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KAIST announced a novel technology to produce gasoline by a metabolically engineered microorganism
A major scientific breakthrough in the development of renewable energy sources and other important chemicals; The research team succeeded in producing 580 mg of gasoline per liter of cultured broth by converting in vivo generated fatty acids For many decades, we have been relying on fossil resources to produce liquid fuels such as gasoline, diesel, and many industrial and consumer chemicals for daily use. However, increasing strains on natural resources as well as environmental issues including global warming have triggered a strong interest in developing sustainable ways to obtain fuels and chemicals. Gasoline, the petroleum-derived product that is most widely used as a fuel for transportation, is a mixture of hydrocarbons, additives, and blending agents. The hydrocarbons, called alkanes, consist only of carbon and hydrogen atoms. Gasoline has a combination of straight-chain and branched-chain alkanes (hydrocarbons) consisted of 4-12 carbon atoms linked by direct carbon-carbon bonds. Previously, through metabolic engineering of Escherichia coli (E. coli), there have been a few research results on the production of long-chain alkanes, which consist of 13-17 carbon atoms, suitable for replacing diesel. However, there has been no report on the microbial production of short-chain alkanes, a possible substitute for gasoline. In the paper (entitled "Microbial Production of Short-chain Alkanes") published online in Nature on September 29, a Korean research team led by Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at the Korea Advanced Institute of Science and Technology (KAIST) reported, for the first time, the development of a novel strategy for microbial gasoline production through metabolic engineering of E. coli. The research team engineered the fatty acid metabolism to provide the fatty acid derivatives that are shorter than normal intracellular fatty acid metabolites, and introduced a novel synthetic pathway for the biosynthesis of short-chain alkanes. This allowed the development of platform E. coli strain capable of producing gasoline for the first time. Furthermore, this platform strain, if desired, can be modified to produce other products such as short-chain fatty esters and short-chain fatty alcohols. In this paper, the Korean researchers described detailed strategies for 1) screening of enzymes associated with the production of fatty acids, 2) engineering of enzymes and fatty acid biosynthetic pathways to concentrate carbon flux towards the short-chain fatty acid production, and 3) converting short-chain fatty acids to their corresponding alkanes (gasoline) by introducing a novel synthetic pathway and optimization of culture conditions. Furthermore, the research team showed the possibility of producing fatty esters and alcohols by introducing responsible enzymes into the same platform strain. Professor Sang Yup Lee said, "It is only the beginning of the work towards sustainable production of gasoline. The titer is rather low due to the low metabolic flux towards the formation of short-chain fatty acids and their derivatives. We are currently working on increasing the titer, yield and productivity of bio-gasoline. Nonetheless, we are pleased to report, for the first time, the production of gasoline through the metabolic engineering of E. coli, which we hope will serve as a basis for the metabolic engineering of microorganisms to produce fuels and chemicals from renewable resources." This research was supported by the Advanced Biomass Research and Development Center of Korea (ABC-2010-0029799) through the Global Frontier Research Program of the Ministry of Science, ICT and Future Planning (MSIP) through the National Research Foundation (NRF), Republic of Korea. Systems metabolic engineering work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (NRF-2012-C1AAA001-2012M1A2A2026556) by MSIP through NRF. Short-Chain Alkanes Generated from Renewable Biomass This diagram shows the metabolic engineering of Escherichia coli for the production of short-chain alkanes (gasoline) from renewable biomass. Nature Cover Page (September 29th, 2013)
A powerful strategy for developing microbial cell factories by employing synthetic small RNAs
The current systems for the production of chemicals, fuels and materials heavily rely on the use of fossil resources. Due to the increasing concerns on climate change and other environmental problems, however, there has been much interest in developing biorefineries for the production of such chemicals, fuels and materials from renewable resources. For the biorefineries to be competitive with the traditional fossil resource-based refineries, development of high performance microorganisms is the most important as it will affect the overall economics of the process most significantly. Metabolic engineering, which can be defined as purposeful modification of cellular metabolic and regulatory networks with an aim to improve the production of a desired product, has been successfully employed to improve the performance of the cell. However, it is not trivial to engineer the cellular metabolism and regulatory circuits in the cell due to their high complexity. In metabolic engineering, it is important to find the genes that need to be amplified and attenuated in order to increase the product formation rate while minimizing the production of undesirable byproducts. Gene knock-out experiments are often performed to delete those metabolic fluxes that will consequently result in the increase of the desired product formation. However, gene knock-out experiments require much effort and time to perform, and are difficult to do for a large number of genes. Furthermore, the gene knock-out experiments performed in one strain cannot be transferred to another organism and thus the whole experimental process has to be repeated. This is a big problem in developing a high performance microbial cell factory because it is required to find the best platform strain among many different strains. Therefore, researchers have been eager to develop a strategy that allows rapid identification of multiple genes to be attenuated in multiple strains at the same time. A Korean research team led by Distinguished Professor Sang Yup Lee at the Department of Chemical and Biomolecular Engineering from the Korea Advanced Institute of Science and Technology (KAIST) reported the development of a strategy for efficiently developing microbial cell factories by employing synthetic small RNAs (sRNAs). They first reported the development of such system in Nature Biotechnology last February. This strategy of employing synthetic sRNAs in metabolic engineering has been receiving great interest worldwide as it allows easy, rapid, high-throughput, tunable, and un-doable knock-down of multiple genes in multiple strains at the same time. The research team published a paper online on August 8 as a cover page (September issue) in Nature Protocols, describing the detailed strategy and protocol to employ synthetic sRNAs for metabolic engineering. In this paper, researchers described the detailed step-by-step protocol for synthetic sRNA-based gene expression control, including the sRNA design principles. Tailor-made synthetic sRNAs can be easily manipulated by using conventional gene cloning method. The use of synthetic sRNAs for gene expression regulation provides several advantages such as portability, conditionality, and tunability in high-throughput experiments. Plasmid-based synthetic sRNA expression system does not leave any scar on the chromosome, and can be easily transferred to many other host strains to be examined. Thus, the construction of libraries and examination of different host strains are much easier than the conventional hard-coded gene manipulation systems. Also, the expression of genes can be conditionally repressed by controlling the production of synthetic sRNAs. Synthetic sRNAs possessing different repression efficiencies make it possible to finely tune the gene expression levels as well. Furthermore, synthetic sRNAs allow knock-down of the expression of essential genes, which was not possible by conventional gene knock-out experiments. Synthetic sRNAs can be utilized for diverse experiments where gene expression regulation is needed. One of promising applications is high-throughput screening of the target genes to be manipulated and multiple strains simultaneously to enhance the production of chemicals and materials of interest. Such simultaneous optimization of gene targets and strains has been one of the big challenges in metabolic engineering. Another application is to fine tune the expression of the screened genes for flux optimization, which would enhance chemical production further by balancing the flux between biomass formation and target chemical production. Synthetic sRNAs can also be applied to finely regulating genetic interactions in a circuit or network, which is essential in synthetic biology. Once a sRNA scaffold-harboring plasmid is constructed, tailor-made, synthetic sRNAs can be made within 3-4 days, followed by the desired application experiments. Dr. Eytan Zlotorynski, an editor at Nature Protocols, said "This paper describes the detailed protocol for the design and applications of synthetic sRNA. The method, which has many advantages, is likely to become common practice, and prove useful for metabolic engineering and synthetic biology studies." This paper published in Nature Protocols will be useful for all researchers in academia and industry who are interested in the use of synthetic sRNAs for fundamental and applied biological and biotechnological studies. This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (NRF-2012-C1AAA001-2012M1A2A2026556) and the Intelligent Synthetic Biology Center through the Global Frontier Project (2011-0031963) of the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea.
Distinguished Professor Sang Yup Lee appointed as an advisor for Shanghai Jiao Tong University in China
In recognition of his outstanding accomplishments in the area of bioengineering, specializing in metabolic engineering, Sang Yup Lee, a distinguished professor of Chemical & Biomolecular Engineering at KAIST, was assigned as an advisory professor for the bioengineering department at Shanghai Jiao Tong University in China for five years from August 2013 to July 2018. Together with Peking University and Tsinghua University, Shanghai Jiao Tong University is one of the top three universities in China. The advisory professors carry out collaborated research programs in special areas and provide advice on education and research issues. Professor Lee, a specialist in metabolic engineering, has initiated systems metabolic engineering which integrates metabolic engineering, systems biology, and synthetic biology and has applied it to various chemical production systems to develop bio fuel and many eco-friendly chemical production processes. Recently, he received the Marvin J. Johnson Award from the American Chemistry Society, the Charles Thom Award from the American Society for Industrial Microbiology, as well as the Amgen Biochemical Engineering Award. As a global leader in the area of bioengineering, Professor Lee is a member of the Korean Academy of Science & Technology, the National Academy of Engineering of Korea, the US National Academy of Engineering, and is the chairman of the Global Agenda Council on Biotechnology at the World Economic Forum.
Top Ten Ways Biotechnology Could Improve Our Everyday Life
The Global Agenda Council on Biotechnology, one of the global networks under the World Economic Forum, which is composed of the world’s leading experts in the field of biotechnology, announced on February 25, 2013 that the council has indentified “ten most important biotechnologies” that could help meet rapidly growing demand for energy, food, nutrition, and health. These new technologies, the council said, also have the potential to increase productivity and create new jobs. “The technologies selected by the members of the Global Agenda Council on Biotechnology represent almost all types of biotechnology.Utilization of waste, personalized medicine,and ocean agricultureare examples of the challenges where biotechnology can offer solutions,”said Sang Yup Lee, Chair of the Global Agenda Council on Biotechnology and Distinguished Professor in the Department of Chemical and Biomolecular Engineering at the Korea Advanced Institute of Science and Technology (KAIST). He also added that “the members of the council concluded that regulatory certainty, public perception, and investment are the key enablers for the growth of biotechnology.” These ideas will be further explored during “Biotechnology Week” at the World Economic Forum’s Blog (http://wef.ch/blog) from Monday, 25 February, 2013. The full list follows below: Bio-based sustainable production of chemicals, energy, fuels and materials Through the last century, human activity has depleted approximately half of the world’s reserves of fossil hydrocarbons. These reserves, which took over 600 million years to accumulate, are non-renewable and their extraction, refining and use contribute significantly to human emissions of greenhouse gases and the warming of our planet. In order to sustain human development going forward, a carbon-neutral alternative must be implemented. The key promising technology is biological synthesis; that is, bio-based production of chemicals, fuels and materials from plants that can be re-grown. Engineering sustainable food production The continuing increase in our numbers and affluence are posing growing challenges to the ability of humanity to produce adequate food (as well as feed, and now fuel). Although controversial, modern genetic modification of crops has supported growth in agricultural productivity. In 2011, 16.7 million farmers grew biotechnology-developed crops on almost 400 million acres in 29 countries, 19 of which were developing countries. Properly managed, such crops have the potential to lower both pesticide use and tilling which erodes soil. Sea-water based bio-processes Over 70% of the earth surface is covered by seawater, and it is the most abundant water source available on the planet. But we are yet to discover the full potential of it. For example with halliophic bacteria capable of growing in the seawater can be engineered to grow faster and produce useful products including chemicals, fuels and polymeric materials. Ocean agriculture is also a promising technology. It is based on the photosynthetic biomass from the oceans, like macroalgae and microalgae. Non-resource draining zero waste bio-processing The sustainable goal of zero waste may become a reality with biotechnology. Waste streams can be processed at bio-refineries and turned into valuable chemicals and fuels, thereby closing the loop of production with no net waste. Advances in biotechnology are now allowing lower cost, less draining inputs to be used, including methane, and waste heat. These advances are simplifying waste streams with the potential to reduce toxicity as well as support their use in other processes, moving society progressively closer to the sustainable goal of zero waste. Using carbon dioxide as a raw material Biotechnology is poised to contribute solutions to mitigate the growing threat of rising CO2 levels. Recent advances are rapidly increasing our understanding of how living organisms consume and use CO2. By harnessing the power of these natural biological systems, scientists are engineering a new wave of approaches to convert waste CO2 and C1 molecules into energy, fuels, chemicals, and new materials. Regenerative medicine Regenerative medicine has become increasingly important due to both increased longevity and treatment of injury. Tissue engineering based on various bio-materials has been developed to speed up the regenerative medicine. Recently, stem cells, especially the induced pluripotent stem cells (iPS), have provided another great opportunity for regenerative medicine. Combination of tissue engineering and stem cell (including iPS) technologies will allow replacements of damaged or old human organs with functional ones in the near future. Rapid and precise development and manufacturing of medicine and vaccines A global pandemic remains one of the most real and serious threats to humanity. Biotechnology has the potential to rapidly identify biological threats, develop and manufacture potential cures. Leading edge biotechnology is now offering the potential to rapidly produce therapeutics and vaccines against virtually any target. These technologies, including messenger therapeutics, targeted immunotherapies, conjugated nanoparticles, and structure-based engineering, have already produced candidates with substantial potential to improve human health globally. Accurate, fast, cheap, and personalized diagnostics and prognostics Identification of better targets and combining nanotechnology and information technology it will be possible to develop rapid, accurate, personalized and inexpensive diagnostics and prognostics systems. Bio-tech improvements to soil and water Arable land and fresh water are two of the most important, yet limited, resources on earth. Abuse and mis-appropriation have threatened these resources, as the demand on them has increased. Advances in biotechnology have already yielded technologies that can restore the vitality and viability of these resources. A new generation of technologies: bio-remediation, bio-regeneration and bio-augmentation are being developed, offering the potential to not only further restore these resources, but also augment their potential. Advanced healthcare through genome sequencing It took more than 13 years and $1.5 billion to sequence the first human genome and today we can sequence a complete human genome in a single day for less than $1,000. When we analyze the roughly 3 billion base pairs in such a sequence we find that we differ from each other in several million of these base pairs. In the vast majority of cases these difference do not cause any issues but in rare cases they cause disease, or susceptibility to disease. Medical research and practice will increasingly be driven by our understanding of such genetic variations together with their phenotypic consequences.
An efficient strategy for developing microbial cell factories by employing synthetic small regulatory RNAs
A new metabolic engineering tool that allows fine control of gene expression level by employing synthetic small regulatory RNAs was developed to efficiently construct microbial cell factories producing desired chemicals and materials Biotechnologists have been working hard to address the climate change and limited fossil resource issues through the development of sustainable processes for the production of chemicals, fuels and materials from renewable non-food biomass. One promising sustainable technology is the use of microbial cell factories for the efficient production of desired chemicals and materials. When microorganisms are isolated from nature, the performance in producing our desired product is rather poor. That is why metabolic engineering is performed to improve the metabolic and cellular characteristics to achieve enhanced production of desired product at high yield and productivity. Since the performance of microbial cell factory is very important in lowering the overall production cost of the bioprocess, many different strategies and tools have been developed for the metabolic engineering of microorganisms. One of the big challenges in metabolic engineering is to find the best platform organism and to find those genes to be engineered so as to maximize the production efficiency of the desired chemical. Even Escherichia coli, the most widely utilized simple microorganism, has thousands of genes, the expression of which is highly regulated and interconnected to finely control cellular and metabolic activities. Thus, the complexity of cellular genetic interactions is beyond our intuition and thus it is very difficult to find effective target genes to engineer. Together with gene amplification strategy, gene knockout strategy has been an essential tool in metabolic engineering to redirect the pathway fluxes toward our desired product formation. However, experiment to engineer many genes can be rather difficult due to the time and effort required; for example, gene deletion experiment can take a few weeks depending on the microorganisms. Furthermore, as certain genes are essential or play important roles for the survival of a microorganism, gene knockout experiments cannot be performed. Even worse, there are many different microbial strains one can employ. There are more than 50 different E. coli strains that metabolic engineer can consider to use. Since gene knockout experiment is hard-coded (that is, one should repeat the gene knockout experiments for each strain), the result cannot be easily transferred from one strain to another. A paper published in Nature Biotechnology online today addresses this issue and suggests a new strategy for identifying gene targets to be knocked out or knocked down through the use of synthetic small RNA. A Korean research team led by Distinguished Professor Sang Yup Lee at the Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), a prestigeous science and engineering university in Korea reported that synthetic small RNA can be employed for finely controlling the expression levels of multiple genes at the translation level. Already well-known for their systems metabolic engineering strategies, Professor Lee’s team added one more strategy to efficiently develop microbial cell factories for the production of chemicals and materials. Gene expression works like this: the hard-coded blueprint (DNA) is transcribed into messenger RNA (mRNA), and the coding information in mRNA is read to produce protein by ribosomes. Conventional genetic engineering approaches have often targeted modification of the blueprint itself (DNA) to alter organism’s physiological characteristics. Again, engineering the blueprint itself takes much time and effort, and in addition, the results obtained cannot be transferred to another organism without repeating the whole set of experiments. This is why Professor Lee and his colleagues aimed at controlling the gene expression level at the translation stage through the use of synthetic small RNA. They created novel RNAs that can regulate the translation of multiple messenger RNAs (mRNA), and consequently varying the expression levels of multiple genes at the same time. Briefly, synthetic regulatory RNAs interrupt gene expression process from DNA to protein by destroying the messenger RNAs to different yet controllable extents. The advantages of taking this strategy of employing synthetic small regulatory RNAs include simple, easy and high-throughput identification of gene knockout or knockdown targets, fine control of gene expression levels, transferability to many different host strains, and possibility of identifying those gene targets that are essential. As proof-of-concept demonstration of the usefulness of this strategy, Professor Lee and his colleagues applied it to develop engineered E. coli strains capable of producing an aromatic amino acid tyrosine, which is used for stress symptom relief, food supplements, and precursor for many drugs. They examined a large number of genes in multiple E. coli strains, and developed a highly efficient tyrosine producer. Also, they were able to show that this strategy can be employed to an already metabolically engineered E. coli strain for further improvement by demonstrating the development of highly efficient producer of cadaverine, an important platform chemical for nylon in the chemical industry. This new strategy, being simple yet very powerful for systems metabolic engineering, is thus expected to facilitate the efficient development of microbial cell factories capable of producing chemicals, fuels and materials from renewable biomass. Source: Dokyun Na, Seung Min Yoo, Hannah Chung, Hyegwon Park, Jin Hwan Park, and Sang Yup Lee, “Metabolic engineering of Escherichia coli using synthetic small regulatory RNAs”, Nature Biotechnology, doi:10.1038/nbt.2461 (2013)
New BioFactory Technique Developed using sRNAs
Professor Sang Yup Lee - published on the online edition of Nature Biotechnology. “Expected as a new strategy for the bio industry that may replace the chemical industry.”- KAIST Chemical & Biomolecular engineering department’s Professor Sang Yup Lee and his team has developed a new technology that utilizes the synthetic small regulatory RNAs (sRNAs) to implement the BioFactory in a larger scale with more effectiveness. * BioFactory: Microbial-based production system which creates the desired compound in mass by manipulating the genes of the cell. In order to solve the problems of modern society, such as environmental pollution caused by the exhaustion of fossil fuels and usage of petrochemical products, an eco-friendly and sustainable bio industry is on the rise. BioFactory development technology has especially attracted the attention world-wide, with its ability to produce bio-energy, pharmaceuticals, eco-friendly materials and more. For the development of an excellent BioFactory, selection for the gene that produces the desired compounds must be accompanied by finding the microorganism with high production efficiency; however, the previous research method had a complicated and time-consuming problem of having to manipulate the genes of the microorganism one by one. Professor Sang Yup Lee’s research team, including Dr. Dokyun Na and Dr. Seung Min Yoo, has produced the synthetic sRNAs and utilized it to overcome the technical limitations mentioned above. In particular, unlike the existing method, this technology using synthetic sRNAs exhibits no strain specificity which can dramatically shorten the experiment that used to take months to just a few days. The research team applied the synthetic small regulatory RNA technology to the production of the tyrosine*, which is used as the precursor of the medicinal compound, and cadaverine**, widely utilized in a variety of petrochemical products, and has succeeded developing BioFactory with the world’s highest yield rate (21.9g /L, 12.6g / L each). *tyrosine: amino acid known to control stress and improve concentration **cadaverine: base material used in many petrochemical products, such as polyurethane Professor Sang Yup Lee highlighted the significance of this research: “it is expected the synthetic small regulatory RNA technology will stimulate the BioFactory development and also serve as a catalyst which can make the chemical industry, currently represented by its petroleum energy, transform into bio industry.” The study was carried out with the support of Global Frontier Project (Intelligent Bio-Systems Design and Synthesis Research Unit (Chief Seon Chang Kim)) and the findings have been published on January 20th in the online edition of the worldwide journal Nature Biotechnology.
Production of chemicals without petroleum
Systems metabolic engineering of microorganisms allows efficient production of natural and non-natural chemicals from renewable non-food biomass In our everyday life, we use gasoline, diesel, plastics, rubbers, and numerous chemicals that are derived from fossil oil through petrochemical refinery processes. However, this is not sustainable due to the limited nature of fossil resources. Furthermore, our world is facing problems associated with climate change and other environmental problems due to the increasing use of fossil resources. One solution to address above problems is the use of renewable non-food biomass for the production of chemicals, fuels and materials through biorefineries. Microorganisms are used as biocatalysts for converting biomass to the products of interest. However, when microorganisms are isolated from nature, their efficiencies of producing our desired chemicals and materials are rather low. Metabolic engineering is thus performed to improve cellular characteristics to desired levels. Over the last decade, much advances have been made in systems biology that allows system-wide characterization of cellular networks, both qualitatively and quantitatively, followed by whole-cell level engineering based on these findings. Furthermore, rapid advances in synthetic biology allow design and synthesis of fine controlled metabolic and gene regulatory circuits. The strategies and methods of systems biology and synthetic biology are rapidly integrated with metabolic engineering, thus resulting in "systems metabolic engineering". In the paper published online in Nature Chemical Biology on May 17, Professor Sang Yup Lee and his colleagues at the Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea present new general strategies of systems metabolic engineering for developing microorganisms for the production of natural and non-natural chemicals from renewable biomass. They first classified the chemicals to be produced into four categories based on whether they have thus far been identified to exist in nature (natural vs. nonnatural) and whether they can be produced by inherent pathways of microorganisms (inherent, noninherent, or created): natural-inherent, natural-noninherent, non-natural-noninherent, and non-natural-created ones. General strategies for systems metabolic engineering of microorganisms for the production of these chemicals using various tools and methods based on omics, genome-scale metabolic modeling and simulation, evolutionary engineering, synthetic biology are suggested with relevant examples. For the production of non-natural chemicals, strategies for the construction of synthetic metabolic pathways are also suggested. Having collected diverse tools and methods for systems metabolic engineering, authors also suggest how to use them and their possible limitations. Professor Sang Yup Lee said "It is expected that increasing number of chemicals and materials will be produced through biorefineries. We are now equipped with new strategies for developing microbial strains that can produce our desired products at very high efficiencies, thus allowing cost competitiveness to those produced by petrochemical refineries." Editor of Nature Chemical Biology, Dr. Catherine Goodman, said "It is exciting to see how quickly science is progressing in this field – ideas that used to be science fiction are taking shape in research labs and biorefineries. The article by Professor Lee and his colleagues not only highlights the most advanced techniques and strategies available, but offers critical advice to progress the field as a whole." The works of Professor Lee have been supported by the Advanced Biomass Center and Intelligent Synthetic Biology Center of Global Frontier Program from the Korean Ministry of Education, Science and Technology through National Research Foundation. Contact: Dr. Sang Yup Lee, Distinguished Professor and Dean, KAIST, Daejeon, Korea (firstname.lastname@example.org, +82-42-350-3930)
Bioengineers develop a new strategy for accurate prediction of cellular metabolic fluxes
A team of pioneering South Korean scientists has developed a new strategy for accurately predicting cellular metabolic fluxes under various genotypic and environmental conditions. This groundbreaking research is published in the journal Proceedings of the National Academy of Sciences of the USA (PNAS) on August 2, 2010. To understand cellular metabolism and predict its metabolic capability at systems-level, systems biological analysis by modeling and simulation of metabolic network plays an important role. The team from the Korea Advanced Institute of Science and Technology (KAIST), led by Distinguished Professor Sang Yup Lee, focused their research on the development of a new strategy for more accurate prediction of cellular metabolism. “For strain improvement, biologists have made every effort to understand the global picture of biological systems and investigate the changes of all metabolic fluxes of the system under changing genotypic and environmental conditions,” said Lee. The accumulation of omics data, including genome, transcriptome, proteome, metabolome, and fluxome, provides an opportunity to understand the cellular physiology and metabolic characteristics at systems-level. With the availability of the fully annotated genome sequence, the genome-scale in silico (means “performed on computer or via computer simulation.”) metabolic models for a number of organisms have been successfully developed to improve our understanding on these biological systems. With these advances, the development of new simulation methods to analyze and integrate systematically large amounts of biological data and predict cellular metabolic capability for systems biological analysis is important. Information used to reconstruct the genome-scale in silico cell is not yet complete, which can make the simulation results different from the physiological performances of the real cell. Thus, additional information and procedures, such as providing additional constraints (constraint: a term to exclude incorrect metabolic fluxes by restricting the solution space of in silico cell) to the model, are often incorporated to improve the accuracy of the in silico cell. By employing information generated from the genome sequence and annotation, the KAIST team developed a new set of constraints, called Grouping Reaction (GR) constraints, to accurately predict metabolic fluxes. Based on the genomic information, functionally related reactions were organized into different groups. These groups were considered for the generation of GR constraints, as condition- and objective function- independent constraints. Since the method developed in this study does not require complex information but only the genome sequence and annotation, this strategy can be applied to any organism with a completely annotated genome sequence. “As we become increasingly concerned with environmental problems and the limits of fossil resources, bio-based production of chemicals from renewable biomass has been receiving great attention. Systems biological analysis by modeling and simulation of biological systems, to understand cellular metabolism and identify the targets for the strain improvement, has provided a new paradigm for developing successful bioprocesses,” concluded Lee. This new strategy for predicting cellular metabolism is expected to contribute to more accurate determination of cellular metabolic characteristics, and consequently to the development of metabolic engineering strategies for the efficient production of important industrial products and identification of new drug targets in pathogens.”
Native-like Spider Silk Produced in Metabolically Engineered Bacterium
Microscopic picture of 285 kilodalton recombinant spider silk fiber Researchers have long envied spiders’ ability to manufacture silk that is light-weighted while as strong and tough as steel or Kevlar. Indeed, finer than human hair, five times stronger by weight than steel, and three times tougher than the top quality man-made fiber Kevlar, spider dragline silk is an ideal material for numerous applications. Suggested industrial applications have ranged from parachute cords and protective clothing to composite materials in aircrafts. Also, many biomedical applications are envisioned due to its biocompatibility and biodegradability. Unfortunately, natural dragline silk cannot be conveniently obtained by farming spiders because they are highly territorial and aggressive. To develop a more sustainable process, can scientists mass-produce artificial silk while maintaining the amazing properties of native silk? That is something Sang Yup Lee at the Korea Advanced Institute of Science and Technology (KAIST) in Daejeon, the Republic of Korea, and his collaborators, Professor Young Hwan Park at Seoul National University and Professor David Kaplan at Tufts University, wanted to figure out. Their method is very similar to what spiders essentially do: first, expression of recombinant silk proteins; second, making the soluble silk proteins into water-insoluble fibers through spinning. For the successful expression of high molecular weight spider silk protein, Professor Lee and his colleagues pieced together the silk gene from chemically synthesized oligonucleotides, and then inserted it into the expression host (in this case, an industrially safe bacterium Escherichia coli which is normally found in our gut). Initially, the bacterium refused to the challenging task of producing high molecular weight spider silk protein due to the unique characteristics of the protein, such as extremely large size, repetitive nature of the protein structure, and biased abundance of a particular amino acid glycine. “To make E. coli synthesize this ultra high molecular weight (as big as 285 kilodalton) spider silk protein having highly repetitive amino acid sequence, we helped E. coli overcome the difficulties by systems metabolic engineering,” says Sang Yup Lee, Distinguished Professor of KAIST, who led this project. His team boosted the pool of glycyl-tRNA, the major building block of spider silk protein synthesis. “We could obtain appreciable expression of the 285 kilodalton spider silk protein, which is the largest recombinant silk protein ever produced in E. coli. That was really incredible.” says Dr. Xia. But this was only step one. The KAIST team performed high-cell-density cultures for mass production of the recombinant spider silk protein. Then, the team developed a simple, easy to scale-up purification process for the recombinant spider silk protein. The purified spider silk protein could be spun into beautiful silk fiber. To study the mechanical properties of the artificial spider silk, the researchers determined tenacity, elongation, and Young’s modulus, the three critical mechanical parameters that represent a fiber’s strength, extensibility, and stiffness. Importantly, the artificial fiber displayed the tenacity, elongation, and Young’s modulus of 508 MPa, 15%, and 21 GPa, respectively, which are comparable to those of the native spider silk. “We have offered an overall platform for mass production of native-like spider dragline silk. This platform would enable us to have broader industrial and biomedical applications for spider silk. Moreover, many other silk-like biomaterials such as elastin, collagen, byssus, resilin, and other repetitive proteins have similar features to spider silk protein. Thus, our platform should also be useful for their efficient bio-based production and applications,” concludes Professor Lee. This work is published on July 26 in the Proceedings of the National Academy of Sciences (PNAS) online.
Inauguration ceremony for the 14th President of KAIST held on July 14, 2010
President Nam Pyo Suh was sworn in as the 14th President of KAIST at an inauguration ceremony taken place on July 14, 2010. He has become the first incumbent president who succeeded to secure a second term in office. While vowing to continue to make his efforts in developing KAIST as one of the world’s leading science and technology universities, President Suh noted, in his inauguration address, that “over the past four years, KAIST has instituted many difficult and controversial policies and procedures, and as a result, the university has become more competitive and stronger for the future.” The president also laid out major goals of education policies and principles to be implemented in the next four years. The full text of the inauguration address follows below: ----------------------------------------------------------------- Inauguration Address Nam Pyo Suh The 14th President of KAIST July 14, 2010 Members of the KAIST family: Thank you for joining this illustrious gathering to commemorate the commencement of the 14th Presidency of KAIST. In many respects, this is the beginning of a new era for KAIST. Today, we march forward – more boldly, more confidently than perhaps ever before – in our mission to become one of the world’s leading science and technology universities. I am indeed honored – and humbled – to be leading this effort for KAIST. I do not take this responsibility lightly, and I would like to express my extreme gratitude to the many people who have given me their confidence and support, without which I would not be standing here today. In particular, I would like to thank the Chairman of KAIST Board of Trustees, Chung Moon Soul, for his guidance and unwavering support. He has been an inspirational leader for KAIST, and it has been my singular honor to learn from and work with him. I also would like to thank all the other members of the Board of Trustees, each of whom has provided thoughtful and productive advice and guidance. I would also like to thank Minister Ahn Byung Man, Vice Minister Kim Joong Hyun, Director Kim Young Sik and Director General Yoon Hun Ju for their support of KAIST and my reappointment as the President of KAIST. Their continuing support of KAIST has enabled KAIST to make major strides toward achieving its goal of becoming one of the best universities in the world. While this commencement signals a beginning, we are building upon a rich past. There are many who have admirably led and served KAIST since its birth in 1971. They achieved a great deal for the good of our beloved institution and for Korea. And thanks to the tremendous efforts of many here today, the past four years have been especially fruitful ones in KAIST’s history. Today, KAIST stands as one of the world’s major research universities. No other university outshines us in terms of the quality of professors, staff and students, financial support for faculty and students, and our physical infrastructure. KAIST has become an idea factory, where education and research co-mingle to create solutions and establish new paradigms that benefit humanity – both present and future. You can see this clearly in the intellectual vigor and “can-do” attitude that permeates our campus. In the field of research, our faculty, students, and staff have made seminal contributions to science and technology – contributions that will change the history of science and technology, and hence the way society functions and people think. In the field of education, our enhanced programs are empowering students with the ability to understand issues, analyze problems, and synthesize solutions. Our physical environment, which is key to the quality of education and research that KAIST provides, has also improved with many newly constructed and renovated buildings, thanks to the generous support of major donors from all around the world, the Korean government, and the Korean people. Today, scholars in a number of countries across five continents pay attention to what we do here at KAIST. We are indeed blazing new pathways in many fields that will guide the work of future generations of scientists and engineers. All this has not been achieved without sacrifice. Over the last four years, we have instituted many difficult and often controversial policies and procedures. I believe these have helped KAIST become more competitive and stronger for the future. But change affects people and institutions in both negative and positive ways. While these new policies have benefited some, I am acutely aware that they have, at the same time, caused discomfort and pain for others. To those who have suffered because of the changes that have been made during the past four years, I ask for your understanding and offer my sincere apologies. We must endeavor to minimize the negative consequences of transformation, as we strive mightily to realize our dreams for this great institution. To do so, we, as a community, must first redefine and recommit to common goals: First, we must arm our students with the ability to think both creatively and logically, to work collegially across cultures, and to lead wisely and with integrity. We must give our students the foundation to become players on the world stage, whether they become captains of industry, heads of state, or leading inventors and academics. Second, we must also support our professors as they impart their vast knowledge and experiences with students. We must also enable them to fulfill their aspirations to become the world’s leading scientists, engineers, and scholars. Third, we must direct KAIST’s energies toward addressing the most pressing problems of the 21st century. Let us not forget that we have a responsibility far greater than ourselves. Finally, we must execute all these undertakings well for the benefit of the Korean people, in whose service KAIST was established 40 years ago. It may now be the right time for us to assess our efforts over the last four years and set the course ahead. KAIST’s successes are largely due to our professors. They have made major discoveries and inventions, which have won them international awards and recognitions. They have received significant research grants and contracts from many government agencies and companies, which have enabled KAIST to make unique contributions. They have published outstanding research results in leading journals and obtained patents in many countries. These achievements have helped bolster KAIST’s global standing. KAIST professors have more opportunities to pursue research because our enviable financial structure provides the ideal balance between teaching and research. I can think of only a few other universities in the world that have such a situation. With these opportunities, we also have our share of challenges. One of the pressing challenges is to hire more professors, since 50 percent of our faculty will retire in 10 years. We will apply some of the gifts KAIST has received to create several junior chaired professorships to recruit promising talent. We also will work with the government to receive more faculty positions to prepare for the future. KAIST also has an outstanding group of staff members, who manages all phases of KAIST’s operations, including our relationships with government and industry. Their workload has been heavy, since we have undertaken many major research projects and innovative educational programs during the past four years. I salute the effort of our staff for the job well done. To reward exceptional performance, we must improve our personnel policies so that the most productive and creative staff members are recognized and promoted in a timely manner. Because of the achievements of our faculty and staff, the Korean people and friends abroad have responded with their support. Major gifts by Chairman Chung Moon Soul, the generosity of Dr. and Mrs. BJ Park, Chairman and Mrs. Neil Pappalardo, Dr. Lyu Keun Chul, Chairman and Mrs. Donald Kim, Chairman and Mrs. Kim Byung-Ho, Chairman and Mrs. Cho Chun-Sik, Chairman Bae Hwi-Yul, Chairman Lee Chong-Moon, Dr. Lim Hyung-Kyu, Chairman Lee Hak-Yong, Dr. Kang Baek-Hyun, Chairman Mr. Ahn Seung-Pil, Mr. Chung Seung-Ryul and his family, and thousands of other donors, including those who wish to remain anonymous, have made KAIST much more competitive. The number of donors has increased exponentially during the past four years to over 4,300 benefactors. On behalf of all members of the KAIST family, I say, “Thank you.” While KAIST is stronger than ever financially, we have a long way to go to be competitive with richer universities of the world. It is up to us to show that we deserve the continued support of the Korean people and our benefactors. We have almost completed the construction of seven new buildings and are about to start four more construction projects. While significant, KAIST still has many old buildings and facilities that require extensive maintenance. We must continue to raise the quality of KAIST’s infrastructure to support the groundbreaking research and teaching being undertaken in these buildings. Because we have neglected some of these buildings for so long, it will take a massive investment to renovate them. Not one of the accomplishments of the past four years could have been made without the world-class leadership of vice presidents, deans, directors, and department heads. They have worked day and night to lead our university. I am particularly indebted to Provost Chang Soon Heung, who has led all aspects of KAIST’s operations. Vice President Yang Jiwon has ably dealt with our relationship with government and external organizations. Vice President Kim Sang Soo has played a key role in establishing and operating the KAIST Institutes, including the construction of the Park KI Building. Vice President Kang Minho effectively led the integration of KAIST and ICU. Dean of Academic Affairs Lee Kwang Hyung has done a superb job of administering our academic programs. Dean of Students Paik Kyung Wook has successfully dealt with all matters pertaining to the well-being of students. Dean Im Yong Taek has been outstanding in all aspects of our relationship with outside organizations. Dean for Research Professor Yang Hyun Seung, Dean for Academic Information Yoon Hyun Soo, Dean for Admissions Kim Do Kyung, Dean for EEWS Lee Jae Kyu, and Dean for Technology Transfer Park Sunwon have been exemplary leaders of KAIST. Our academic deans, Dean Do Young Kyu, Dean Dong Won Kim, Dean Sang Yup Lee, Dean Seung O Park, Dean Lee Yong Hoon, and Dean Ravi Kumar have shown great leadership and served KAIST most effectively. Professor Kim Soo Hyun has done a great job for the KAIST Development Foundation and for the KAIST Alumni Association. Director Lee Sang Moon has been a distinguished leader of our administration. Also I would like to thank the head of the Planning Office Jang Jae Suk and Team Leader Kim Kihan for their exceptional work, notwithstanding the difficult tasks they had to perform. Many of our faculty members who have not held any office formally have made KAIST what it is today. Their commitment, scholarship, mentorship to our students, and their service for KAIST and Korea have made strengthened KAIST as an institution. In this regard, I would like to thank Professor Kim Jung Hoi for his great leadership of the Faculty Association. Finally, I owe a great debt and special thanks to my office staff. Chief of Staff Won Dong Hyuck has been an exceptional colleague in executing the work of the office of the President of KAIST. He was ably assisted by Mr. Cho Boram, Ms. Hong Yoonju, and Mr. Kang Yong Seop. They have worked tirelessly and their achievements on behalf of KAIST have been tremendous. I would be remiss not to recognize the most important member of my life, my wife, who shares my commitment and passion for KAIST’s success. Without her undying support and wise counsel, I would not be here today. I am eternally grateful. There is a great deal of exciting and challenging work ahead. We will now begin to form a new team for the next phase of KAIST’s development. As of August 1, 2010, Professor Choi Byung Kyu will be the Provost, Professor Yang Dong Yul will be VP in charge of KI and research, Professor Joo Dae Joon will be VP for External Affairs, and Professor Lee Gyun Min will be the Dean for Academic Affairs. There will be some other changes as well. I ask each and every one of you to give them your support as they undertake new tasks for KAIST. Our work will not be easy. We must move forward with an unparalleled dedication to excellence, a palpable and contagious sense of enthusiasm, a genuine trust in and respect for one another, and an unfailing belief in what KAIST should and can be. I pledge to do my best to serve you and KAIST most effectively. With your help and through our work, we will fuel the pride into Korea and its people through the education of our young people and through innovative research that will fundamentally change our world for the better. Thank you.
The 8th International Conference on Metabolic Engineering was held on June 13-18, 2010 in Jeju Island, South Korea.
From left to right, top row: Distinguished Professor and the conference chair Sang Yup Lee, Sang-Hyup Kim - Secretary to the President of Korea, Dr. Jay Keasling, Dr. Greg Stephanopoulos. Left to right, bottom row: Dr. William Provine, Dr. Terry Papoutsakis, Dr, Jens Nielsen, Dr. Lars Nielsen. The importance of industrial biotechnology that produces chemicals and materials from renewable biomass is increasing due to climate change and the dearth of natural resources. Industrial biotechnology refers to a technology that allows sustainable bio-based production of chemicals and materials that could enrich human"s lives using microorganisms. This is where metabolic engineering comes into play for successful application of microorganisms, in which they are engineered in our intended way for improved production capability. The 8th International Conference on Metabolic Engineering, the longest running conference of its kind, was held on June 13-18, 2010 at the International Convention Center in Jeju Island, South Korea. Distinguished Professor Sang Yup Lee of KAIST, Dean of College of Life Science and Bioengineering and Co-Director of Institute for the BioCentury, chaired the conference with the main theme of "metabolic engineering for green growth." With 300 delegates selected by the committee, papers on production of biofuels, chemicals, biopolymers, and pharmaceutics and the development of fundamental metabolic engineering techniques were presented at the conference along with examples of successful commercialization of products developed by several global companies. Sang Hyup Kim, Secretary to the President of Korea, gave an opening plenary lecture entitled "Korean green growth initiative," to inform experts from around the globe of the leadership on green growth in Korea. Young Hoon Park, President of Korea Research Institute of Bioscience and Biotechnology (KRIBB, Korea) delivered his congratulatory address. Sang Hyup Kim said, "Hosting an international conference in Korea on metabolic engineering, which forms a core technology necessary for the development of environmentally friendly processes for producing chemicals and biofuels from renewable biomass, is very meaningful as green growth is a big issue around the globe. This is a great chance to show the excellence of Korea"s green growth associated technology to experts in metabolic engineering and industrial biotechnology." A total of 47 invited lectures in this conference included recent and important topics, for instance, "Synthetic biology for synthetic fuels" by Dr. Jay Keasling from the Joint BioEnergy Institute (USA), "Microbial oil production from renewable feedstocks" by Dr. Greg Stephanopoulos from MIT (USA), "Yeast as a platform cell factory for production of fuels and chemicals" by Dr. Jens Nielsen from Chalmers University (Sweden), "Mammalian synthetic biology - from tools to therapies" by Dr. Martin Fussengger from ETH (Switzerland), "Building, modeling, and applications of metabolic and transcriptional regulatory networks at a genome-scale" by Dr. Bernhard Palsson from the University of California - San Diego (USA), "Genome analysis and engineering Eschericha coli for sucrose utilization" by Dr. Lars Nielsen from the University of Queensland (Australia), "Artificial microorganisms by synthetic biology" by Dr. Daniel Gibson from JCVI (USA), and "Metabolomics and its applications" by Dr. Masaru Tomita from Keio University (Japan). From Korea, Dr. Jin Hwan Park from the research group of Dr. Sang Yup Lee at KAIST presented "Systems metabolic engineering of Escherichia coli for amino acid production," and Dr. Ji Hyun Kim from KRIBB presented "Genome sequencing and omics systems analysis of the protein cell factory of Escherichia coli". Global companies involved in biorefinery presented their recent research outcomes with emphasis on commercialized technologies. They included "Metabolic and process engineering for commercial outcomes" by Dr. William Provine from DuPont (USA), "Direct production of 1,4-butanediol from renewable feedstocks" by Dr. Mark Burk from Genomatica (USA), "Development of an economically sustainable bioprocess for the production of bio 1,2-propanediol" by Dr. Francis Voelker from Metabolic Explorer (France), "Biotechnology to the bottom-line: low pH lactic acid production at industrial scale" by Dr. Pirkko Suominen from Cargill (USA), "Bioisoprene™: traditional monomer, traditional chemistry, sustainable source" by Dr. Gregg Whited from Danisco (USA) and "Efficient production of pharmaceuticals by engineered fungi" by Dr. Roel Bovenberg from DSM (Netherlands). This biennial conference also presented the International Metabolic Engineering Award (expanded version of the previous Merck Metabolic Engineering Award) to the best metabolic engineer in the world. The 2010 International Metabolic Engineering Award went to Dr. E. Terry Papoutsakis from the University of Delaware (USA) who has contributed to the production of biobutanol through the metabolic engineering of Clostridia in the last three decades, and he gave an award lecture. Dr. Sang Yup Lee, the current chair of the upcoming conference, was the previous recipient of this award at the last metabolic engineering conference in 2008. In addition to the invited lectures, a total of 156 carefully selected poster papers were chosen for presentation, and awards were presented to the best posters after rigorous review by the committee members. Such awards included "The 2010 Metabolic Engineering Best Poster Award" and the "2010 Young Metabolic Engineer Award" from the Metabolic Engineering conference, and prestigious international journal awards, including "Wiley Biotechnology Journal Best Poster Award", "Wiley Biotechnology and Bioengineering Best Poster Award" and "Elsevier Metabolic Engineering Best Paper Award." Dr. Catherine Goodman, a senior editor of Nature Chemical Biology, also presented the "Nature Chemical Biology Best Poster Award on Metabolic Engineering." Regarding this conference, Dr. Sang Yup Lee, the conference chair, said, "This conference is the best international conference in the field of metabolic engineering, which is held every two years, and Korea is the first Asian country to host it. All the experts and students spend time together from early breakfast to late poster sessions, which is a distinct feature of this conference. Although the number of delegates had typically been limited to 200, around 300 delegates were selected this year to accept more attendees from many people who have been interested in metabolic engineering. Also, it is very fitting that "green growth" is the main topic of this conference because Korea is playing a key role in this field. I"m grateful to the Lotte Scholarship Foundation, COFCO, GS Caltex, Bioneer, US DOE, US NSF, Daesang, CJ Cheiljedang, Genomatica and DuPont who provided us with generous financial support that allowed the successful organization of this conference." The conference was organized by the Systems Biology Research Project Team supported by the Ministry of Eduction, Science and Technology (MEST), Microbial Frontier Research Project Group, World Class University Project Group at KAIST, Institute for the BioCentury at KAIST, Korean Society for Biotechnology and Bioengineering, and the Engineering Conference International (ECI) of the United States. Inquiries: Professor Sang Yup Lee (+82-42-350-3930), email@example.com
New drug targeting method for microbial pathogens developed using in silico cell
A ripple effect is expected on the new antibacterial discovery using “in silico” cells Featured as a journal cover paper of Molecular BioSystems A research team of Distinguished Professor Sang Yup Lee at KAIST recently constructed an in silico cell of a microbial pathogen that is resistant to antibiotics and developed a new drug targeting method that could effectively disrupt the pathogen"s growth using the in silico cell. Hyun Uk Kim, a graduate research assistant at the Department of Chemical and Biomolecular Engineering, KAIST, conducted this study as a part of his thesis research, and the study was featured as a journal cover paper in the February issue of Molecular BioSystems this year, published by The Royal Society of Chemistry based in Europe. It was relatively easy to treat infectious microbes using antibiotics in the past. However, the overdose of antibiotics has caused pathogens to increase their resistance to various antibiotics, and it has become more difficult to cure infectious diseases these days. A representative microbial pathogen is Acinetobacter baumannaii. Originally isolated from soils and water, this microorganism did not have resistance to antibiotics, and hence it was easy to eradicate them if infected. However, within a decade, this miroorganism has transformed into a dreadful super-bacterium resistant to antibiotics and caused many casualties among the U.S. and French soldiers who were injured from the recent Iraqi war and infected with Acinetobacter baumannaii. Professor Lee’s group constructed an in silico cell of this A. baumannii by computationally collecting, integrating, and analyzing the biological information of the bacterium, scattered over various databases and literatures, in order to study this organism"s genomic features and system-wide metabolic characteristics. Furthermore, they employed this in silico cell for integrative approaches, including several network analysis and analysis of essential reactions and metabolites, to predict drug targets that effectively disrupt the pathogen"s growth. Final drug targets are the ones that selectively kill pathogens without harming human body. Here, essential reactions refer to enzymatic reactions required for normal metabolic functioning in organisms, while essential metabolites indicate chemical compounds required in the metabolism for proper functioning, and their removal brings about the effect of simultaneously disrupting their associated enzymes that interact with them. This study attempted to predict highly reliable drug targets by systematically scanning biological components, including metabolic genes, enzymatic reactions, that constitute an in silico cell in a short period of time. This research achievement is highly regarded as it, for the first time, systematically scanned essential metabolites for the effective drug targets using the concept of systems biology, and paved the way for a new antibacterial discovery. This study is also expected to contribute to elucidating the infectious mechanism caused by pathogens. "Although tons of genomic information is poured in at this moment, application research that efficiently converts this preliminary information into actually useful information is still lagged behind. In this regard, this study is meaningful in that medically useful information is generated from the genomic information of Acinetobacter baumannii," says Professor Lee. "In particular, development of this organism"s in silico cell allows generation of new knowledge regarding essential genes and enzymatic reactions under specific conditions," he added. This study was supported by the Korean Systems Biology Project of the Ministry of Education, Science and Technology, and the patent for the development of in silico cells of microbial pathogens and drug targeting methods has been filed. [Picture 1 Cells in silico] [Picture 2 A process of generating drug targets without harming human body while effectively disrupting the growth of a pathogen, after predicting metabolites from in silico cells]
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