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Mutations Unveiled that Predispose Lung Cancer Cells to Refractory Histologic Transformation
Cancer pedigree analysis reveals the mutations in RB1 and TP53 genes play a key role in treatment-resistant, cancer cell-type transformation during EGFR inhibitor therapy for lung cancers. Research led by Korean medical scientists has discovered that a specific type of drug resistance mechanism to EGFR inhibitor therapy in lung cancer is predisposed by mutations in two canonical cancer-related genes: RB1 and TP53. Published in Journal of Clinical Oncology on May 12, the study also found those mutations can be detectable in patients' tumors at the point of clinical diagnosis. Therefore, it can be used as strong markers in clinic for predicting poor outcome for the targeted treatment for lung adenocarcinoma. Lung adenocarcinoma is the most common type of lung cancer, and about 15% of patients in Western countries and 50% of patients in Asian countries have mutations in the EGFR gene, which is critical for the development of lung cancer. Patients with lung adenocarcinoma harboring the EGFR mutation show favorable responses to EGFR inhibitors such as erlotinib (Tarceva) or gefitinib (Iressa), but ultimately relapse with drug-resistant tumors. Since the initial report in 2006, it has been known that in about 5~15% of patients, the lung adenocarcinoma cells undergo a mysterious transformation into a very different cancer cell type called “small cell lung cancer,” a much more aggressive lung cancer subtype, common in cigarette smokers. To find out the genetic basis of this process, the researchers compared the genome sequences of multiple cancer tissues acquired during the treatment courses of patients whose tumors underwent small-cell transformation. They reconstructed the cancer cell pedigree by comparing mutations between cancer tissues, and identified that RB1 and TP53 genes are completely inactivated by mutations already in their lung adenocarcinoma tissues. "We tried to compare the somatic mutational profile of pre-EGFR inhibitor treatment lung adenocarcinomas and post-treatment small cell carcinomas and to reconstruct the pedigrees of the cancer evolution in each patient. Strikingly, both copies of RB1 and TP53 genes were already inactivated at the stage of lung adenocarcinomas in all sequenced cases," said Dr. Jake June-Koo Lee, the first author from KAIST. They further pursued the clinical implications of RB1 and TP53 inactivation by investigating 75 EGFR-mutated lung adenocarcinoma tissues from patients who received EGFR inhibitor therapy, including patients with small-cell transformation. In this analysis, the lung adenocarcinomas with a complete inactivation of both RB1 and TP53 genes tended to have a 43-times greater risk of transformation into small cell lung cancer during their EGFR inhibitor treatment courses. Dr. Young Seok Ju, the co-last author from KAIST, explained, "This study shows the power of entire genome analyses to better understand the mechanisms underlying mysterious phenomenon encountered in clinic. Upon accurate bioinformatics, we are finding cancer-specific somatic mutations from the whole-genomes of patients’ cancer cells. These mutations allow us to track the evolution of cancer cells throughout the extraordinary clinical course of a special set of lung cancers." The complete inactivation of both RB1 and TP53 tumor suppressor genes is found in a minor (<10%) subset of lung adenocarcinoma. This study suggests that the clinical course against targeted therapy is endogenously different for the cancers in the subgroup, and specific drug-resistance mechanisms are predisposed by the two genetic mutations. Indeed, RB1 and TP53 double inactivation is a genetic hallmark of primary small cell lung cancer, observed in nearly all cases. "We are actively investigating patient tumor tissues to develop optimal surveillance plans and treatment options for patients with lung adenocarcinomas more prone to small-cell transformation," said Dr. Tae Min Kim, the co-last author from Seoul National University Hospital. The researchers are implementing their findings into lung cancer clinics by screening the RB1 and TP53 mutational status in lung adenocarcinoma patients receiving EGFR inhibitor treatment, and following their treatment courses to develop a treatment strategy for those patients. This research (doi.org/10.1200/JCO.2016.71.9096) was funded by the National Research Foundation of Korea (NRF-2013H1A2A1032691 to J.-K.L., NRF-2014R1A2A2A05003665 to Y.T.K.); Korea Institute of Science and Technology Information (K-16-L03-C02-S02 to J.L.); and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, which was funded by the Ministry of Health and Welfare (HI14C1234 to T.M.K., HI16C2387 to Y.S.J.) Figure. Phylogeny analysis of serially-acquired tumors A. Phylogeny trees of sequenced cases (LC1−LC4) are reconstructed from the WGS data. Conceptual illustrations are depicted with grey color. Circles indicate major clones of the tumors. The length of each branch is proportional to the number of mutations that occurred in the branch. Mutations of cancer-related genes in each branch are indicated with arrows. The time points of relevant treatments are summarized below the trees. B. Mutations of RB1 and TP53 in two early LADCs (LC1b and LC4a) are visualized using Integrative Genomics Viewer (left panel). Allele-specific copy number analysis shows loss of heterozygosity of chromosomes 13 and 17 in both early LADCs and EGFR TKI-resistant SCLCs (right panel). C. Clonal evolution of LC1 is described with clinical history and tumor volumes. The horizontal axis represents the time from the diagnosis (0), and the vertical axis indicates the volume of tumors calculated from the computed tomography images. Abbreviations: LADC, lung adenocarcinoma; SCLC, small cell lung cancer
Bio-based p-Xylene Oxidation into Terephthalic Acid by Engineered E.coli
KAIST researchers have established an efficient biocatalytic system to produce terephthalic acid (TPA) from p-xylene (pX). It will allow this industrially important bulk chemical to be made available in a more environmentally-friendly manner. The research team developed metabolically engineered Escherichia coli (E.coli) to biologically transform pX into TPA, a chemical necessary in the manufacturing of polyethylene terephthalate (PET). This biocatalysis system represents a greener and more efficient alternative to the traditional chemical methods for TPA production. This research, headed by Distinguished Professor Sang Yup Lee, was published in Nature Communications on May 31. The research team utilized a metabolic engineering and synthetic biology approach to develop a recombinant microorganism that can oxidize pX into TPA using microbial fermentation. TPA is a globally important chemical commodity for manufacturing PET. It can be applied to manufacture plastic bottles, clothing fibers, films, and many other products. Currently, TPA is produced from pX oxidation through an industrially well-known chemical process (with a typical TPA yield of over 95 mol%), which shows, however, such drawbacks as intensive energy requirements at high temperatures and pressure, usage of heavy metal catalysts, and the unavoidable byproduct formation of 4-carboxybenzaldehyde. The research team designed and constructed a synthetic metabolic pathway by incorporating the upper xylene degradation pathway of Pseudomonas putida F1 and the lower p-toluene sulfonate pathway of Comamonas testosteroni T-2, which successfully produced TPA from pX in small-scale cultures, with the formation of p-toluate (pTA) as the major byproduct. The team further optimized the pathway gene expression levels by using a synthetic biology toolkit, which gave the final engineered E. coli strain showing increased TPA production and the complete elimination of the byproduct. Using this best-performing strain, the team designed an elegant two-phase (aqueous/organic) fermentation system for TPA production on a larger scale, where pX was supplied in the organic phase. Through a number of optimization steps, the team ultimately achieved production of 13.3 g TPA from 8.8 g pX, which represented an extraordinary yield of 97 mol%. The team has developed a microbial biotechnology application which is reportedly the first successful example of the bio-based production of TPA from pX by the microbial fermentation of engineered E. coli. This bio-based TPA technology presents several advantages such as ambient reaction temperature and pressure, no use of heavy metals or other toxic chemicals, the removable of byproduct formation, and it is 100% environmentally compatible. Professor Lee said, “We presented promising biotechnology for producing large amounts of the commodity chemical TPA, which is used for PET manufacturing, through metabolically engineered gut bacterium. Our research is meaningful in that it demonstrates the feasibility of the biotechnological production of bulk chemicals, and if reproducible when up-scaled, it will represent a breakthrough in hydrocarbon bioconversions.” Ph.D. candidate Zi Wei Luo is the first author of this research (DOI:10.1038/ncomms15689).The research was supported by the Intelligent Synthetic Biology Center through the Global Frontier Project (2011-0031963) of the Ministry of Science, ICT & Future Planning through the National Research Foundation of Korea. Figure: Biotransformation of pX into TPA by engineered E. coli. This schematic diagram shows the overall conceptualization of how metabolically engineered E. coli produced TPA from pX. The engineered E. coli was developed through reconstituting a synthetic metabolic pathway for pX conversion to TPA and optimized for increased TPA yield and byproduct elimination. Two-phase partitioning fermentation system was developed for demonstrating the feasibility of large-scale production of TPA from pX using the engineered E. coli strains, where pX was supplied in the organic phase and TPA was produced in the aqueous phase.
Observation of the Phase Transition of Liquid Crystal Defects
KAIST researchers observed the phase transition of topological defects formed by liquid crystal (LC) materials for the first time. The phase transition of topological defects, which was also the theme of the Nobel Prize for Physics in 2016, can be difficult to understand for a layperson but it needs to be studied to understand the mysteries of the universe or the underlying physics of skyrmions, which have intrinsic topological defects. If the galaxy is taken as an example in the universe, it is difficult to observe the topological defects because the system is too large to observe some changes over a limited period of time. In the case of defect structures formed by LC molecules, they are not only a suitable size to observe with an optical microscope, but also the time period in which the phase transition of a defect occurring can be directly observed over a few seconds, which can be extended to a few minutes. The defect structures formed by LC material have radial, circular, or spiral shapes centering on a singularity (defect core), like the singularity that was already introduced in the famous movie "Interstellar,” which is the center point of black hole. In general, LC materials are mainly used in liquid crystal displays (LCDs) and optical sensors because it is easy to control their specific orientation and they have fast response characteristics and huge anisotropic optical properties. It is advantageous in terms of the performance of LCDs that the defects of the LC materials are minimized. The research team led by Professor Dong Ki Yoon in the Graduate School of Nanoscience and Technology did not simply minimize such defects but actively tried to use the LC defects as building blocks to make micro- and nanostructures for the patterning applications. During these efforts, they found the way to directly study the phase transition of topological defects under in-situ conditions. Considering the LC material from the viewpoint of a device like a LCD, robustness is important. Therefore, the LC material is injected through the capillary phenomenon between a rigid two-glass plate and the orientation of the LCs can be followed by the surface anchoring condition of the glass substrate. However, in this conventional case, it is difficult to observe the phase transition of the LC defect due to this strong surface anchoring force induced by the solid substrate. In order to solve this problem, the research team designed a platform, in which the movement of the LC molecules was not restricted, by forming a thin film of LC material on water, which is like oil floating on water. For this, a droplet of LC material was dripped onto water and spread to form a thin film. The topological defects formed under this circumstance could show the thermal phase transition when the temperature was changed. In addition, this approach can trace back the morphology of the original defect structure from the sequential changes during the temperature changes, which can give hints to the study of the formation of topological defects in the cosmos or skyrmions. Prof. Yoon said, “The study of LC crystal defects itself has been extensively studied by physicists and mathematicians for about 100 years. However, this is the first time that we have observed the phase transition of LC defects directly.” He also added, "Korea is leading in the LCD industry, but our basic research on LCs is not at the world's research level." The first author of this study is Dr. Min-Jun Gimand supported by a grant from the National Research Foundation (NRF) and funded by the Korean Government (MSIP). The research result was published on May 30, 2017 in Nature Communications. Figure 1. The phase transition of the LC topological defect on cooling. Figure 2. Polarizing optical microscopy images of topological defects depending on the strength of the director field. (a,b,e) Convergent director field arrangements of LC molecules and corresponding schematic images; (c,d,f) Divergent director field arrangements of LC molecules and corresponding schematic images.
Total Synthesis of Flueggenine C via an Accelerated Intermolecular Rauhut-Currier Reaction
The first total synthesis of dimeric securinega alkaloid (-)-flueggenine C was completed via an accelerated intermolecular Rauhut–Currier (RC) reaction. The research team led by Professor Sunkyu Han in the Department of Chemistry succeeded in synthesizing the natural product by reinventing the conventional RC reaction. The total synthesis of natural products refers to the process of synthesizing secondary metabolites isolated from living organisms in the laboratory through a series of chemical reactions. Each stage of chemical reaction needs to be successful to produce the final target molecule, and thus the process requires high levels of patience and creativity. For that reason, the researchers working on natural products total synthesis are often called “molecular artists”. Despite numerous reports on the total synthesis of monomeric securinegas, the synthesis of dimeric securinegas, whose monomeric units are connected by a putative enzymatic RC reaction, has not been reported to date. The team used a Rauhut-Currier (RC) reaction, a carboncarbon bond forming a reaction between two Michael acceptors first reported by Rauhut and Currier in 1963, to successfully synthesize a dimeric natural product, flueggenine C. This new work featured the first application of an intermolecular RC reaction in total synthesis. The conventional intermolecular RC reaction was driven non-selectively by a toxic nucleophilic catalyst at a high temperature of over 150°C and a highly concentrated reaction mixture, and thus has never been applied to natural products total synthesis. To overcome this long-standing problem, the research team placed a nucleophilic moiety at the γ-position of the enone derivative. As a result, the RC reaction could be induced by the simple addition of a base at ambient temperature and dilute solution, without the need of a nucleophilic catalyst. Using this newly discovered reactivity, the team successfully synthesized the natural product (-)-flueggenine C from commercially available amino acid derivative in 12 steps. Professor Han said, “Our key finding regarding the remarkably improved reactivity and selectivity of the intermolecular RC reaction will serve as a significant stepping stone in allowing this reaction to be considered a practical and reliable chemical tool with broad applicability in natural products, pharmaceuticals, and materials syntheses. ” This research was led by Ph.D. candidate Sangbin Jeon and was published in The Journal of the American Chemical Society (JACS) on May 10. This research was funded by KAIST start-up funds, HRHR (High-Risk High-Return), RED&B (Research, Education, Development & Business) projects, the National Research Foundation of Korea, and the Institute for Basic Science. (Figure 1: Representative dimeric/oligomeric securinega alkaloids) (Figure 2: Our reinvented Rauhut-Currier reaction) (Figure 3: Total Synthesis of (-)-flueggenine C)
Processable High Internal Phase Pickering Emulsion Using Depletion Attraction
Professor Siyoung Choi’s research team from the KAIST Department of Chemical & Biomolecular Engineering used physical force to successfully produce a stable emulsion. Emulsions, commonly known as cosmetic products, refer to stably dispersed structures of oil droplets in water (or water droplets in oil). Pickering emulsions refer to emulsions stabilized using solid particles, instead of detergent. Traditionally, it is said that water and oil do not mix. Until recently, detergent was added to mix oil and water for dispersion. Emulsions have traditionally been produced using this technique and are currently used for products such as mayonnaise, sun block, and lotion. On the other hand, Pickering emulsions have been used after stabilization of chemical treatments on solid particle surfaces to enhance adsorption power. However, there were limitations in its application, since the treatment process is complex and its applicable range remains limited. Instead of chemical treatment on Pickering emulsion surfaces, the research team mixed small macromolecules a few nanometer in size with larger solid particles (tens of nanometers to a few micrometers). This induced depletion force was used to successfully stabilize the emulsion. Depletion force refers to the force a large number of small particles induces to aggregate the bigger particles, in order to secure free space for themselves. In short, the force induces an attraction between larger particles. Until now, depletion force could only be applied to solids and solid particles. However, the research team used macromolecules and large particles such as solid particles and oil droplets to show the applicability of depletion force between solids and liquids. By introducing macromolecules that act as smaller particles, hydrophilic solid particles enhanced the adsorption of solid particles to the oil droplet surface, while preventing dissociation from the particle surface, resulting in the maintenance of a stable state. The research team confirmed the possibility of the simple production of various porous macromolecular materials using stable Pickering emulsions. Such porous macromolecules are expected to be applicable in separation film, systems engineering, drug delivery, and sensors, given their large surface area. Professor KyuHan Kim, the first author said, “Until now, depletion force has only been used between solid colloid particles. This research has scientific significance since it is the first example of using depletion force between solid particles and liquid droplets.” Professor Choi said, “Beyond its academic significance, this technology could contribute to industries and national competitiveness.” He continued, “Since this technology uses physical force, not chemical, to produce stable emulsion, it can be used regardless of the type of solid particle and macromolecule. Further, it could be used in customized porous material production for special purposes.” The research was published in Nature Communications online on February 1. In particular, this research is significant since an undergraduate student, Subeen Kim, participated in the project as a second author through the KAIST Undergraduate Research Program (URP). This research was funded by the National Research Foundation of Korea. (Figure 1: Images of the inner structure of porous macromolecules produced using the new technology) (Figure 2: Images showing the measurement of rheological properties of Pickering emulsions and system processability) (Figure 3: Images showing a stable Pickering emulsion system)
Professor Won Do Heo Receives 'Scientist of the Month Award'
Professor Won Do Heo of the Department of Biological Sciences was selected as the “Scientist of the Month” for April 2017 by the Ministry of Science, ICT and Future Planning and the National Research Foundation of Korea. Professor Heo was recognized for his suggestion of a new biological research method developing various optogenetics technology which controls cell function by using light. He developed the technology using lasers or LED light, without the need for surgery or drug administration, to identify the cause of diseases related to calcium ions such as Alzheimer’s disease and cancer. The general technique used in optogenetics, that control cells in the body with light, is the simple activation and deactivation of neurons. Professor Heo developed a calcium ion channel activation technique (OptoSTIM1) to activate calcium ions in the body using light. He also succeeded in increasing calcium concentrations with light to enhance the memory capacity of mice two-fold. Using this technology, the desired amount and residing time of calcium ion influx can be controlled by changing light intensity and exposure periods, enabling the function of a single cell or various cells in animal tissue to be controlled remotely. The experimental results showed that calcium ion influx can be activated in cells that are affected by calcium ions, such as normal cells, cancer cells, and human embryonic stem cells. By controlling calcium concentrations with light, it is possible to control biological phenomena, such as cellular growth, neurotransmitter transmission, muscle contraction, and hormone control. Professor Heo said, “Until now, it was standard to use optogenetics to activate neurons using channelrhodopsin. The development of this new optogenetic technique using calcium ion channel activation can be applied to various biological studies, as well as become an essential research technique in neurobiology. The “Scientist of the Month Award” is given every month to one researcher who made significant contributions to the advancement of science and technology with their outstanding research achievement. The awardee will receive prize money of ten million won.
A Transport Technology for Nanowires Thermally Treated at 700 Celsius Degrees
Professor Jun-Bo Yoon and his research team of the Department of Electrical Engineering at KAIST developed a technology for transporting thermally treated nanowires to a flexible substrate and created a high performance device for collecting flexible energy by using the new technology. Mr. Min-Ho Seo, a Ph.D. candidate, participated in this study as the first author. The results were published online on January 30th in ACS Nano, an international journal in the field of nanoscience and engineering. (“Versatile Transfer of an Ultralong and Seamless Nanowire Array Crystallized at High Temperature for Use in High-performance Flexible Devices,” DOI: 10.1021/acsnano.6b06842) Nanowires are one of the most representative nanomaterials. They have wire structures with dimensions in nanometers. The nanowires are widely used in the scientific and engineering fields due to their prominent physical and chemical properties that depend on a one-dimensional structure, and their high applicability. Nanowires have much higher performance if their structure has unique features such as an excellent arrangement and a longer-than-average length. Many researchers are thus actively participating in the research for making nanowires without much difficulty, analyzing them, and developing them for high performance application devices. Scientists have recently favored a research topic on making nanowires chemically and physically on a flexible substrate and applies the nanowires to a flexible electric device such as a high performance wearable sensor. The existing technology, however, mixed nanowires from a chemical synthesis with a solution and spread the mixture on a flexible substrate. The resultant distribution was random, and it was difficult to produce a high performance device based on the structural advantages of nanowires. In addition, the technology used a cutting edge nano-process and flexible materials, but this was not economically beneficial. The production of stable materials at a temperature of 700 Celsius degrees or higher is unattainable, a great challenge for the application. To solve this problem, the research team developed a new nano-transfer technology that combines a silicon nano-grating board with a large surface area and a nano-sacrificial layer process. A nano-sacrificial layer exists between nanowires and a nano-grating board, which acts as the mold for the nano-transfer. The new technology allows the device undergo thermal treatment. After this, the layer disappears when the nanowires are transported to a flexible substrate. This technology also permits the stable production of nanowires with secured properties at an extremely high temperature. In this case, the nanowires are neatly organized on a flexible substrate. The research team used the technology to manufacture barium carbonate nanowires on top of the flexible substrate. The wires secured their properties at a temperature of 700℃ or above. The team employed the collection of wearable energy to obtain much higher electrical energy than that of an energy collecting device designed based on regular barium titanate nanowires. The researchers said that their technology is built upon a semiconductor process, known as Physical Vapor Deposition that allows various materials such as ceramics and semiconductors to be used for flexible substrates of nanowires. They expected that high performance flexible electric devices such as flexible transistors and thermoelectric elements can be produced with this method. Mr. Seo said, “In this study, we transported nanowire materials with developed properties on a flexible substrate and showed an increase in device performance. Our technology will be fundamental to the production of various nanowires on a flexible substrate as well as the feasibility of making high performance wearable electric devices.” This research was supported by the Leap Research Support Program of the National Research Foundation of Korea. Fig. 1. Transcription process of new, developed nanowires (a) and a fundamental mimetic diagram of a nano-sacrificial layer (b) Fig. 2. Transcription results from using gold (AU) nanowires. The categories of the results were (a) optical images, (b) physical signals, (c) cross-sectional images from a scanning electron microscope (SEM), and (d-f) an electric verification of whether the perfectly arranged nanowires were made on a large surface. Fig. 3. Transcription from using barium titanate (BaTiO3) nanowires. The results were (a) optical images, (b-e) top images taken from an SEM in various locations, and (f, g) property analysis. Fig. 4. Mimetic diagram of the energy collecting device from using a BaTiO3 nanowire substrate and an optical image of the experiment for the miniature energy collecting device attached to an index finger.
An Improved Carbon Nanotube Semiconductor
Professor Yang-Kyu Choi and his research team of the School of Electrical Engineering at KAIST collaborated with Professor Sung-Jin Choi of Kookmin University to develop a large-scale carbon nanotube semiconductor by using a 3-D fin-gate structure with carbon nanotubes on its top. Dong Il Lee, a postdoctoral researcher at KAIST’s Electrical Engineering School, participated in this study as the first author. It was published in ACS Nano on November 10, 2016, and was entitled “Three-Dimensional Fin-Structured Semiconducting Carbon Nanotube Network Transistor.” A semiconductor made with carbon nanotubes operates faster than a silicon semiconductor and requires less energy, yielding higher performance. Most electronic equipment and devices, however, use silicon semiconductors because it is difficult to fabricate highly purified and densely packed semiconductors with carbon nanotubes (CNTs). To date, the performance of CNTs was limited due to their low density. Their purity was also low, so it was impossible to make products that had a constant yield on a large-surface wafer or substrate. These characteristics made the mass production of semiconducting CNTs difficult. To solve these difficulties, the research team used a 3-D fin-gate to vapor-deposit carbon nanotubes on its top. They developed a semiconductor that had a high current density with a width less than 50 nm. The three-dimensional fin structure was able to vapor-deposit 600 carbon nanotubes per micrometer. This structure could have 20 times more nanotubes than the two dimensional structure, which could only vapor-deposit thirty in the same 1 micrometer width. In addition, the research team used semi-conductive carbon nanotubes having a purity rating higher than 99.9% from a previous study to obtain a high yield semiconductor. The semiconductor from the research group has a high current density even with a width less than 50 μm. The new semiconductor is expected to be five times faster than a silicon-based semiconductor and will require five times less electricity during operation. Furthermore, the new semiconductor can be made by or will be compatible with the equipment for producing silicon-based semiconductors, so there will be no additional costs. Researcher Lee said, “As a next generation semiconductor, the carbon nanotube semiconductor will have better performance, and its effectiveness will be higher.” He also added, “Hopefully, the new semiconductor will replace the silicon-based semiconductors in ten years.” This study received support from the Center for Integrated Smart Sensors funded by the Ministry of Science, ICT & Future Planning of Korea as the Global Frontier Project, and from the CMOS (Complementary Metal-Oxide-Semiconductor) THz Technology Convergence Center of the Pioneer Research Center Program sponsored by the National Research Foundation of Korea. Picture 1: 3D Diagram of the Carbon Nanotube Electronic Device and Its Scanning Electron Microscope (SEM) Image Picture 2: 3D Transistor Device on an 8-inch Base and the SEM Image of Its Cross Section
Professor Tae-Eog Lee Receives December's Scientist of the Month Award by the Korean Government
Professor Tae-Eog Lee of the Industrial and Systems Engineering at KAIST received the Scientist of the Month Award for December 2015. The award is sponsored by the Ministry of Science, ICT and Future Planning of Korea, which was hosted by the National Research Foundation of Korea. The award recognizes Professor Lee’s efforts to advance the field of semiconductor device fabrication processing. This includes the development of the most efficient scheduling and controlling of cluster tools. He also created mathematical solutions to optimize the complicated cycle time of cluster tools in semiconductor manufacturing and the process of robot task workload. Professor Lee contributed to the formation of various discrete event systems and automation systems based on his mathematical theories and solutions and advanced a scheduling technology for the automation of semiconductor production. He has published 18 research papers in the past three years and has pioneered to develop Korean tool schedulers through the private sector-university cooperation.
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.
3D Plasmon Antenna Capable of Focusing Light into Few Nanometers
Professors Myung-Ki Kim and Yong-Hee Lee, both of the Physics Department at KAIST, and their research teams have developed a three dimensional (3D) gap-plasmon antenna which can focus light into a space a few nanometers wide. Their research findings were published in the June 10th issue of Nano Letters. Focusing light into a point-like space is an active research field with many applications. However, concentrating light into a smaller space than its wavelength is often hindered by diffraction. To tackle this problem, many researchers have utilized the plasmonic phenomenon of a metal where light can be confined to a greater extent by overcoming the diffraction limit. Many researchers have focused on developing a two dimensional (2D) plasmon antenna and were able to focus a light under 5 nanometers wide. However, this 2D antenna revealed a challenge: the light disperses to the opposite end regardless of how small its beam was focused. To solve this difficulty, a 3D structure had to be employed to maximize the light's intensity. Adopting the proximal focused-ion-beam milling technology, the KAIST research team developed a 3D four nanometer wide gap-plasmon antenna. By squeezing the photons into a 3D nano space of 4 x 10 x 10 nm3 size, the researchers were able to increase the intensity of light by 400,000 times stronger than that of the incident light. Capitalizing on the enhanced intensity of light within the antenna, they intensified the second-harmonic signal and verified that the light was focused in the nano gap by scanning cathodoluminescent images. The researchers anticipate that this technology will improve the speed of data transfer and processing up to the level of a terahertz (one trillion times per second) and to enlarge the storage volume per unit area on hard disks by 100 times. In addition, high definition images of submolecule size can be taken with actual light, instead of with an electron microscope, while improving the semiconductor process to a smaller size of few nanometers. Professor Kim said, “A simple yet ingenious idea has shifted the research paradigm from 2D gap-plasmon antennas to 3D antennas. This technology will see numerous applications including in the field of information technology, data storage, imaging medical science, and semiconductor processes.” The research was sponsored by the National Research Foundation of Korea. Figure 1: 3D Gap-Plasmon Antenna Structure and Simulation Results Figure 2 – Constructed 3D Gap-Plasmon Antenna Structure Figure 3 – Amplified Second Harmonic Signal Generation and Light Focused in the Nano Gap
Hierarchically-Porous Polymers with Fast Absorption
KAIST's Professor Myungeun Seo and his research team from the Graduate School of Nanoscience and Technology has developed a method to form micropores of less than 2 nanometers within porous polymers where 10 nanometers long mesopores connect like a net. The advantage of the porous polymers is fast absorption of molecules. Porous polymers with micropores of less than 2 nanometers, like a zeolite, have a large surface area. They are used as a means to store hydrogen-based molecules or as a catalytic support that can be used as a surface to convert a material into a desired form. However, because the size of the pores in its path was too small for the molecules, it took a long time to spread into the pores and reach the surface. To reach the surface efficiently, a lung cell or the vein of a leaf has a structure wherein the pores are subdivided into different sizes so that the molecule can spread throughout the organ. A technology that can create not only micropores but also bigger pores was necessary in order to create such structure. The research team solved the issue by implementing a "self-assembly" of block polymers to easily form a net-like nanostructure from mesopores of 10 nanometers. The team created hierarchically-porous polymers consisting of two different types of pores by using a hypercrosslinking reaction along with the "self-assembly" method. The reaction creates micropores within the chain after the polymer chain is confined by a chemical bond. This porous polymer has micropores that are smaller than 2 nanometers on the walls of mesopores while 10 nanometers long mesopores forming 3-dimensional net structures. Because of the "self-assembly" method, the size of mesopores can be adjusted within the range of 6 to 15 nanometers. This is the first case where a porous polymer has both well-defined mesopores and micropores. The research team verified the effect of hierarchically-porous structures on absorption of molecules by confirming that the porous polymer had faster absorption speeds than a polymer consisting only of micropores. Professor Seo said, “The study has found a simple way to create different sizes of pores within a polymer.” He expected that the hierarchically-porous polymers can be used as a catalytic support in which fast diffusion of molecules is essential, or for molecule collection. The research was sponsored by National Research Foundation of Korea and published online in the Journal of the American Chemical Society. Figure 1 – Net-like Structure of Hierarchically-Porous Polymers with Mesopores and Micropores on the walls of Mesopores. Figure 2 - Hierarchically-Porous Polymers Figure 3 – Comparison of Porous-Polymers consisting of Mesopores only (left), and Mesopores and Micropores (right)
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