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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)
2013.11.04
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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.
2013.10.31
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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.
2013.10.31
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Professor Kwang-Hyun Cho publishes Encyclopaedia of Systems Biology
Professor Kwang-Hyun Cho KAIST Biological and Brain Engineering Department’s Professor Kwang-Hyun Cho edited the Encyclopaedia of Systems Biology with three scholars, all experts of Systems Biology in England, Germany and the United States. It is rare that a Korean scientist edits a world renowned academic science encyclopaedia. The Encyclopaedia, published by the New York office of Springer Verlag, was a grand international project five years in the making by 28 editors and 391 scientists with expertise in Systems Biology from around the world. The Encyclopaedia compiles various research areas of Systems Biology, the new academic paradigm of the 21st century through the integration of IT and BT, comprehensively on 3,000 pages in 4 four volumes. Professor Kwang-Hyun Cho, who led this international project, majored in electrical engineering and pioneered the field of Systems Biology, the integrated study of biological sciences and engineering, as a new integrated field of IT since the 1990s. The professor has achieved various innovative research results since then. Recently he has investigated “kernel,” an evolutionary core structure in complex biological networks and developed a new cancer treatment through the state space analysis of the molecular network of cancer cells. His work was published in Science Signalling, a sister journal of Science, as a cover story several times, and contributed to foundational research as well as commercialisation of the integrated fields of IT and BT.
2013.08.27
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Complex responsible for protein breakdown in cells identified using Bio TEM
Professor Ho-Min Kim - High resolution 3D structure analysis success using Bio Transmission Electron Microscopy (TEM), a giant step towards new anticancer treatment development - Published in Nature on May 5th Using TEM to observe protein molecules and analysing its high resolution 3D structure is now possible. KAIST Biomedical Science and Engineering Department’s Professor Ho-Min Kim has identified the high resolution structure of proteasome complexes, which is responsible for protein breakdown in cells, using Bio TEM. This research has been published on the world"s most prestigious journal, Nature, online on May 5th. Our body controls many cellular processes through production and degradation of proteins to maintain homeostasis. A proteasome complex acts as a garbage disposal system and degrades cellular proteins when needed for regulation, which is one of the central roles of the body. However, a mutation in proteasome complex leads to diseases such as cancer, degenerative brain diseases, and autoimmune diseases. Currently, the anticancer drug Velcade is used to decrease proteasome function to treat Multiple Myeloma, a form of blood cancer. Research concerning proteasome complexes for more effective anticancer drugs and treatments with fewer side effects has been taking place for more than 20 years. There have been many difficulties in understanding proteasome function through 3D structure analysis since a proteasome complex, consisting of around 30 different proteins, has a great size and complexity. The research team used Bio TEM instead of conventionally used protein crystallography technique. The protein sample was inserted into Bio TEM, hundreds of photographs were taken from various angles, and then a high–performance computer was used to analyse its structure. Bio TEM requires a smaller sample and can analyse the complexes of great size of proteins. Professor Ho-Min Kim said, “Identifying proteasome complex assembly process and 3D structure will increase our understanding of cellular protein degradation process and hence assist in new drug development using this knowledge.” He added, “High resolution protein structure analysis using Bio TEM, used for the first time in Korea, will enable us to observe structure analysis of large protein complexes that were difficult to approach using protein crystallography.” Professor Kim continued, “If protein crystallography technology and Bio TEM could be used together to complement one another, it would bring a great synergetic effect to protein complex 3D structure analysis research in the future.” Professor Ho-Min Kim has conducted this research since his post-doctorate at the University of California, San Francisco, under the advice of Professor Yifan Cheng; in co-operation with Harvard University and Colorado University. Figure 1: A picture taken by Bio TEM of open state protein sample (proteasome complex) Figure 2: Bio TEM image analysis showing protein 3D structure
2013.05.25
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Distinguished Professor Sang-Yup Lee received 2013 Amgen Biochemical Engineering Award
- Previous award winners are world-renowned scholars of biochemical engineering including James Bailey, Michael Shuler and Daniel Wang KAIST Chemical and Biomolecular Engineering Department’s Professor Sang-Yup Lee has been selected to receive the 2013 Amgen Biochemical Engineering Award. The award ceremony will take place this June at the International Biochemical and Molecular Engineering conference in Beijing, China. The Amgen Biochemical Engineering Award was established by Amgen, a world renowned American pharmaceutical company, in 1993. Amgen awards leading biochemical engineers every two years. The first Amgen award recipient was James Bailey of the California Institute of Technology (Caltech) in 1993. Since then leading engineers that are sometimes called “founding fathers of biochemical engineering” have received the award including MIT Professor Daniel Wang and Michael Shuler of Cornell University. The first nine award winners were Americans and in 2011 Jens Nielson of Chalmers University of Technology, Sweden, received the Amgen award as a non-American. Professor Sang-Yup Lee is the first Asian to receive the award. The Amgen award panel said, “Professor Lee made an incredible contribution to the fields of synthetic biology and industrial bioengineering by finding chemical material, fuel, protein and drug production and system bioengineering through metabolic engineering of microorganisms.” Professor Lee is an expert in metabolic engineering of microorganisms and contributed to the development of system metabolic engineering and system bioengineering. Furthermore, he developed various medical and chemical products and processes which were then applied to synthesise strains of succinate, plastics, butanol and nylon. Professor Lee is a fellow of the Korean Academy of Science and Technology and National Academy Engineering of Korea; an international member of National Academy of Engineering (US); a former fellow of the American Association for the Advancement of Science; a member of the American Institute of Chemical Engineers, the American Industrial Microbiology Society and American Academy of Microbiology. He is currently Head of Global Agenda Council on Biotechnology and is world renowned for his work in biotechnology field.
2013.04.30
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The new era of personalized cancer diagnosis and treatment
Professor Tae-Young Yoon - Succeeded in observing carcinogenic protein at the molecular level - “Paved the way to customized cancer treatment through accurate analysis of carcinogenic protein” The joint KAIST research team of Professor Tae Young Yoon of the Department of Physics and Professor Won Do Huh of the Department of Biological Sciences have developed the technology to monitor characteristics of carcinogenic protein in cancer tissue – for the first time in the world. The technology makes it possible to analyse the mechanism of cancer development through a small amount of carcinogenic protein from a cancer patient. Therefore, a personalised approach to diagnosis and treatment using the knowledge of the specific mechanism of cancer development in the patient may be possible in the future. Until recently, modern medicine could only speculate on the cause of cancer through statistics. Although developed countries, such as the United States, are known to use a large sequencing technology that analyses the patient’s DNA, identification of the interactions between proteins responsible for causing cancer remained an unanswered question for a long time in medicine. Firstly, Professor Yoon’s research team has developed a fluorescent microscope that can observe even a single molecule. Then, the “Immunoprecipitation method”, a technology to extract a specific protein exploiting the high affinity between antigens and antibodies was developed. Using this technology and the microscope, “Real-Time Single Molecule co-Immunoprecipitation Method” was created. In this way, the team succeeded in observing the interactions between carcinogenic and other proteins at a molecular level, in real time. To validate the developed technology, the team investigated Ras, a carcinogenic protein; its mutation statistically is known to cause around 30% of cancers. The experimental results confirmed that 30-50% of Ras protein was expressed in mouse tumour and human cancer cells. In normal cells, less than 5% of Ras protein was expressed. Thus, the experiment showed that unusual increase in activation of Ras protein induces cancer. The increase in the ratio of active Ras protein can be inferred from existing research data but the measurement of specific numerical data has never been done before. The team suggested a new molecular level diagnosis technique of identifying the progress of cancer in patients through measuring the percentage of activated carcinogenic protein in cancer tissue. Professor Yoon Tae-young said, “This newly developed technology does not require a separate procedure of protein expression or refining, hence the existing proteins in real biological tissues or cancer cells can be observed directly.” He also said, “Since carcinogenic protein can be analyzed accurately, it has opened up the path to customized cancer treatment in the future.” “Since the observation is possible on a molecular level, the technology confers the advantage that researchers can carry out various examinations on a small sample of the cancer patient.” He added, “The clinical trial will start in December 2012 and in a few years customized cancer diagnosis and treatment will be possible.” Meanwhile, the research has been published in Nature Communications (February 19). Many researchers from various fields have participated, regardless of the differences in their speciality, and successfully produced interdisciplinary research. Professor Tae Young Yoon of the Department of Physics and Professors Dae Sik Lim and Won Do Huh of Biological Sciences at KAIST, and Professor Chang Bong Hyun of Computational Science of KIAS contributed to developing the technique. Figure 1: Schematic diagram of observed interactions at the molecular level in real time using fluorescent microscope. The carcinogenic protein from a mouse tumour is fixed on the microchip, and its molecular characteristics are observed live. Figure 2: Molecular interaction data using a molecular level fluorescent microscope. A signal in the form of spike is shown when two proteins combine. This is monitored live using an Electron Multiplying Charge Coupled Device (EMCCD). It shows signal results in bright dots. An organism has an immune system as a defence mechanism to foreign intruders. The immune system is activated when unwanted pathogens or foreign protein are in the body. Antibodies form in recognition of the specific antigen to protect itself. Organisms evolved to form antibodies with high specificity to a certain antigen. Antibodies only react to its complementary antigens. The field of molecular biology uses the affinity between antigens and antibodies to extract specific proteins; a technology called immunoprecipitation. Even in a mixture of many proteins, the protein sought can be extracted using antibodies. Thus immunoprecipitation is widely used to detect pathogens or to extract specific proteins. Technology co-IP is a well-known example that uses immunoprecipitation. The research on interactions between proteins uses co-IP in general. The basis of fixing the antigen on the antibody to extract antigen protein is the same as immunoprecipitation. Then, researchers inject and observe its reaction with the partner protein to observe the interactions and precipitate the antibodies. If the reaction occurs, the partner protein will be found with the antibodies in the precipitations. If not, then the partner protein will not be found. This shows that the two proteins interact. However, the traditional co-IP can be used to infer the interactions between the two proteins although the information of the dynamics on how the reaction occurs is lost. To overcome these shortcomings, the Real-Time Single Molecule co-IP Method enables observation on individual protein level in real time. Therefore, the significance of the new technique is in making observation of interactions more direct and quantitative. Additional Figure 1: Comparison between Conventional co-IP and Real-Time Single Molecule co-IP
2013.04.01
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Ligand Recognition Mechanism of Protein Identified
Professor Hak-Sung Kim -“Solved the 50 year old mystery of how protein recognises and binds to ligands” - Exciting potential for understanding life phenomena and the further development of highly effective therapeutic agent development KAIST’s Biological Science Department’s Professor Hak-Sung Kim, working in collaboration with Professor Sung-Chul Hong of Department of Physics, Seoul National University, has identified the mechanism of how the protein recognizes and binds to ligands within the human body. The research findings were published in the online edition of Nature Chemical Biology (March 18), which is the most prestigious journal in the field of life science. Since the research identified the mechanism, of which protein recognises and binds to ligands, it will take an essential role in understanding complex life phenomenon by understanding regulatory function of protein. Also, ligand recognition of proteins is closely related to the cause of various diseases. Therefore the research team hopes to contribute to the development of highly effective treatments. Ligands, well-known examples include nucleic acid and proteins, form the structure of an organism or are essential constituents with special functions such as information signalling. In particular, the most important role of protein is recognising and binding to a particular ligand and hence regulating and maintaining life phenomena. The abnormal occurrence of an error in recognition of ligands may lead to various diseases. The research team focused on the repetition of change in protein structure from the most stable “open form” to a relatively unstable “partially closed form”. Professor Kim’s team analysed the change in protein structure when binding to a ligand on a molecular level in real time to explain the ligand recognition mechanism. The research findings showed that ligands prefer the most stable protein structure. The team was the first in the world to identify that ligands alter protein structure to the most stable, the lowest energy level, when it binds to the protein. In addition, the team found that ligands bind to unstable partially-closed forms to change protein structure. The existing models to explain ligand recognition mechanism of protein are “Induced Custom Model”, which involves change in protein structure in binding to ligands, and the “Structure Selection Model”, which argues that ligands select and recognise only the best protein structure out of many. The academic world considers that the team’s research findings have perfectly proved the models through experiments for the first time in the world. Professor Kim explained, “In the presence of ligands, there exists a phenomenon where the speed of altering protein structure is changed. This phenomenon is analysed on a molecular level to prove ligand recognition mechanism of protein for the first time”. He also said, “The 50-year old mystery, that existed only as a hypothesis on biology textbooks and was thought never to be solved, has been confirmed through experiments for the first time.” Figure 1: Proteins, with open and partially open form, recognising and binding to ligands. Figure 2: Ligands temporarily bind to a stable protein structure, open form, which changes into the most stable structure, closed form. In addition, binding to partially closed form also changes protein structure to closed form.
2013.04.01
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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.
2013.03.19
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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)
2013.03.19
View 8107
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.
2013.02.21
View 8653
High Efficiency Bio-butanol production technology developed
KAIST and Korean Company cooperative research team has developed the technology that increases the productivity of bio-butanol to equal that of bio-ethanol and decreases the cost of production. Professor Lee Sang Yeop (Department of Biological-Chemical Engineering) collaborated with GS Caltex and BioFuelChem Ltd. to develop a bio-butanol production process using the system metabolism engineering method that increased the productivity and decreased the production cost. Bio-butanol is being widely regarded as the environmentally friendly next generation energy source that surpasses bio-ethanol. The energy density of bio-butanol is 29.9MJ (mega Joule) per Liter, 48% larger than bio-ethanol (19.6MJ) and comparable to gasoline (32MJ). Bio-butanol is advantageous in that it can be processed from inedible biomass and is therefore unrelated to food crises. Especially because bio-butanol shows similar characteristics especially in its octane rating, enthalpy of vaporization, and air-fuel ratio, it can be used in a gasoline engine. However barriers such as difficulty in gene manipulation of producer bacterium and insufficient information prevented the mass production of bio-butanol. Professor Lee’s team applied the system metabolism engineering method that he had invented to shift the focus to the production pathway of bio-butanol and made a new metabolism model. In the new model the bio-butanol production pathway is divided into the hot channel and the cold channel. The research team focused on improving the efficiency of the hot channel and succeeded in improving the product yield of 49% (compared to theoretical yield) to 87%. The team furthered their research and developed a live bio-butanol collection and removal system with GS Caltex. The collaboration succeeded in producing 585g of butanol using 1.8kg of glucose at a rate of 1.3g per hour, boasting world’s highest concentration, productivity, and rate and improving productivity of fermentation by three fold and decreasing costs by 30%. The result of the research was published in world renowned ‘mBio’ microbiology journal.
2012.12.21
View 7716
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