Frontier Research and Translational Applications of Synthetic Biology

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HUANG Jiandong, Professor
Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 999077, China.

Professor Huang has long been engaged in theoretical and applied research in synthetic biology.

Article List

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  • 1  Frontier Research and Translational Applications of Synthetic Biology
    HUANG Jiandong
    2021, 10(4):1-2. DOI: 10.12146/j.issn.2095-3135.20210601001
    [Abstract](381) [HTML](0) [PDF 618.29 K](1832)
    Abstract:
    2  Analysis on the Trends of Synthetic Biology Research in Medical Applications
    LI Yujuan QIU Huabing LIU Tianqing XIA Lin
    2021, 10(4):3-16. DOI: 10.12146/j.issn.2095-3135.20210510002
    [Abstract](231) [HTML](0) [PDF 2.45 M](1719)
    Abstract:
    Synthetic biology is an emerging and popular engineering science in the field of life sciences.Its essence is to rationally design, transform and even resynthesize biological systems according to specific goals under the guidance of engineering thoughts, and to study the life sciences focusing on basic problems or major challenges of human beings by constructing artificial biological systems. The core of synthetic biology is to understand the essence of life (build to learn) and creating social and economic value (build to use) through research. Synthetic biotechnology has been evaluated by many countries as one of the disruptive technologies in the future. With broad application prospects in the biomedical field, synthetic biology has become a disruptive science and technology field that developed countries such as Europe and the United States are striving to develop. Based on bibliometrics and patent analysis of synthetic biomedicine, synthetic biomedicine-related literature and patents have shown explosive growth since 2014. The development of synthetic biomedicine in the United States has first-mover advantages, outstanding achievements, while China with outstanding strength is catching up with and surpassing by degrees. This article analyzes the development trend of synthetic biomedicine applications in order to provide a reference for the development and layout of synthetic biomedicine in China.
    3  Strategies for the Application of Engineered Phages in Solving Bacterial Tolerance problems
    ZHANG He ZHANG Xinyu AN Wenlin TONG Yigang
    2021, 10(4):17-32. DOI: 10.12146/j.issn.2095-3135.20210427014
    [Abstract](317) [HTML](0) [PDF 1.04 M](1549)
    Abstract:
    The development of bacterial resistance to antimicrobial drugs is a major challenge in the clinical treatment of infectious diseases and has received widespread attention. Bacteria acquire resistance through a variety of mechanisms to evade killing by antimicrobial drugs. Phage is a generic term for bacteriophage that infects microorganisms such as bacteria, fungi, actinomycetes or spirochetes. Its application in the treatment of infectious diseases with drug-resistant bacteria in clinical settings has achieved some success in recent years, but the ensuing problem of phage resistance has limited its application. This paper reviews the main mechanisms of bacterial drug resistance and phage resistance, and the main current advances in synthetic biology in addressing bacterial resistance to antibiotics and resistance to natural phages.
    4  The Application of CRISPR/Cas in Directed Evolution
    JIN Fan LI Fengting XIA Lin
    2021, 10(4):33-49. DOI: 10.12146/j.issn.2095-3135.20210427012
    [Abstract](386) [HTML](0) [PDF 2.39 M](2027)
    Abstract:
    To gain the desirable activity of biomolecules, directed evolution is served as a competent technology depending on high quality mutant library, effective selection and screening, which has been widely used in food, industry and medical fields. CRISPR (clustered regularly interspaced short palindromic repeats) has developed rapidly in recent years, and various CRISPR derivatives have been developed to meet directed evolution, allowing people to evolve specific genes in situ in a wide range of hosts. At the same time, the way of generating genetic diversity through artificial or natural pathways has given people more choices, and more efficient evolution strategies can be adopted according to research needs. This article will first introduce the CRISPR tools, then summarize the CRISPR-mediated mutation and screening platforms and finally discuss the development trends and opportunities of the CRISPR in the field of directed evolution.
    5  Current therapies for Pseudomonas Aeruginosa Infection
    JIN Fan GAO Yanmei HUANG Yajia PU Lu XIA Lin
    2021, 10(4):50-66. DOI: 10.12146/j.issn.2095-3135.20210427010
    [Abstract](341) [HTML](0) [PDF 1.47 M](3499)
    Abstract:
    Pseudomonas aeruginosa has strong intrinsic antibiotic drug resistance and the ability to acquire further resistance mechanisms to multiple antibiotics. Therefore, for patients with Pseudomonas aeruginosa infection, the emergence of multidrug-resistant Pseudomonas aeruginosa often means that the efficacy of antibiotics has deteriorated or even completely ineffective. The development of new antibiotics takes a long time and is costly. Therefore, looking for new antibacterial drugs to replace antibiotics, finding new drug carriers, and new treatment methods to increase the activity of antibacterial drugs against multidrug resistant Pseudomonas aeruginosa infection treatment is of great significance. In this paper, some basic laboratory and clinical studies about using organic acids, antimicrobial peptides, nanoparticles, bacteriophages, hydrogels, bacterias in the treatment of Pseudomonas aeruginosa infection were reviewed and summarized to provide a reference for the treatment of multi-antibiotics resistant Pseudomonas aeruginosa infection.
    6  Recent Progress in Bio-Engineered Nanoparticles for Epstein-Barr Virus Vaccines
    HUANG Jiandong HUANG Kun
    2021, 10(4):67-77. DOI: 10.12146/j.issn.2095-3135.20210427003
    [Abstract](222) [HTML](0) [PDF 1.19 M](1363)
    Abstract:
    Epstein-Barr virus causes a ubiquitous infection in adults worldwide. It is also a oncogenic virus that is associated with many cancers, including nasopharyngeal carcinoma which is one of the predominant tumor in South China. However, so far, a vaccine against Epstein-Barr virus was not yet available in the world and there is no effective immunotherapy against those Epstein-Barr virus associated carcinomas. With the advantages of high stability, biocompatibility, low toxicity and multifunctional regions, the nextgeneration nanoparticles has been successfully applied in the research of Epstein-Barr virus vaccines. In this article, the recent advances of nanoparticles, including exosomes, virus-like particles, self-assembling ferritin nanoparticles and other nanoparticles using for prevention and against of Epstein-Barr virus infections have been reviewed and further discussed. Finally, the opportunities and challenges faced by engineered nanoparticles in the clinical application are prospected.
    7  Application of Synthetic Biology in Promoting Preclinical and Clinical Advances of Bacterial Anti-Cancer Therapy
    LIU Chenli DONG Yuxuan GUO Xuan
    2021, 10(4):78-92. DOI: 10.12146/j.issn.2095-3135.20210427011
    [Abstract](336) [HTML](0) [PDF 1.12 M](1752)
    Abstract:
    Bacteriotherapy is one of the important direction in the field of cancer therapy. The increasing development of synthetic biology provides more diversified, more effective and safer therapeutic strategies for bacterial anti-cancer therapy. In this review, the excellent clinical examples in the field of bacterial anti-cancer therapy are summarized, the current research progress and bottleneck problems are introduced in detail. The application of synthetic biology in promoting the clinical development of live bacterial therapeutics is also discussed. Moreover, the important role and the future development trend of synthetic biology are prospected in view of the effectiveness and biosafety of clinical live bacterial therapeutics.
    8  Research Progress in Bacterial Tumor Therapy
    HUANG Jiandong WEI Mengxi ZHOU Nan
    2021, 10(4):93-101. DOI: 10.12146/j.issn.2095-3135.20210427004
    [Abstract](482) [HTML](0) [PDF 955.09 K](3233)
    Abstract:
    The efficacy of current anti-tumor therapies has suffered from possible side effects and the poor accessibility of drugs to the tumor core. Although a variety of bacteria in nature have the potential to be used as anti-tumor drugs, lacking controllability and potential safety issues have limited their usage in tumor treatment. With the development of synthetic biology, bacteria are extensively programmed under engineering disciplines to possess less toxicity and enhanced ability to target tumors, sense the lesions and locate the lesions accurately. Applying engineered bacteria as vectors to directly carry drugs or express and release molecular therapeutics has greatly improved the efficacy of the tumor treatment. This article will summarize the recent progress in engineering bacteria for the treatment of tumors.
    9  Advances in Intestinal Microbial Communities and Challenges in Synthetic Microbial Communities
    HU Zheng ZHOU Qian ZHANG Mengmeng XIAO Minfeng
    2021, 10(4):102-114. DOI: 10.12146/j.issn.2095-3135.20210427008
    [Abstract](276) [HTML](0) [PDF 1.07 M](1855)
    Abstract:
    In recent years, research on the intestinal microbial communities and human health has developed rapidly. However, the regulation and application of the intestinal microbial community are still in their infancy. The reason for this is that our understanding of the structure and function of the human gut microbiome is inadequate. Synthetic microbiota is a new microbial community established by artificial synthesis of multiple species, which is simulated, tested, and optimized by various experimental models and mathematical modeling methods in vitro and in vivo. It is helpful to deepen the understanding of the structure, stability, and functional activity of the complex microbiota in the human gut. We summarized the research methods of the intestinal microbiome, the factors affecting the stability of the intestinal microbiome, and the challenges facing the synthesis of the intestinal microbiome, in order to provide a reference for the bidirectional transformation of the theoretical research and clinical application of intestinal microbial community.
    10  Bacterial Single-Cell Culture and Real Time Observation Under Strict Anaerobic Condition Based on Microfluidic Technology
    MA Zhixin DENG Yufang YU Yue LI Sihong LIANG Fan XIA Lin HUANG Shuqiang
    2021, 10(4):115-125. DOI: 10.12146/j.issn.2095-3135.20210427001
    [Abstract](262) [HTML](0) [PDF 1.87 M](1925)
    Abstract:
    There are two trends in current microbiological research. First, researchers have increasingly realized that intestinal microbes, especially a large number of anaerobic bacteria, are closely related to human health with the development of intestinal microbe-related research. Because the intestine itself belongs to an anaerobic environment to a certain extent, the cell physiology research of intestinal bacteria needs to be based on the anaerobic culture environment. Second, it is difficult to meet the requirements of cell heterogeneity only by relying on classical microbial population culture methods. Research on heterogeneity requires the development of methods to study bacterial physiology at the single-cell level for in-depth study of the physiological laws that are hidden by cell populations and ignored by researchers. Here, a method is developed for culturing bacteria under anaerobic conditions, including the design of related culturing equipment and corresponding experimental procedures. Based on stably maintaining the strict anaerobic condition of the culture environment, the microfluidic chip is used to long-term singlecell culture. Combined with high-resolution microscope time-lapse imaging technology, the real-time observation and data collection of growth dynamics of single bacterial cell can be realized. This method provides powerful technical support for single-cell analysis of bacterial cells under anaerobic conditions.
    11  Construction of Lung-on-a-Chip for High-Resolution Imaging and Application of Pneumonia Model
    XIN Ying XU Baoqi WANG Junjie ZHANG Rongrong WEN Hui WANG Jinjuan LIANG Fan JIN Fan LIANG Zhuo HUANG Jiandong HUANG Shuqiang
    2021, 10(4):126-136. DOI: 10.12146/j.issn.2095-3135.20210427007
    [Abstract](299) [HTML](0) [PDF 1.92 M](1604)
    Abstract:
    The lung is an important part of the human respiratory system, and the airway epithelium is the first barrier between the lung and the external. It is involved in defending against foreign particles, pathogens, etc, expelling foreign bodies as sputum and plays a vital role in maintaining the normal function of the respiratory tract. Commonly used in vitro cell culture models and mammalian models cannot fully simulate the human lung-airway microenvironment yet, and have limitations in the study of human cellpathogen interactions and drug development. In this research, we designed a microfluidic chip by improving the preparation process to meet the requirements of very short working distance of high magnification microscope for high-resolution imaging. The lung-on-a-chip reproduced the air-liquid interface airway epithelial culture, simulated human lung-airway microenvironment and obtained real-time observation of the co-culture process of cells and bacteria. It provides a powerful research platform for studying the interaction between airway epithelium and pathogenic microorganisms in vitro.
    12  Application of Artificial Intelligence in Synthetic Biology: A Review
    LI Min LIN Zijie LIAO Wenbin CHEN Tingbo LI Jianqiang CHEN Jie XIAO Minfeng
    2021, 10(5):43-56. DOI: doi: 10.12146/j.issn.2095-3135.20210510001
    [Abstract](424) [HTML](0) [PDF 1.90 M](2557)
    Abstract:
    Living systems are extremely sophisticated and difficult to accurately describe and predict, posing challenges in designing synthetic biological systems. Therefore, massively parallel trial-and-error processes are often required to optimize synthetic biological systems. In recent years, intelligent technology has experienced rapid development and has demonstrated continual learning capacity from massive data and intelligent exploring ability in unknown space, which perfectly meets the needs of the current trial-and error platform of synthetic biology engineering and shows great potential in mining complex biological patterns and in designing biosystems. This article reviews the progresses of applying artificial intelligence (AI) in the fields of synthetic biological parts engineering, circuit engineering, metabolic engineering, and genome engineering. This article also analyzes a series of challenges in data standardization, platform intellectualization, experimental automation, and accurate prediction of cross-over studies between AI and synthetic biology. By solving these challenges, the entire workflow of “design-build-test-learn” in synthetic biology is expected to be revolutionized by AI, and creating an “AI synthetic biologist” would in turn lead to the technological advances in AI.
    13  Cell Cycle Synchronization and Its Application in the Studies of Bacterial Cell Cycle
    FU Xiongfei HUANG Xiongliang XIA Lin
    2021, 10(5):57-66. DOI: doi: 10.12146/j.issn.2095-3135.20210427013
    [Abstract](364) [HTML](0) [PDF 1.10 M](1891)
    Abstract:
    Population of cells, growing under constant conditions, is a mixture of cells at different stages of the cell cycle. To study specific stage of the cell cycle, synchronization methods are required to make cells grow synchronously. Physical or chemical methods can be used to isolate subpopulation of cells at distinct cell cycle stages or to block cells at certain stage. Via synchronization methods, cell population can grow and divide synchronously during the subsequent culture and maintain 2-3 cycles. As a direct and powerful method, cell cycle synchronization attracts great interests of scientists in the field of bacterial cell cycle researches. Although there are many kinds of synchronization methods, different methods have their own advantages and disadvantages in terms of the degree of synchronization, yield, ease of operation steps, and the degree of interference to the cell cycle. This paper aims to introduce the cell cycle synchronization methods used in the bacterial cell cycle studies and what advantages or disadvantages they have.
    14  A Novel Design and Experimental Tests of a Small Distance Device for High Throughout Electroporation
    WANG Zhong CUI Jinming TOKUYASU Taku Andrew
    2021, 10(5):67-71. DOI: doi: 10.12146/j.issn.2095-3135.20210427006
    [Abstract](112) [HTML](0) [PDF 1.19 M](1093)
    Abstract:
    Electroporation technology can penetrate the cell membrane by reversibly applying a certain electric field, forming holes or pathways in the cell membrane, so that the genetic material can be transferred into the cell. Traditional electroporation devices often require several hundred to several thousand volts and are very dangerous to operate. In this study, an electrically insulated polyvinyl chloride (PVC) film was used to make a small distance electroporation device with the electrodes’ distance of 80 μm, which can undertake high flux operation. The experiments show that the proposed small distance electroporation device facilitates cell electroporation with the voltage one order of magnitude lower than the 1 mm standard shock cup, greatly enhance the safety of the experimental operation, high flux also greatly improves the efficiency of experimental operation. But the electroporation efficiency is one order of magnitude lower, and experimental parameters need to be further optimized.
    15  Design and Implementation of Metabolic Pathway Based on Multi-path Breadth-first Searching Algorithm
    HUANG Zucheng SHEN Mengyuan HOU Zhicheng TOKUYASU Taku Andrew MENG Hailin
    2021, 10(5):72-79. DOI: doi: 10.12146/j.issn.2095-3135.20210427005
    [Abstract](186) [HTML](0) [PDF 1.49 M](1664)
    Abstract:
    To find possible reactions that exist in metabolic networks is essential for metabolic engineering. The K-shortest path (KSP) algorithm is a traditional method that is usually used to identify alternative metabolic pathways. To improve the computation efficiency of conventional KSP method, an efficient KSP-based searching method is proposed in this paper. The basic idea is to introduce the critical edge to reduce the redundant calculation. A web-platform is constructed to design metabolic pathways. The parallel computing technique is introduced to improve the computing efficiency. The proposed method is validated on the KEGG metabolic pathways map, and the results show that the proposed method improve the computation efficiency by 5-9 times, compared with the traditional KSP algorithm.
    16  The Review of DNA Synthesis Technologies and Instruments Development
    JIANG Xianger WANG Yong SHEN Yue
    2021, 10(5):80-95. DOI: doi: 10.12146/j.issn.2095-3135.20210427002
    [Abstract](647) [HTML](0) [PDF 2.16 M](3543)
    Abstract:
    Comparing with genome sequencing, which facilitates the digitization of life, synthetic biology has enabled human beings to explore the nature of life and promote the cross-disciplinary applications in medicine, chemical industry, agriculture and IT technologies. Since DNA synthesis serves as the fundamental technology of synthetic biology. This paper makes a systematic review of DNA synthesis technology and its instrumental development. In addition, the current technical bottlenecks and potential approaches for breaking through are also discussed.
    17  Recombinant Expression and Functional Analysis of bkt Gene and crtR-B Gene in Synechocystis sp. PCC 6803
    LIU Yaming WANG Kang CUI Yulin CHEN Gao QIN Song
    2021, 10(5):96-103. DOI: doi: 10.12146/j.issn.2095-3135.20210427015
    [Abstract](163) [HTML](0) [PDF 1.59 M](1414)
    Abstract:
    The β-carotene ketolase gene (bkt) and β-carotene hydroxylase gene (crtR-B) from Haematococcus pluvialis were codon-optimized and transferred to Synechocystis sp. PCC 6803 genome by natural transformation method. High performance liquid chromatography analysis showed that cells transfected with bkt gene produced canthaxanthin, while echinone decreased; the cells with crtR-B gene produced adonixanthin, while zeaxanthin was reduced. The results showed that the exogenous β-carotene ketolase converted echinone to canthaxanthin and the exogenous β-carotene hydroxylase converted zeaxanthin into adonixanthin. In this paper, the pathway of astaxanthin biosynthesis in Synechocystis sp. PCC 6803 was constructed by metabolic engineering strategy, which laid a foundation for astaxanthin production in Synechocystis sp. PCC 6803 with metabolic engineering.
    18  Strategic Research of the Development and Financing Status of Synthetic Biology Industry
    ZENG Zhengyang LIU Xinyu MA Mingju AN Yishuo ZHANG Yihao LUO Wei XIA Lin
    2021, 10(5):104-116. DOI: doi: 10.12146/j.issn.2095-3135.20210511001
    [Abstract](608) [HTML](0) [PDF 1.34 M](2329)
    Abstract:
    As a multidisciplinary approach, synthetic biology has been developing for almost two decades. It involves almost all fields of biological research, combines the modules of engineering and abstract concepts, introduces new quantitative research methods, and improves people’s understanding of life system. Unlike traditional basic science or single technology, the complexity of synthetic biology significantly increases people’s capacity to apply biology and distribute it among different applications. At present, synthetic biology has made remarkable achievements in the development of enable technology, the establishment of synthetic biology platform, and the application in medical treatment, agriculture and food, and bio-based goods, promoting the development of the blue ocean market. Based on the concept of synthetic biology, numerous companies have emerged in many industrial areas recently. Some startups have thrived, and dominant companies have commercialized the technology through cost advantages. Based on this, the paper briefly introduces and analyzes the development of the synthetic biology industry, combining enterprise type, technology platform and financing conditions to provide reference for the development of technology, industry and investment in synthetic biology.
    19  Analysis on the Development Frontier of Global Synthetic Biology Industry
    QIU Weilong LIAO Xiuling LUO Wei LI Hang XIA Lin ZHANG Lan
    2021, 10(5):117-127. DOI: doi: 10.12146/j.issn.2095-3135.20210427009
    [Abstract](471) [HTML](0) [PDF 1.13 M](2108)
    Abstract:
    Synthetic biology is experiencing rapid growth and commercialization in the second decade of the 21st century, after an earlier groundbreaking technological innovation and initial exploration of commercialization. This paper combs and analyzes the current situation of global synthetic biology industry from three aspects: market scale, industry financing and industry development. The analysis shows, in terms of market scale, the synthetic biology market is growing rapidly, but there is an obvious gap in its scale in different geographical regions and industrial fields; in terms of industry financing, the investment and financing trend of synthetic biology industry shows an obvious upward trend. In 2020, the number and amount of investment and financing events in synthetic biology industry reached a historical record, but the development between different geographical regions is still unbalanced; in terms of industry development, the landing application scenarios of synthetic biology are very diverse, have taken root in all walks of life, and show great application potential.

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