamentous fungi and the strategy of consolidated bioprocessing of biomass. Based on this, malic acid, fuel ethanol and other bulk chemicals were produced through one-step conversion of biomass. Besides, the commercial processes for production of bulk chemicals such as succinic and lactic acid from renewable carbon resources, which were developed by TIB, were also be discussed. These examples clearly demonstrated that bulk chemicals can be obtained from biomass instead of from petroleum. Research on plant biomass biotransformation and renewable chemicals production in TIB has provided an alternative route for the development of low-carbon bioeconomy in China, and will contribute to the goal of carbon neutralization of China.

Abstract:Affected by the rapid population growth, the unbalanced level of social and economic development, the aging population and unhealthy eating patterns, we are facing problems such as lack of food and nutrition, and the high incidence of nutrition related diseases. At the same time, the demand for low-carbon development calls for a sustainable food supply model. Therefore, technologies that meet the taste and nutritional needs of consumers, and serve as a green and sustainable food supply model, such as functional sugar, alternative meat and other future food technologies, have attracted increasing attention. The rapidly developed emerging biomanufacturing technology and its products will support the development of a green and low-carbon future food industry and trigger profound changes in the traditional production mode. Collectively, this represents a major strategic development direction of the emerging bioeconomy. This review summarizes the biomanufacturing technology of functional sugars, microbial proteins and key auxiliary ingredients of alternative meat. We discuss the latest progress in cell factory construction, strain evaluation and process optimization in industrial environment and derived product development. Moreover, future development trend was prospected, with the aim to facilitate industrial development of biomanufacturing of future food.

Abstract:Traditionally, amino acids are produced mainly by chemical synthesis or aerobic fermentation. Compared to chemical synthesis, production of amino acids by microbial fermentation directly uses renewable resources as feedstock and this reduces the dependence on petroleum-based compounds and decreases pollutants generation and toxic substrates usage. Fermentation under aerobic conditions has been used widely for its fast growth and high titers. However, a large amount of carbon is used for cell growth and this results in high biomass but low yield of target chemicals. Unlike the long history of aerobic fermentation, the commercial production of amino acids by anaerobic fermentation is realized only in recent years. It has several advantages such as simpler operation, no need for oxygen supply, and high yield close to the theoretical maximum value. L-alanine is the first amino acid commercially produced by anaerobic fermentation. In this article, we summarize the key technology for anaerobic fermentative production of L-alanine and its commercialization. As it is shown to be low-cost, high-efficiency, and environmental-friendly, anaerobic fermentation is expected to be widely used in industrial process and brings greater economic values and social benefits in the future.

Abstract:Steroidal hormone pharmaceuticals are the second largest class of medicines after antibiotics. At present, the initial materials of the steroidal industry have shifted from sapogenins, which were extracted from plants of the genus Dioscore to phytosterols. As a byproduct of soybean oil production, phytosterols are readily available and of low prices. Androstenedione (AD), androstadiendione (ADD), 9α-hydroxy-androstenedione (9α-OH-AD) and a series of key intermediates used in the synthesis of steroidal pharmaceuticals can be produced from phytosterols by microbial transformation. Nevertheless, due to the long metabolic pathways, the byproducts and the complex regulation, traditional microbial screening, mutagenizing methods and the oil-water biphasic transformation systems are no longer suitable for current industrial production. A new generation strains for the production of key steroidal pharmaceutical intermediates have been constructed and an intelligent production process has been jointly developed by us and Zhejiang Xianju Junye Pharmaceutical Co. Ltd.. Taking these products and processes as an example, this article reviews the improvement of strains for the production of steroidal pharmaceutical intermediates and the development of biotransformation process on an industrial scale. With the development of synthetic biology, it is expected to develop a new generation of intermediates which are more suitable for the synthesis of steroidal medicines. Moreover, de novo biosynthesis the steroidal active pharmaceutical ingredients from glucose is also expected. The application of these new-generation strains constructed by biotechnology (BT) in modern factories based on informatization and intelligent technology (IT) will be more efficient and greener, and create remarkable social and economic values.

Abstract:The fermentative production of L-glutamate is by far the largest among the amino acids commercially produced. L-glutamate is also the largest fermentation product in China in terms of the production scale. With the rapid development in synthetic biotechnology, production equipment and process technologies, the performance of industrial strains and the production technology of L-glutamate have been advanced remarkably in recent years. By analyzing the current situation of L-glutamate industry and the demand for innovation of key technologies, this review summarizes the research progress of L-glutamate production strains and technologies, as well as the development of other key technologies in L-glutamate production and industrial application.