Opportunities for yeast metabolic engineering: Lessons from synthetic biology

Constant progress in genetic engineering has given rise to a number of promising areas of research that facilitated the expansion of industrial biotechnology. The field of metabolic engineering, which utilizes genetic tools to manipulate microbial metabolism to enhance the production of compounds of interest, has had a particularly strong impact by providing new platforms for chemical production. Recent developments in synthetic biology promise to expand the metabolic engineering toolbox further by creating novel biological components for pathway design. The present review addresses some of the recent advances in synthetic biology and how these have the potential to affect metabolic engineering in the yeast Saccharomyces cerevisiae. While S. cerevisiae for years has been a robust industrial organism and the target of multiple metabolic engineering trials, its potential for synthetic biology has remained relatively unexplored and further research in this field could strongly contribute to industrial biotechnology. This review also addresses are general considerations for pathway design, ranging from individual components to regulatory systems, overall pathway considerations and whole-organism engineering, with an emphasis on potential contributions of synthetic biology to these areas. Some examples of applications for yeast synthetic biology and metabolic engineering are also discussed.     

Translational synthetic biology

Synthetic biology is a recent scientific approach towards engineering biological systems from both pre-existing and novel parts. The aim is to introduce computational aided design approach in biology leading to rapid delivery of useful applications. Though the term reprogramming has been frequently used in the synthetic biology community, currently the technological sophistication only allows for a probabilistic approach instead of a precise engineering approach. Recently, several human health applications have emerged that suggest increased usage of synthetic biology approach in developing novel drugs. This mini review discusses recent translational developments in the field and tries to identify some of the upcoming future developments.     

Synthetic therapeutic gene circuits in mammalian cells

In the emerging field of synthetic biology, scientists are focusing on designing and creating functional devices, systems, and organisms with novel functions by engineering and assembling standardised biological building blocks. The progress of synthetic biology has significantly advanced the design of functional gene networks that can reprogram metabolic activities in mammalian cells and provide new therapeutic opportunities for future gene- and cell-based therapies. In this review, we describe the most recent advances in synthetic mammalian gene networks designed for biomedical applications, including how these synthetic therapeutic gene circuits can be assembled to control signalling networks and applied to treat metabolic disorders, cancer, and immune diseases. We conclude by discussing the various challenges and future prospects of using synthetic mammalian gene networks for disease therapy.     

从DNA合成技术角度阐述合成生物学

合成生物学是一个拥有巨大潜力的新兴学科,合成生物学技术的发展将会对未来生物、医药、农业、能源、材料和环保等方面产生巨大的推进作用。基因合成是合成生物学中最基本和使用最多的一种技术手段,合成生物学的快速发展对基因合成能力提出了空前需求。综述基因合成技术的发展历史、现状和未来趋势,探讨基因合成技术存合成生物学以及整个生命科学研究中的应用和重要意义。     

Microbial production of small peptide: pathway engineering and synthetic biology

Small peptides are a group of natural products with low molecular weights and complex structures. The diverse structures of small peptides endow them with broad bioactivities and suggest their potential therapeutic use in the medical field. The remaining challenge is methods to address the main limitations, namely (i) the low amount of available small peptides from natural sources, and (ii) complex processes required for traditional chemical synthesis. Therefore, harnessing microbial cells as workhorse appears to be a promising approach to synthesize these bioactive peptides. As an emerging engineering technology, synthetic biology aims to create standard, well-characterized and controllable synthetic systems for the biosynthesis of natural products. In this review, we describe the recent developments in the microbial production of small peptides. More importantly, synthetic biology approaches are considered for the production of small peptides, with an emphasis on chassis cells, the evolution of biosynthetic pathways, strain improvements and fermentation.     

Synthetic biology advancing clinical applications

The 'omics' era, with its identification of genetic and protein components, has combined with systems biology, which provided insights into network structures, to set the stage for synthetic biology, an emerging interdisciplinary life science that uses engineering principles. By capitalizing on an iterative design cycle that involves molecular and computational biology tools to assemble functional designer devices from a comprehensive catalogue of standardized biological components with predictable functions, synthetic biology has significantly advanced our understanding of complex control dynamics that program living systems. Such insights, collected over the past decade, are priming a variety of synthetic biology-inspired biomedical applications that have the potential to revolutionize drug discovery and production technologies, as well as treatment strategies for infectious diseases and metabolic disorders.     

Understanding drugs and diseases by systems biology?

Systems biology aims to provide a holistic and in many cases dynamic picture of biological function and malfunction, in case of disease. Technology developments in the generation of genome-wide datasets and massive improvements in computer power now allow to obtain new insights into complex biological networks and to copy nature by computing these interactions and their kinetics and by generating in silico models of cells, tissues and organs. The expectations are high that systems biology will pave the way to the identification of novel disease genes, to the selection of successful drug candidates—that do not fail in clinical studies due to toxicity or lack of human efficacy—and finally to a more successful discovery of novel therapeutics. However, further research is necessary to fully unleash the potential of systems biology. Within this review we aim to highlight the most important and promising top-down and bottom-up systems biology applications in drug discovery.     

Synthetic Genomics and Synthetic Biology Applications Between Hopes and Concerns

New organisms and biological systems designed to satisfy human needs are among the aims of synthetic genomics and synthetic biology. Synthetic biology seeks to model and construct biological components, functions and organisms that do not exist in nature or to redesign existing biological systems to perform new functions. Synthetic genomics, on the other hand, encompasses technologies for the generation of chemically-synthesized whole genomes or larger parts of genomes, allowing to simultaneously engineer a myriad of changes to the genetic material of organisms. Engineering complex functions or new organisms in synthetic biology are thus progressively becoming dependent on and converging with synthetic genomics. While applications from both areas have been predicted to offer great benefits by making possible new drugs, renewable chemicals or clean energy, they have also given rise to concerns about new safety, environmental and socio-economic risks – stirring an increasingly polarizing debate. Here we intend to provide an overview on recent progress in biomedical and biotechnological applications of synthetic genomics and synthetic biology as well as on arguments and evidence related to their possible benefits, risks and governance implications.     

Exploiting plug-and-play synthetic biology for drug discovery and production in microorganisms

One of the most promising applications of synthetic biology is the biosynthesis of new drugs from secondary metabolites. Here, we survey a wide range of strategies that control the activity of biosynthetic modules in the cell in space and time, and illustrate how these strategies can be used to design efficient cellular synthetic production systems. Re-engineered versions of secondary metabolite biosynthetic pathways identified from any genomic sequence can then be inserted into these systems in a plug-and-play fashion.     

Programming living sensors for environment,health and biomanufacturing

Synthetic biology offers new tools and capabilities of engineering cells with desired functions for example as new biosensing platforms leveraging engineered microbes. In the last two decades, bacterial cells have been programmed to sense and respond to various input cues for versatile purposes including environmental monitoring, disease diagnosis and adaptive biomanufacturing. Despite demonstrated proof-of-concept success in the laboratory, the real-world applications of microbial sensors have been restricted due to certain technical and societal limitations. Yet, most limitations can be addressed by new technological developments in synthetic biology such as circuit design, biocontainment and machine learning. Here, we summarize the latest advances in synthetic biology and discuss how they could accelerate the development, enhance the performance and address the present limitations of microbial sensors to facilitate their use in the field. We view that programmable living sensors are promising sensing platforms to achieve sustainable, affordable and easy-to-use on-site detection in diverse settings.     

Innovation at the intersection of synthetic and systems biology

The promises of modern biotechnology hinge upon the hope that we can understand microscopic cellular complexity and in doing so create novel function. In this regard, the fields of systems and synthetic biology are important for accelerating both our understanding of biological systems and our ability to quantitatively engineer cells. At the nexus of these two fields is a unique synergy that can help attain these goals. Thus, the next greatest advances in biology and biotechnology are arising at the intersection of the top-down systems approach and the bottom-up synthetic approach. Collectively, these developments enable the precise control of cellular state for systems studies and the discovery of novel parts, control strategies, and interactions for the design of robust synthetic function. This review seeks to highlight this activity as well as provide a perspective for future directions. Combining these efforts can provide novel insights into cellular function and lead to robust, novel synthetic design.     

基于合成基因线路的智能药物

合成生物学自诞生以来对生物学领域的研究产生了重要的影响。利用工程学思维与方法,合成生物学揭开了生命系统许多调控机制,改造并扩展了一系列生物元件,同时带来了广泛的生物医学应用,为疾病诊断与治疗提供了新的思路。本文综述了适用于哺乳动物细胞或者细菌的合成基因线路并用于疾病诊断与治疗领域的最新进展,为未来智能药物设计提供新的思路。     

哺乳动物合成生物学在生物医学领域的研究进展

虽然合成生物学还处于早期研究阶段,但最近十年,该领域取得了非常显著的研究进展。合成生物学是以工程学思想为基础,通过人工设计、改造基因线路,从而赋予细胞或生物体新的功能,现已广泛应用于各个领域。随着人们对基因线路设计的深入研究,使得合成生物学研究走向临床应用成为可能。本文将围绕哺乳动物合成生物学在疾病治疗方面的研究进展,介绍基因线路的设计思路和方法、不同诱导因子调控的开环式基因线路以及用于疾病诊疗的闭环式基因环路在生物医学领域的应用。最后对合成生物学走向临床治疗的应用前景和挑战进行展望。     

Engineering and applications of genetic circuits

In the field of synthetic biology, recent genetic engineering efforts have enabled the construction of novel genetic circuits with diverse functionalities and unique activation mechanisms. Because of these advances, artificial genetic networks are becoming increasingly complex, and are demonstrating more robust behaviors with reduced crosstalk between defined modules. These properties have allowed for the identification of a growing set of design principles that govern genetic networks, and led to an increased number of applications for genetic circuits in the fields of metabolic engineering and biomedical engineering. Such progress indicates that synthetic biology is rapidly evolving into an integrated engineering practice that uses rational and combinatorial design of synthetic gene networks to solve complex problems in biology, medicine, and human health.     

Systems solutions by lactic acid bacteria: from paradigms to practice

Lactic acid bacteria are among the powerhouses of the food industry, colonize the surfaces of plants and animals, and contribute to our health and well-being. The genomic characterization of LAB has rocketed and presently over 100 complete or nearly complete genomes are available, many of which serve as scientific paradigms. Moreover, functional and comparative metagenomic studies are taking off and provide a wealth of insight in the activity of lactic acid bacteria used in a variety of applications, ranging from starters in complex fermentations to their marketing as probiotics. In this new era of high throughput analysis, biology has become big science. Hence, there is a need to systematically store the generated information, apply this in an intelligent way, and provide modalities for constructing self-learning systems that can be used for future improvements. This review addresses these systems solutions with a state of the art overview of the present paradigms that relate to the use of lactic acid bacteria in industrial applications. Moreover, an outlook is presented of the future developments that include the transition into practice as well as the use of lactic acid bacteria in synthetic biology and other next generation applications.     

非常规酵母的分子遗传学及合成生物学研究进展

先进的合成生物学技术与传统的分子遗传学技术的结合更有助于实现酵母底盘细胞的快速改造和优化。酵母合成生物学研究最早开始于常规酵母——酿酒酵母(Saccharomyces cerevisiae),近些年来又迅速扩展至一些非常规酵母,包括巴斯德毕赤酵母(Pichiapastoris)、解脂耶氏酵母(Yarrowialipolytica)、乳酸克鲁维酵母(Kluyveromyces lactis)和多形汉逊酵母(Hansenula polymorpha)等。借助合成生物学技术与工具,目前科学家们已经成功开发出了能够高效生产生物材料、生物燃料、生物基化学品、蛋白质制剂、食品添加剂和药物等工业产品的重组非常规酵母工程菌株。本文系统总结了合成生物学工具(主要是基因组编辑工具)、合成生物学组件(主要是启动子和终止子)和相关分子遗传学方法在上述非常规酵母系统(底盘细胞)中的最新研究进展和应用情况,并讨论了其他合成生物学技术在这些非常规酵母表达系统中的潜在适用性和应用前景。这为研究人员利用合成生物学方法在这一新型非模式微生物底盘细胞中设计和构建各种高附加值工业产品的异源合成模块并最终实现目标化合物的高效生物合成提供了科学的理论指导。     

Harnessing synthetic biology for mushroom farming

Recent advances in synthetic biology have transformed mushroom farming from a focus on traditional cultivation to comprehensive applications based on cutting-edge biotechnologies. Synthetic biology has promising applications in this field, including precision breeding, mining biosynthetic gene clusters, developing mushroom chassis cells, and constructing cell factories for high value-added products.     

Microbial synthetic biology for human therapeutics

The emerging field of synthetic biology holds tremendous potential for developing novel drugs to treat various human conditions. The current study discusses the scope of synthetic biology for human therapeutics via microbial approach. In this context, synthetic biology aims at designing, engineering and building new microbial synthetic cells that do not pre-exist in nature as well as re-engineer existing microbes for synthesis of therapeutic products. It is expected that the construction of novel microbial genetic circuitry for human therapeutics will greatly benefit from the data generated by ??omics?? approaches and multidisciplinary nature of synthetic biology. Development of novel antimicrobial drugs and vaccines by engineering microbial systems are a promising area of research in the field of synthetic biology for human theragnostics. Expression of plant based medicinal compounds in the microbial system using synthetic biology tools is another avenue dealt in the present study. Additionally, the study suggest that the traditional medicinal knowledge can do value addition for developing novel drugs in the microbial systems using synthetic biology tools. The presented work envisions the success of synthetic biology for human therapeutics via microbial approach in a holistic manner. Keeping this in view, various legal and socio-ethical concerns emerging from the use of synthetic biology via microbial approach such as patenting, biosafety and biosecurity issues have been touched upon in the later sections.     

合成生物学中的DNA组装技术

合成生物学旨在应用工程学的研究思路及手段去设计或改造生物系统,是一个综合了科学与工程的拥有发展潜力的新兴学科,在生物医药、农业、能源、环保等方面发挥着巨大作用。DNA组装技术是合成生物学中的关键技术,也是合成生物学快速发展的限制性技术。综述了众多DNA组装技术的发展及其在合成生物学研究中的意义和应用。