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Non-Natural Biomedical Polymers Produced from Microorganisms
KAIST researchers have developed metabolically engineered Escherichia coli strains to synthesize non-natural, biomedically important polymers including poly(lactate-co-glycolate) (PLGA), previously considered impossible to obtain from biobased materials. Renewable non-food biomass could potentially replace petrochemical raw materials to produce energy sources, useful chemicals, or a vast array of petroleum-based end products such as plastics, lubricants, paints, fertilizers, and vitamin capsules. In recent years, biorefineries which transform non-edible biomass into fuel, heat, power, chemicals, and materials have received a great deal of attention as a sustainable alternative to decreasing the reliance on fossil fuels. A research team headed by Distinguished Professor Sang Yup Lee of the Chemical and Biomolecular Engineering Department at KAIST has established a biorefinery system to create non-natural polymers from natural sources, allowing various plastics to be made in an environmentally-friendly and sustainable manner. The research results were published online in Nature Biotechnology on March 7, 2016. The print version will be issued in April 2016. The research team adopted a systems metabolic engineering approach to develop a microorganism that can produce diverse non-natural, biomedically important polymers and succeeded in synthesizing poly(lactate-co-glycolate) (PLGA), a copolymer of two different polymer monomers, lactic and glycolic acid. PLGA is biodegradable, biocompatible, and non-toxic, and has been widely used in biomedical and therapeutic applications such as surgical sutures, prosthetic devices, drug delivery, and tissue engineering. Inspired by the biosynthesis process for polyhydroxyalkanoates (PHAs), biologically-derived polyesters produced in nature by the bacterial fermentation of sugar or lipids, the research team designed a metabolic pathway for the biosynthesis of PLGA through microbial fermentation directly from carbohydrates in Escherichia coli (E. coli) strains. The team had previously reported a recombinant E. coli producing PLGA by using the glyoxylate shunt pathway for the generation of glycolate from glucose, which was disclosed in their patents KR10-1575585-0000 (filing date of March 11, 2011), US08883463 and JP5820363. However, they discovered that the polymer content and glycolate fraction of PLGA could not be significantly enhanced via further engineering techniques. Thus, in this research, the team introduced a heterologous pathway to produce glycolate from xylose and succeeded in developing the recombinant E. coli producing PLGA and various novel copolymers much more efficiently. In order to produce PLGA by microbial fermentation directly from carbohydrates, the team incorporated external and engineered enzymes as catalysts to co-polymerize PLGA while establishing a few additional metabolic pathways for the biosynthesis to produce a range of different non-natural polymers, some for the first time. This bio-based synthetic process for PLGA and other polymers could substitute for the existing complicated chemical production that involves the preparation and purification of precursors, chemical polymerization processes, and the elimination of metal catalysts. Professor Lee and his team performed in silico genome-scale metabolic simulations of the E. coli cell to predict and analyze changes in the metabolic fluxes of cells which were caused by the introduction of external metabolic pathways. Based on these results, genes are manipulated to optimize metabolic fluxes by eliminating the genes responsible for byproducts formation and enhancing the expression levels of certain genes, thereby achieving the effective production of target polymers as well as stimulating cell growth. The team utilized the structural basis of broad substrate specificity of the key synthesizing enzyme, PHA synthase, to incorporate various co-monomers with main and side chains of different lengths. These monomers were produced inside the cell by metabolic engineering, and then copolymerized to improve the material properties of PLGA. As a result, a variety of PLGA copolymers with different monomer compositions such as the US Food and Drug Administration (FDA)-approved monomers, 3-hydroxyburate, 4-hydroxyburate, and 6-hydroxyhexanoate, were produced. Newly applied bioplastics such as 5-hydroxyvalerate and 2-hydroxyisovalerate were also made. The team employed a systems metabolic engineering application which, according to the researchers, is the first successful example of biological production of PGLA and several novel copolymers from renewable biomass by one-step direct fermentation of metabolically engineered E.coli. Professor Lee said, “We presented important findings that non-natural polymers, such as PLGA which is commonly used for drug delivery or biomedical devices, were produced by a metabolically engineered gut bacterium. Our research is meaningful in that it proposes a platform strategy in metabolic engineering, which can be further utilized in the development of numerous non-natural, useful polymers.” Director Ilsub Baek at the Platform Technology Division of the Ministry of Science, ICT and Future Planning of Korea, who oversees the Technology Development Program to Solve Climate Change, said, “Professor Lee has led one of our research projects, the Systems Metabolic Engineering for Biorefineries, which began as part of the Ministry’s Technology Development Program to Solve Climate Change. He and his team have continuously achieved promising results and been attracting greater interest from the global scientific community. As climate change technology grows more important, this research on the biological production of non-natural, high value polymers will have a great impact on science and industry.” The title of the research paper is “One-step Fermentative Production of Poly(lactate-co-glycolate) from Carbohydrates in Escherichia coli (DOI: 10.1038/nbt.3485).” The lead authors are So Young Choi, a Ph.D. candidate in the Department of Chemical and Biomolecular Engineering at KAIST, and Si Jae Park, Assistant Professor of the Environmental Engineering and Energy Department at Myongji University. Won Jun Kim and Jung Eun Yang, both doctoral students in the Department of Chemical and Biomolecular Engineering at KAIST, also participated in the research. This research was supported by the Technology Development Program to Solve Climate Change’s research project titled “Systems Metabolic Engineering for Biorefineries” from the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea (NRF-2012M1A2A2026556). Figure: Production of PLGA and Other Non-Natural Copolymers This schematic diagram shows the overall conceptualization of how metabolically engineered E. coli produced a variety of PLGAs with different monomer compositions, proposing the chemosynthetic process of non-natural polymers from biomass. The non-natural polymer PLGA and its other copolymers, which were produced by engineered bacteria developed by taking a systems metabolic engineering approach, accumulate in granule forms within a cell.
A New Way to Look at MOFs
An international research team composed of researchers from KAIST (led by Professors Osamu Terasaki and Jeung Ku Kang at the Graduate School of Energy, Environment, Water and Sustainability) and other universities, including UC Berkeley, has recently published research results on the adsorption process of metal-organic frameworks (MOFs) in Nature (November 9, 2015). MOFs are porous three-dimensional crystals with a high internal surface area, which have a wide range of applications involving adsorption such as hydrogen, methane, or carbon dioxide storage. In the paper entitled “Extra Adsorption and Adsorbate Superlattice Formation in Metal-organic Frameworks,” the research team described their observation of a very specific interpore interaction process in MOFs. For additional information, please see: A New Way to Look at MOFs International study challenges prevailing view on how metal organic frameworks store gases EurekAlert, November 9, 2015 http://www.eurekalert.org/pub_releases/2015-11/dbnl-anw110915.php (Courtesy of the US Department of Energy and Lawrence Berkeley National Laboratory news release)
Mapping the Folding Process of a Single Membrane Protein
KAIST and UCLA scientists were able to observe an individual membrane protein fold and unfold by pulling and releasing magnetically trapped protein molecules. Proteins are huge molecules containing hundreds to thousands of atoms that adopt a unique three dimensional structure, placing chemical groups in just the right place to catalyze reactions or build cellular structures. How all those atoms manage to find the right location - the so-called folding problem - has fascinated molecular biologists since the first structures were seen in the 1950s. Moreover, folding has important medical implications because most genetic defects cause protein misfolding. About a third of all proteins float around in the cell membrane where they ensure the right chemicals get in the cell in the right amounts. Membrane proteins also provide key information links between the cell and its environment. Indeed, most drugs target membrane proteins. Nevertheless, the folding of membrane proteins has been particularly difficult to study and has rarely been studied in natural environments, leaving the folding process for a large fraction of the protein universe still largely cloaked in mystery. In a recent issue of Nature Chemical Biology, published on October 19, 2015, a research team led by Tae-Young Yoon of the Department of Physics at the Korea Advanced Institute of Science and Technology (KAIST) and James U. Bowie of the Department of Chemistry and Biochemistry at the University of California, Los Angeles (UCLA), report a new method for manipulating the folding of membrane proteins in a membrane environment using a tool called a magnetic tweezer. Researchers first attach long DNA handles to the ends of the protein. One handle is attached to a glass surface and the other to a magnetic bead. Using a magnet, they can essentially grab the protein and pull on it, inducing it to unfold. By playing with the bead attached to the protein, they can force the protein to unfold or allow it to refold, and watch all this happening by 3D-tracking of the magnetic bead. With this novel strategy, they were able to quantitatively map the folding energy landscape, the folding kinetic rate, and folding intermediates of a membrane protein in a membrane environment for the first time. “I have been dreaming about this experiment for a decade. To see it work so well is really gratifying,” said Dr. Bowie. One of the major surprises in the study was that essentially all the atoms of the protein jump into the correct structure together. The researchers expected that the protein structure would come together in a more piecemeal fashion, with different parts of the structure forming separately, but that was not the case. It is possible that nature evolved such a smooth, highly cooperative folding process to prevent partially folded forms that could get into trouble in the crowded cell membrane. On the other hand, the cooperative folding seen here might not apply to other membrane proteins. “We need to look at more proteins. The technique developed here may allow us to do just that,” said Dr. Yoon. The single molecule mechanical manipulation technique could enable detailed folding studies of many other membrane proteins. A major barrier to the study of membrane proteins previously is that the proteins tend to stick together and get tangled up, as computer cords lying at your feet tend to do. With the tweezer technique used in this work, the protein cords are held apart from other cords so they can’t get knotted up. It is hoped that the new approach will open up an important part of the protein universe to scrutiny, including many proteins that become misfolded in disease states. The title of the research paper is “Mapping the energy landscape for second-stage folding of a single membrane protein” (DOI: 10.1038/nchembio.1939). Picture: Single-molecule magnetic tweezers that induce mechanical unfolding and refolding of a single membrane protein. Since the force applied is parallel to the biological lipid membrane, the unfolding and refolding processes occur within the membrane.
Establishment of System Metabolic Engineering Strategies
Although conventional petrochemical processes have generated chemicals and materials which have been useful to mankind, they have also triggered a variety of environmental problems including climate change and relied too much on nonrenewable natural resources. To ameliorate this, researchers have actively pursued the development of industrial microbial strains around the globe in order to overproduce industrially useful chemicals and materials from microbes using renewable biomass. This discipline is called metabolic engineering. Thanks to advances in genetic engineering and our knowledge of cellular metabolism, conventional metabolic engineering efforts have succeeded to a certain extent in developing microbial strains that overproduce bioproducts at an industrial level. However, many metabolic engineering projects launched in academic labs do not reach commercial markets due to a failure to fully integrate industrial bioprocesses. In response to this, Distinguished Professor Sang Yup Lee and Dr. Hyun Uk Kim, both from the Department of Chemical and Biomolecular Engineering at KAIST, have recently suggested ten general strategies of systems metabolic engineering to successfully develop industrial microbial strains. Systems metabolic engineering differs from conventional metabolic engineering by incorporating traditional metabolic engineering approaches along with tools of other fields, such as systems biology, synthetic biology, and molecular evolution. The ten strategies of systems metabolic engineering have been featured in Nature Biotechnology released online in October 2015, which is entitled "Systems strategies for developing industrial microbial strains." The strategies cover economic, state-of-the-art biological techniques and traditional bioprocess aspects. Specifically, they consist of: 1) project design including economic evaluation of a target bioproduct; 2) selection of host strains to be used for overproduction of a bioproduct; 3) metabolic pathway reconstruction for bioproducts that are not naturally produced in the selected host strains; 4) increasing tolerance of a host strain against the bioproduct; 5) removing negative regulatory circuits in the microbial host limiting overproduction of a bioproduct; 6) rerouting intracellular fluxes to optimize cofactor and precursor availability necessary for the bioproduct formation; 7) diagnosing and optimizing metabolic fluxes towards product formation; 8) diagnosis and optimization of microbial culture conditions including carbon sources; 9) system-wide gene manipulation to further increase the host strain's production performance using high-throughput genome-scale engineering and computational tools; and 10) scale-up fermentation of the developed strain and diagnosis for the reproducibility of the strain's production performance. These ten strategies were articulated with successful examples of the production of L-arginine using Corynebacterium glutamicum, 1,4-butanediol using Escherichia coli, and L-lysine and bio-nylon using C. glutamicum. Professor Sang Yup Lee said, "At the moment, the chance of commercializing microbial strains developed in academic labs is very low. The strategies of systems metabolic engineering outlined in this analysis can serve as guidelines when developing industrial microbial strains. We hope that these strategies contribute to improving opportunities to commercialize microbial strains developed in academic labs with drastically reduced costs and efforts, and that a large fraction of petroleum-based processes will be replaced with sustainable bioprocesses." Lee S. Y. & Kim, H. U. Systems Strategies for Developing Industrial Microbial Strains. Nature Biotechnology (2015). This work was supported by the Technology Development Program to Solve Climate Change on Systems Metabolic Engineering for Biorefineries (NRF-2012M1A2A2026556) and by the Intelligent Synthetic Biology Center through the Global Frontier Project (2011-0031963) from the Ministry of Science, ICT and Future Planning (MSIP), Korea, and through the National Research Foundation (NRF) of Korea. This work was also supported by the Novo Nordisk Foundation. Picture: Concept of the Systems Metabolic Engineering Framework (a) Three major bioprocess stages (b) Considerations in systems metabolic engineering to optimize the whole bioprocess. List of considerations for the strain development and fermentation contribute to improving microbial strain's production performance (red), whereas those for the separation and purification help in reducing overall operation costs by facilitating the downstream process (blue). Some of the considerations can be repeated in the course of systems metabolic engineering.
Discovery of Redox-Switch of KEenzyme Involved in N-Butanol Biosynthesis
Research teams at KAIST and Kyungpook National University (KNU) have succeeded in uncovering the redox-switch of thiolase, a key enzyme for n-butanol production in Clostridium acetobutylicum, one of the best known butanol-producing bacteria. Biological n-butanol production was first reported by Louis Pasteur in 1861, and the bioprocess was industrialized usingClostridium acetobutylicum. The fermentation process by Clostridium strains has been known to be the most efficient one for n-butanol production. Due to growing world-wide issues such as energy security and climate change, the biological production of n-butanol has been receiving much renewed interest. This is because n-butanol possesses much better fuel characteristics compared to ethanol, such as higher energy content (29.2 MJ/L vs 19.6 MJ/L), less corrosiveness, less hygroscopy, and the ease with which it can be blended with gasoline and diesel. In the paper published in Nature Communications, a broad-scope, online-only, and open access journal issued by the Nature Publishing Group (NPG), on September 22, 2015, Professor Kyung-Jin Kim at the School of Life Sciences, KNU, and Distinguished Professor Sang Yup Lee at the Department of Chemical and Biomolecular Engineering, KAIST, have proved that the redox-switch of thiolase plays a role in a regulation of metabolic flux in C. acetobutylicum by using in silico modeling and simulation tools. The research team has redesigned thiolase with enhanced activity on the basis of the 3D structure of the wild-type enzyme. To reinforce a metabolic flux toward butanol production, the metabolic network of C. acetobutylicum strain was engineered with the redesigned enzyme. The combination of the discovery of 3D enzyme structure and systems metabolic engineering approaches resulted in increased n-butanol production in C. acetobutylicum, which allows the production of this important industrial chemical to be cost competitive. Professors Kim and Lee said, "We have reported the 3D structure of C. acetobutylicum thiolase-a key enzyme involved in n-butanol biosynthesis, for the first time. Further study will be done to produce butanol more economically on the basis of the 3D structure of C. acetobutylicum thiolase." This work was published online in Nature Communications on September 22, 2015. Reference: Kim et al. "Redox-switch regulatory mechanism of thiolase from Clostridium acetobutylicum," Nature Communications This research was supported by the Technology Development Program to Solve Climate Changes from the Ministry of Education, Science and Technology (MEST), Korea, the National Research Foundation of Korea, and the Advanced Biomass Center through the Global Frontier Research Program of the MEST, Korea. For further information, contact Dr. Sang Yup Lee, Distinguished Professor, KAIST, Daejeon, Korea (email@example.com, +82-42-350-3930); and Dr. Kyung-Jin Kim, Professor, KNU, Daegu, Korea (firstname.lastname@example.org, +82-53-950-6088). Figure 1: A redox-switch of thiolase involves in butanol biosynthesis in Clostridium acetobutylicum. Thiolase condenses two acetyl-CoA molecules for initiating four carbon flux towards butanol. Figure 2: Thiolase catalyzes the condensation reaction of acetyl-CoA to acetoacetyl-CoA. Two catalytic cysteine residues at 88th and 378th are oxidized and formed an intermolecular disulfide bond in an oxidized status, which results in inactivation of the enzyme for n-butanol biosynthesis. The intermolecular disulfide bond is broken enabling the n-butanol biosynthesis, when the environment status is reduced.
Nature Biotechnology Nominates Sang Yup Lee of KAIST for Top 20 Translational Researchers of 2014
Nature Biotechnology, recognized as the most prestigious journal in the field of biotechnology, has released today its list of the Top 20 Translational Researchers of 2014. Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST (Korea Advanced Institute of Science and Technology) ranked seventh in the list. He is the only Asian researcher listed. The journal, in partnership with IP Checkups, a patent analytics firm, presents an annual ranking of researchers based on their paper and patent output. The list includes, among others, each researcher’s most-cited patent in the past five years and their H index, a measurement to evaluate the impact of a researcher’s published work utilizing citation analysis. (More details can be found at http://www.nature.com/bioent/2015/150801/full/bioe.2015.9.html.) American institutions made up the majority of the list, with 18 universities and research institutes, and the remainder was filled by KAIST in Korea and the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Australia. Globally known as a leading researcher in systems metabolic engineering, Professor Lee has published more than 500 journal papers and 580 patents. He has received many awards, including the Citation Classic Award, Elmer Gaden Award, Merck Metabolic Engineering Award, ACS Marvin Johnson Award, SIMB Charles Thom Award, POSCO TJ Park Prize, Amgen Biochemical Engineering Award, and the Ho Am Prize in Engineering.
'Engineered Bacterium Produces 1,3-Diaminopropane'
A research team led by Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST reported, for the first time, the production of 1,3-diaminopropane via fermentation of an engineered bacterium. 1,3-Diaminopropane is a three carbon diamine, which has a wide range of industrial applications including epoxy resin and cross-linking agents, as well as precursors for pharmaceuticals, agrochemicals, and organic chemicals. It can also be polymerized with dicarboxylic acids to make polyamides (nylons) for use as engineering plastics, medical materials, and adhesives. Traditionally, 1,3-diaminopropane is derived from petroleum-based processes. In effort to address critical problems such as the depletion of petroleum and environmental issues inherent to the petroleum-based processes, the research team has developed an Escherichia coli (E. coli) strain capable of producing 1,3-diaminopropane. Using this technology, 1,3-diaminopropane can now be produced from renewable biomass instead of petroleum. E. coli as found in nature is unable to produce 1,3-diaminopropane. Metabolic engineering, a technology to transform microorganisms into highly efficient microbial cell factories capable of producing chemical compounds of interest, was utilized to engineer the E. coli strain. First, naturally existing metabolic pathways for the biosynthesis of 1,3-diaminopropane were introduced into a virtual cell in silico to determine the most efficient metabolic pathway for the 1,3-diaminopropane production. The metabolic pathway selected was then introduced into an E. coli strain and successfully produced 1,3-diaminopropane for the first time in the world. The research team applied metabolic engineering additionally, and the production titer of 1,3-diaminopropane increased about 21 fold. The Fed-batch fermentation of the engineered E. coli strain produced 13 grams per liter of 1,3-diaminoproapne. With this technology, 1,3-diaminopropane can be produced using renewable biomass, and it will be the starting point for replacing the current petroleum-based processes with bio-based processes. Professor Lee said, “Our study suggested a possibility to produce 1,3-diaminopropane based on biorefinery. Further study will be done to increase the titer and productivity of 1,3-diaminopropane.” This work was published online in Scientific Reports on August 11, 2015. Reference: Chae, T.U. et al. "Metabolic engineering of Escherichia coli for the production of 1,3-diaminopropane, a three carbon diamine," Scientific Reports: http://www.nature.com/articles/srep13040 This research was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries from Ministry of Science, ICT and Future Planning (MSIP) through the National Research Foundation (NRF) of Korea. Figure 1: Metabolic engineering strategies for 1,3-diaminopropane production using C4 pathway Figure 2: Fed-batch fermentation profiles of two final engineered E. coli strains
Novel Photolithographic Technology Enabling 3D Control over Functional Shapes of Microstructures
Professor Shin-Hyun Kim and his research team in the Department of Chemical and Biomolecular Engineering at KAIST have developed a novel photolithographic technology enabling control over the functional shapes of micropatterns using oxygen diffusion. The research was published online in the March 13th issue of Nature Communications and was selected as a featured image for the journal. Photolithography is a standard optical process for transferring micropatterns on to a substrate by exposing specific regions of the photoresist layer to ultraviolet (UV) light. It is used widely throughout industries that require micropatterns, especially in the semiconductor manufacturing industry. Conventional photolithography relied on photomasks which protected certain regions of the substrate from the input UV light. Areas covered by the photomasks remain intact with the base layer while the areas exposed to the UV light are washed away, thus creating a micropattern. This technology was limited to a two-dimensional, disc-shaped design as the boundaries between the exposed and roofed regions are always in a parallel arrangement with the direction of the light. Professor Kim’s research team discovered that: 1) the areas exposed to UV light lowered the concentration of oxygen and thus resulted in oxygen diffusion; and 2) manipulation of the diffusion speed and direction allowed control of the growth, shape and size of the polymers. Based on these findings, the team developed a new photolithographic technology that enabled the production of micropatterns with three-dimensional structures in various shapes and sizes. Oxygen was considered an inhibitor during photopolymerization. Photoresist under UV light creates radicals which initialize a chemical reaction. These radicals are eliminated with the presence of oxygen and thus prevents the reaction. This suggests that the photoresist must be exposed to UV light for an extended time to completely remove oxygen for a chemical reaction to begin. The research team, however, exploited the presence of oxygen. While the region affected by the UV light lowered oxygen concentration, the concentration in the untouched region remained unchanged. This difference in the concentrations caused a diffusion of oxygen to the region under UV light. When the speed of the oxygen flow is slow, the diffusion occurs in parallel with the direction of the UV light. When fast, the diffusion process develops horizontally, outward from the area affected by the UV light. Professor Kim and his team proved this phenomenon both empirically and theoretically. Furthermore, by injecting an external oxygen source, the team was able to manipulate diffusion strength and direction, and thus control the shape and size of the polymer. The use of the polymerization inhibitors enabled and facilitated the fabrication of complex, three-dimensional micropatterns. Professor Kim said, “While 3D printing is considered an innovative manufacturing technology, it cannot be used for mass-production of microscopic products. The new photolithographic technology will have a broad impact on both the academia and industry especially because existing, conventional photolithographic equipment can be used for the development of more complex micropatterns.” His newest technology will enhance the manufacturing process of three-dimensional polymers which were considered difficult to be commercialized. The research was also dedicated to the late Professor Seung-Man Yang of the Department of Chemical and Biomolecular Engineering at KAIST. He was considered one of the greatest scholars in Korea in the field of hydrodynamics and colloids. Picture 1: Featured Image of Nature Communications, March 2015 Picture 2: Polymers with various shapes and sizes produced with the new photolithographic technology developed by Professor Kim
Mutations Occurring Only in Brain Responsible for Intractable Epilepsy Identified
KAIST researchers have discovered that brain somatic mutations in MTOR gene induce intractable epilepsy and suggest a precision medicine to treat epileptic seizures. Epilepsy is a brain disorder which afflicts more than 50 million people worldwide. Many epilepsy patients can control their symptoms through medication, but about 30% suffer from intractable epilepsy and are unable to manage the disease with drugs. Intractable epilepsy causes multiple seizures, permanent mental, physical, and developmental disabilities, and even death. Therefore, surgical removal of the affected area from the brain has been practiced as a treatment for patients with medically refractory seizures, but this too fails to provide a complete solution because only 60% of the patients who undergo surgery are rendered free of seizures. A Korean research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering at the Korea Advanced Institute of Science and Technology (KAIST) and Professor Dong-Seok Kim of Epilepsy Research Center at Yonsei University College of Medicine has recently identified brain somatic mutations in the gene of mechanistic target of rapamycin (MTOR) as the cause of focal cortical dysplasia type II (FCDII), one of the most important and common inducers to intractable epilepsy, particularly in children. They propose a targeted therapy to lessen epileptic seizures by suppressing the activation of mTOR kinase, a signaling protein in the brain. Their research results were published online in Nature Medicine on March 23, 2015. FCDII contributes to the abnormal developments of the cerebral cortex, ranging from cortical disruption to severe forms of cortical dyslamination, balloon cells, and dysplastic neurons. The research team studied 77 FCDII patients with intractable epilepsy who had received a surgery to remove the affected regions from the brain. The researchers used various deep sequencing technologies to conduct comparative DNA analysis of the samples obtained from the patients’ brain and blood, or saliva. They reported that about 16% of the studied patients had somatic mutations in their brain. Such mutations, however, did not take place in their blood or saliva DNA. Professor Jeong Ho Lee of KAIST said, “This is an important finding. Unlike our previous belief that genetic mutations causing intractable epilepsy exist anywhere in the human body including blood, specific gene mutations incurred only in the brain can lead to intractable epilepsy. From our animal models, we could see how a small fraction of mutations carrying neurons in the brain could affect its entire function.” The research team recapitulated the pathogenesis of intractable epilepsy by inducing the focal cortical expression of mutated mTOR in the mouse brain via electroporation method and observed as the mouse develop epileptic symptoms. They then treated these mice with the drug called “rapamycin” to inhibit the activity of mTOR protein and observed that it suppressed the development of epileptic seizures with cytomegalic neurons. “Our study offers the first evidence that brain-somatic activating mutations in MTOR cause FCDII and identifies mTOR as a treatment target for intractable epilepsy,” said co-author Dr. Dong-Seok Kim, a neurosurgeon at Yonsei Medical Center with the country’s largest surgical experiences in treating patients with this condition. The research paper is titled “Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy.” (Digital Object Identifier #: 10.1038/nm.3824) Picture 1: A schematic image to show how to detect brain specific mutation using next-generation sequencing technology with blood-brain paired sample. Simple comparison of non-overlapping mutations between affected and unaffected tissues is able to detect brain specific mutations. Picture 2: A schematic image to show how to generate focal cortical dysplasia mouse model. This mouse model open the new window of drug screening for seizure patients. Picture 3: Targeted medicine can rescue the focal cortical dysplasia symptoms including cytomegalic neuron & intractable epilepsy.
KAIST Develops Ultrathin Polymer Insulators Key to Low-Power Soft Electronics
Using an initiated chemical vapor deposition technique, the research team created an ultrathin polymeric insulating layer essential in realizing transistors with flexibility and low power consumption. This advance is expected to accelerate the commercialization of wearable and soft electronics. A group of researchers at the Korea Advanced Institute of Science and Technology (KAIST) developed a high-performance ultrathin polymeric insulator for field-effect transistors (FETs). The researchers used vaporized monomers to form polymeric films grown conformally on various surfaces including plastics to produce a versatile insulator that meets a wide range of requirements for next-generation electronic devices. Their research results were published online in Nature Materials on March 9th, 2015. FETs are an essential component for any modern electronic device used in our daily life from cell phones and computers, to flat-panel displays. Along with three electrodes (gate, source, and drain), FETs consist of an insulating layer and a semiconductor channel layer. The insulator in FETs plays an important role in controlling the conductance of the semiconductor channel and thus current flow within the translators. For reliable and low-power operation of FETs, electrically robust, ultrathin insulators are essential. Conventionally, such insulators are made of inorganic materials (e.g., oxides and nitrides) built on a hard surface such as silicon or glass due to their excellent insulating performance and reliability. However, these insulators were difficult to implement into soft electronics due to their rigidity and high process temperature. In recent years, many researchers have studied polymers as promising insulating materials that are compatible with soft unconventional substrates and emerging semiconductor materials. The traditional technique employed in developing a polymer insulator, however, had the limitations of low surface coverage at ultra-low thickness, hindering FETs adopting polymeric insulators from operating at low voltage. A KAIST research team led by Professor Sung Gap Im of the Chemical and Biomolecular Engineering Department and Professor Seunghyup Yoo and Professor Byung Jin Cho of the Electrical Engineering Department developed an insulating layer of organic polymers, “pV3D3,” that can be greatly scaled down, without losing its ideal insulating properties, to a thickness of less than 10 nanometers (nm) using the all-dry vapor-phase technique called the “initiated chemical vapor deposition (iCVD).” The iCVD process allows gaseous monomers and initiators to react with each other in a low vacuum condition, and as a result, conformal polymeric films with excellent insulating properties are deposited on a substrate. Unlike the traditional technique, the surface-growing character of iCVD can overcome the problems associated with surface tension and produce highly uniform and pure ultrathin polymeric films over a large area with virtually no surface or substrate limitations. Furthermore, most iCVD polymers are created at room temperature, which lessens the strain exerted upon and damage done to the substrates. With the pV3D3 insulator, the research team built low-power, high-performance FETs based on various semiconductor materials such as organics, graphene, and oxides, demonstrating the pV3D3 insulator’s wide range of material compatibility. They also manufactured a stick-on, removable electronic component using conventional packaging tape as a substrate. In collaboration with Professor Yong-Young Noh from Dongguk University in Korea, the team successfully developed a transistor array on a large-scale flexible substrate with the pV3D3 insulator. Professor Im said, “The down-scalability and wide range of compatibility observed with iCVD-grown pV3D3 are unprecedented for polymeric insulators. Our iCVD pV3D3 polymeric films showed an insulating performance comparable to that of inorganic insulating layers, even when their thickness were scaled down to sub-10 nm. We expect our development will greatly benefit flexible or soft electronics, which will play a key role in the success of emerging electronic devices such as wearable computers.” The title of the research paper is “Synthesis of ultrathin polymer insulating layers by initiated chemical vapor deposition for low-power soft electronics” (Digital Object Identifier (DOI) number is 10.1038/nmat4237). Picture 1: A schematic image to show how the initiated chemical vapor deposition (iCVD) technique produces pV3D3 polymeric films: (i) introduction of vaporized monomers and initiators, (ii) activation of initiators to thermally dissociate into radicals, (iii) adsorption of monomers and initiator radicals onto a substrate, and (iv) transformation of free-radical polymerization into pV3D3 thin films. Picture 2: This is a transistor array fabricated on a large scale, highly flexible substrate with pV3D3 polymeric films. Picture 3: This photograph shows an electronic component fabricated on a conventional packaging tape, which is attachable or detachable, with pV3D3 polymeric films embedded.
System Approach Using Metabolite Structural Similarity Toward TOM Suggested
A Korean research team at KAIST suggests that a system approach using metabolite structural similarity helps to elucidate the mechanisms of action of traditional oriental medicine. Traditional oriental medicine (TOM) has been practiced in Asian countries for centuries, and is gaining increasing popularity around the world. Despite its efficacy in various symptoms, TOM has been practiced without precise knowledge of its mechanisms of action. Use of TOM largely comes from empirical knowledge practiced over a long period of time. The fact that some of the compounds found in TOM have led to successful modern drugs such as artemisinin for malaria and taxol (Paclitaxel) for cancer has spurred modernization of TOM. A research team led by Sang-Yup Lee at KAIST has focused on structural similarities between compounds in TOM and human metabolites to help explain TOM’s mechanisms of action. This systems approach using structural similarities assumes that compounds which are structurally similar to metabolites could affect relevant metabolic pathways and reactions by biosynthesizing structurally similar metabolites. Structural similarity analysis has helped to identify mechanisms of action of TOM. This is described in a recent study entitled “A systems approach to traditional oriental medicine,” published online in Nature Biotechnology on March 6, 2015. In this study, the research team conducted structural comparisons of all the structurally known compounds in TOM and human metabolites on a large-scale. As a control, structures of all available approved drugs were also compared against human metabolites. This structural analysis provides two important results. First, the identification of metabolites structurally similar to TOM compounds helped to narrow down the candidate target pathways and reactions for the effects from TOM compounds. Second, it suggested that a greater fraction of all the structurally known TOM compounds appeared to be more similar to human metabolites than the approved drugs. This second finding indicates that TOM has a great potential to interact with diverse metabolic pathways with strong efficacy. This finding, in fact, shows that TOM compounds might be advantageous for the multitargeting required to cure complex diseases. “Once we have narrowed down candidate target pathways and reactions using this structural similarity approach, additional in silico tools will be necessary to characterize the mechanisms of action of many TOM compounds at a molecular level,” said Hyun Uk Kim, a research professor at KAIST. TOM’s multicomponent, multitarget approach wherein multiple components show synergistic effects to treat symptoms is highly distinctive. The researchers investigated previously observed effects recorded since 2000 of a set of TOM compounds with known mechanisms of action. TOM compounds’ synergistic combinations largely consist of a major compound providing the intended efficacy to the target site and supporting compounds which maximize the efficacy of the major compound. In fact, such combination designs appear to mirror the Kun-Shin-Choa-Sa design principle of TOM. That principle, Kun-Shin-Choa-Sa (君臣佐使 or Jun-Chen-Zuo-Shi in Chinese) literally means “king-minister-assistant-ambassador.” In ancient East Asian medicine, treating human diseases and taking good care of the human body are analogous to the politics of governing a nation. Just as good governance requires that a king be supported by ministers, assistants and/or ambassadors, treating diseases or good care of the body required the combined use of herbal medicines designed based on the concept of Kun-Shin-Choa-Sa. Here, the Kun (king or the major component) indicates the major medicine (or herb) conveying the major drug efficacy, and is supported by three different types of medicines: the Shin (minister or the complementary component) for enhancing and/or complementing the efficacy of the Kun, Choa (assistant or the neutralizing component) for reducing any side effects caused by the Kun and reducing the minor symptoms accompanying major symptom, and Sa (ambassador or the delivery/retaining component) which facilitated the delivery of the Kun to the target site, and retaining the Kun for prolonged availability in the cells. The synergistic combinations of TOM compounds reported in the literature showed four different types of synergisms: complementary action (similar to Kun-Shin), neutralizing action (similar to Kun-Choa), facilitating action or pharmacokinetic potentiation (both similar to Kun-Choa or Kun-Sa). Additional structural analyses for these compounds with synergism show that they appeared to affect metabolism of amino acids, co-factors and vitamins as major targets. Professor Sang Yup Lee remarks, “This study lays a foundation for the integration of traditional oriental medicine with modern drug discovery and development. The systems approach taken in this analysis will be used to elucidate mechanisms of action of unknown TOM compounds which will then be subjected to rigorous validation through clinical and in silico experiments.” Sources: Kim, H.U. et al. “A systems approach to traditional oriental medicine.” Nature Biotechnology. 33: 264-268 (2015). This work was supported by the Bio-Synergy Research Project (2012M3A9C4048759) of the Ministry of Science, ICT and Future Planning through the National Research Foundation. This work was also supported by the Novo Nordisk Foundation. The picture below presents the structural similarity analysis of comparing compounds in traditional oriental medicine and those in all available approved drugs against the structures of human metabolites.
KAIST Develops Subminiature, Power-Efficient Air Pollution Sensing Probe
Professor Inkyu Park and his research team from the Department of Mechanical Engineering at KAIST have developed a subminiature, power-efficient air-pollution sensing probe that can be applied to mobile devices. Their research findings were published online in the January 30th issue of Scientific Reports. As air pollution has increased, people have taken greater interest in health care. The developed technology could allow people to measure independently the air pollution level of their surrounding environments. Previous instruments used to measure air pollution levels were bulky and consumed a lot of power. They also often produced inaccurate results when measuring air pollution in which different toxic gases were mixed. These problems could not be resolved with existing semiconductor manufacturing process. Using local temperature field control technology, Professor Park’s team succeeded in integrating multiple heterogeneous nanomaterials and fitting them onto a small, low-power electronic chip. This microheating sensor can heat microscale regions through local hydrothermal synthesis. Because it requires a miniscale amount of nanomaterials to manufacture, the sensor is most suitable for mobile devices. Professor Park said, “Our research will contribute to the development of convergence technology in such field as air pollution sensing probes, biosensors, electronic devices, and displays.” The team's research was supported by the Ministry of Education and the Ministry of Science, ICT and Future Planning, Republic of Korea. Figure 1 – The Concept of Multiple Nanomaterial Device and Numerical Simulation Results of Precursor Solutions Figure 2 - Multiple Nanomaterial Manufactured in a Microscale Region
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