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A Novel Biosensor to Advance Diverse High-Level Production of Microbial Cell Factories
A research group at KAIST presented a novel biosensor which can produce diverse, high-level microbial cell factories. The biosensor monitors the concentration of products and even intermediates when new strains are being developed. This strategy provides a new platform for manufacturing diverse natural products from renewable resources. The team succeeded in creating four natural products of high-level pharmaceutical importance with this strategy. Malonyl-CoA is a major building block for many value-added chemicals including diverse natural products with pharmaceutical importance. However, due to the low availability of malonyl-CoA in bacteria, many malonyl-CoA-derived natural products have been produced by chemical synthesis or extraction from natural resources that are harmful to the environment and are unsustainable. For the sustainable biological production of malonyl-CoA-derived natural products, increasing the intracellular malonyl-CoA pool is necessary. To this end, the development of a robust and efficient malonyl-CoA biosensor was required to monitor the concentration of intracellular malonyl-CoA abundance as new strains are developed. Metabolic engineering researchers at KAIST addressed this issue. This research reports the development of a simple and robust malonyl-CoA biosensor by repurposing a type III polyketide synthase (also known as RppA), which produces flaviolin, a colorimetric indicator of malonyl-CoA. Subsequently, the RppA biosensor was used for the rapid and efficient colorimetric screening of gene manipulation targets enabling enhanced malonyl-CoA abundance. The screened beneficial gene targets were employed for the high-level production of four representative natural products derived from malonyl-CoA. Compared with the previous strategies, which were expensive and time-consuming, the new biosensor could be easily applied to industrially relevant bacteria including Escherichia coli, Pseudomonas putida, and Corynebacterium glutamicum to enable a one-step process. The study employs synthetic small regulatory RNA (sRNA) technology to rapidly and efficiently reduce endogenous target gene expression for improved malonyl-CoA production. The researchers constructed an E. coli genome-scale synthetic sRNA library targeting 1,858 genes covering all major metabolic genes in E. coli. This library was employed with the RppA biosensor to screen for gene targets which are believed to be beneficial for enhancing malonyl-CoA accumulation upon their expression knockdown. From this colorimetric screening, 14 gene targets were selected, all of which were successful at significantly increasing the production of four natural products (6-methylsalicylic acid, aloesone, resveratrol, and naringenin). Although specific examples are demonstrated in E. coli as a host, the researchers showed that the biosensor is also functional in P. putida and C. glutamicum, industrially important representative gram-negative and gram-positive bacteria, respectively. The malonyl-CoA biosensor developed in this research will serve as an efficient platform for the rapid development of strains capable of producing natural products crucial for the pharmaceutical, chemical, cosmetics, and food industries. An important aspect of this work is that the high-performance strains constructed in this research were developed rapidly and easily by utilizing the simple approach of colorimetric screening, without involving extensive metabolic engineering approaches. 6-Methylsalicylic acid (an antibiotic) could be produced to the highest titer reported for E. coli, and the microbial production of aloesone (a precursor of aloesin, an anti-inflammatory agent/whitening agent) was achieved for the first time. “A sustainable process for producing diverse natural products using renewable resources is of great interest. This study represents the development of a robust and efficient malonyl-CoA biosensor generally applicable to a wide range of industrially important bacteria. The capability of this biosensor for screening a large library was demonstrated to show that the rapid and efficient construction of high-performance strains is feasible. This research will be useful for further accelerating the development process of strains capable of producing valuable chemicals to industrially relevant levels,” said Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering, who led the research. This study entitled “Repurposing type III polyketide synthase as a malonyl-CoA biosensor for metabolic engineering in bacteria,” was published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) on October 02. PhD students Dongsoo Yang and Won Jun Kim, MS student Shin Hee Ha, research staff Mun Hee Lee, Research Professor Seung Min Yoo, and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering and Dr. Jong Hyun Choi of the Applied Microbiology Research Center at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) participated in this research. Figure: Type III polyketide synthase (RppA) as a malonyl-CoA biosensor. RppA converts five molecules of malonyl-CoA into one molecule of red-colored flaviolin. This schematic diagram shows the overall conceptualization of the malonyl-CoA biosensor by indicating that higher malonyl-CoA abundance leads to higher production and secretion of flaviolin, resulting in a deeper red color of the culture. This system was employed for the enhanced production of four representative natural products (6-methylsalicylic acid, aloesone, resveratrol, and naringenin) from engineered E. coli strains.
KAIST Develops VRFB with Longer Durability
(from left: PhD candidate Soohyun Kim, Professor Hee-Tak Kim and PhD candidate Junghoon Choi) There has been growing demand for large-scale storage for energy produced from renewable energy sources in an efficient and stable way. To meet this demand, a KAIST research team developed a new vanadium redox-flow battery (VRFB) with 15 times greater capacity retention and five times longer durability. This VRFB battery can be an excellent candidate for a large-scale rechargeable battery with no risk of explosion. The VRFB has received much attention for its high efficiency and reliability with the absence of cross-contamination. However, it has the limitation of having insufficient charge and discharge efficiency and a low capacity retention rate because its perfluorinated membrane is very permeable to any active materials. To minimize energy loss, it needs a membrane that has low vanadium ion permeability and high ion conductivity. Hence, there was an attempt to incorporate a hydrocarbon membrane that has low cost and high ion selectivity but it turned out that the VO₂+ caused chemical degradation, which led to shortening the battery life drastically. To develop a membrane with pore sizes smaller than the hydrated size of vanadium ions yet larger than that of the protons, a research team co-led by Professor Hee-Tae Jung and Professor Hee-Tak Kim from the Department of Chemical and Biomolecular Engineering implemented a graphene-oxide framework (GOF) membrane by cross-linking graphene oxide nanosheets. They believed that GOF, having strong ion selectivity, would be a good candidate for the membrane component for the VRFB. The interlayer spacing between the GO sheets limited moisture expansion and provided selective ion permeation. The GOF membrane increased the capacity retention of the VRFB, which showed a 15 times higher rate than that of perfluorinated membranes. Its cycling stability was also enhanced up to five times, compared to conventional hydrocarbon membranes. These pore-sized-tuned graphene oxide frameworks will allow pore-sized tuning of membranes and will be applicable to electrochemical systems that utilize ions of various sizes, such as rechargeable batteries and sensors. Professor Kim said, “Developing a membrane that prevents the mixing of positive and negative active materials has been a chronic issue in the field of redox-flow batteries. Through this research, we showed that nanotechnology can prevent this crossover issue and membrane degradation. I believe that this technology can be applied to various rechargeable batteries requiring large-scale storage.” This research was published in Nano Letters on May 3. Figure 1. Electrochemical performances of the VRFBs with Nafion 115, SPAES (sulfonated poly), and GOF/SPAES: discharge capacity Figure 2. Schematic of the selective ion transfer of hydrated vanadium ions and protons in the GOF membrane and the molecular structure of the GOF membrane, showing that the GO nanosheets are cross-linked with EDA (ethylenediamine)
Using Donut-shaped Lithium Sulfide for Higher Performing Batteries
(from left: Research Professor Fangmin Ye and Professor Hee-Tak Kim) A KAIST research team developed a lithium-sulfur battery with a doughnut-shaped active material structure showing a record lifecycle of over 600 cycles. Having higher energy density and lower production cost than a lithium-ion battery (LIB), it can be used in electric vehicles that require a longer battery life. There has been an intense research conducted for developing lithium-sulfur batteries with high energy density because LIBs only allow for a very short travel distance per charge. However, Li-S batteries are still unable to provide a longer lifecycle due to the poor reversibility of the lithium metal cathode. To tackle this issue, Professor Hee-Tak Kim from the Department of Chemical and Biomolecular Engineering and his team used lithium sulfide (Li₂S) cathodes and combine them with graphite anodes to enhance energy density and lifecycles for the batteries. Yet, lithium sulfide is costly and, so far, there has not been an electrode architecture and electrolyte design that enables a longer lifecycle between the graphite anodes and lithium sulfide cathodes. Hence, the team produced a doughnut-shaped lithium sulfide cathode active material from low-cost lithium sulfide developed from raw materials. They have also developed a lithium sulfide ion battery with a graphite anode and lithium sulfide cathode using a high concentration salt electrolyte. This doughnut-shaped lithium sulfide showed outstanding charge and discharge reversibility through improving the transfer of lithium ions. Its highly concentrated salt electrolyte formed a stable film on the surface of the graphite electrode, which showed strong durability. Through this technology, the team achieved 30% higher energy density than that of conventional LIBs and secured a lifecycle of more than 600 cycles. This doughnut-shaped lithium sulfide-based electrode can be manufactured using low-cost raw materials and a single heat treatment process. The electrode can also be applied to existing LIBs. Professor Kim said, “We have demonstrated that applying low-cost sulfur compounds to LIBs can improve both energy density and the lifecycle simultaneously.” This research, led by Research Professor Fangmin Ye, was published in Advanced Science on May 7. Figure 1. Structural characterization of Li₂SO₄/CNT and Li₂S/CNT electrodes and suggested mechanism for the formation of the holey-Li₂S nanoarchitecture
Engineered E. coli Using Formic Acid and CO2 As a C1-Refinery Platform Strain
(Figure: Formic acid and CO2 assimilation pathways consisting of the reconstructed THF cycle and reverse glycine cleavage reaction. This schematic diagram shows the formic acid and CO2 assimilation procedure through the pathway. Plasmids used in this study and the genetic engineering performed in this study are illustrated.) A research group at KAIST has developed an engineered E. coli strain that converts formic acid and CO2 to pyruvate and produces cellular energy from formic acid through reconstructed one-carbon pathways. The strategy described in this study provides a new platform for producing value-added chemicals from one-carbon sources. Formic acid is a carboxylic acid composed of one carbon. Formic acid was produced from CO2 by the chemical method. Recently, the C1 Gas Refinery R&D Center has successfully developed a biological process that produces formic acid from carbon monoxide for the first time. Formic acid is in a liquid state when at room temperature and atmospheric pressure. In addition, it is chemically stable and less toxic, thus, easy to store and transport. Therefore, it can be used as an alternative carbon source in the microbial fermentation process. In order to produce value-added chemicals using formic acid, a metabolic pathway that converts formic acid into cellular molecules composed of multiple carbons is required. However, a metabolic pathway that can efficiently convert formic acid into cellular molecules has not been developed. This acted as an obstacle for the production of value-added chemicals using formic acid A research group of Ph.D. student Junho Bang and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering addressed this issue. This study, entitled “Assimilation of Formic Acid and CO2 by Engineered Escherichia coli Equipped with Reconstructed One-Carbon Assimilation Pathways”, has been published online in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) on September 18. There has been increasing interest in utilizing formic acid as an alternative carbon source for the production of value-added chemicals. This research reports the development of an engineered E. coli strain that can convert formic acid and CO2 to pyruvate and produce cellular energy from formic acid through the reconstructed one-carbon pathways. The metabolic pathway that efficiently converts formic acid and CO2 into pyruvate was constructed by the combined use of the tetrahydrofolate cycle and reverse glycine cleavage reaction. The tetrahydrofolate cycle was reconstructed by utilizing Methylobacterium extorquens formate-THF ligase, methenyl-THF cyclohydrolase, and methylene-THF dehydrogenase. The glycine cleavage reaction was reversed by knocking out the repressor gene (gcvR) and overexpressing the gcvTHP genes that encode enzymes related with the glycine cleavage reaction. Formic acid and CO2 conversion to pyruvate was increased via metabolic engineering of the E. coli strain equipped with the one-carbon assimilation pathway. In addition, in order to reduce glucose consumption and increase formic acid consumption, Candida boidnii formate dehydrogenase was additionally introduced to construct a cellular energy producing pathway from formic acid. This reduces glucose consumption and increases formic acid consumption. The reconstructed one-carbon pathways can supply cellular molecules and cellular energies from the formic acid and CO2. Thus, the engineered E. coli strain equipped with the formic acid and CO2 assimilation pathway and cellular energy producing pathway from formic acid showed cell growth from formic acid and CO2 without glucose. Cell growth was monitored and 13C isotope analysis was performed to confirm E. coli growth from the formic acid and CO2. It was found that the engineered E. coli strain sustained cell growth from the formic acid and CO2 without glucose. Professor Lee said, “To construct the C1-refinery system, a platform strain that can convert one-carbon materials to higher carbon materials needs to be developed. In this report, a one-carbon pathway that can efficiently convert formic acid and CO2 to pyruvate was developed and a cellular energy producing pathway from formic acid was introduced. This resulted in an engineered E. coli strain that can efficiently utilize formic acid as a carbon source while glucose consumption was reduced. The reconstructed one-carbon pathways in this research will be useful for the construction of the C1-refinery system.” This work was supported by the C1 Gas Refinery Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2016M3D3A1A01913250). For further information: Sang Yup Lee, Distinguished Professor of Chemical and Biomolecular Engineering, KAIST (firstname.lastname@example.org, Tel: +82-42-350-3930)
Rh Ensemble Catalyst for Effective Automobile Exhaust Treatment
(from left: Professor Hyunjoo Lee and PhD candidate Hojin Jeong) A KAIST research team has developed a fully dispersed Rh ensemble catalyst (ENS) that shows better performance than commercial diesel oxidation catalyst (DOC). This newly developed ENSs could improve low-temperature automobile exhaust treatment. Precious metals have been used for various heterogeneous reactions, but it is crucial to maximize efficiency of catalysts due to their high cost. Single-atom catalysts (SACs) have received much attention because it is possible for all of the metal atoms to be used for reactions, yet they do not show catalytic activity for reactions that require ensemble sites. Meanwhile, hydrocarbons, such as propylene (C3H6) and propane (C3H8) are typical automobile exhaust gas pollutants and must be converted to carbon dioxide (CO2) and water (H2O) before they are released as exhaust. Since the hydrocarbon oxidation reaction proceeds only during carbon-carbon (C-C) or carbon-hydrogen (C-H) bond cleavage, it is essential to secure the metal ensemble site for the catalytic reaction. Therefore, precious metal catalysts with high dispersion and ensemble sites are greatly needed. To solve this issue, Professor Hyunjoo Lee from the Department of Chemical and Biomolecular Engineering and Professor Jeong Woo Han from POSTECH developed an Rh ensemble catalyst with 100% dispersion, and applied it to automobile after-treatment. Having a 100% dispersion means that every metal atom is used for the reaction since it is exposed on the surface. SACs also have 100% dispersion, but the difference is that ENSs have the unique advantage of having an ensemble site with two or more atoms. As a result of the experiment, the ENSs showed excellent catalytic performance in CO, NO, propylene, and propane oxidation at low temperatures. This complements the disadvantage of nanoparticle catalyst (NPs) that perform catalysis poorly at low temperatures due to low metal dispersion, or SACs without hydrocarbon oxidation. In particular, the ENSs have superior low-temperature activity even better than commercial DOC, hence they are expected to be applied to automobile exhaust treatment. Professor Lee said, “I believe that the ENSs have given academic contribution for proposing a new concept of metal catalysts, differentiating from conventional SACs and NPs. At the same time, they are of great value in the industry of exhaust treatment catalysts.” This research, led by PhD candidate Hojin Jeong, was published in the Journal of the American Chemical Society on July 5. Figure 1. Concept of Rh ensemble catalyst for automobile exhaust treatment Figure 2. Structure and performance comparison of single-atom catalyst and ensemble catalyst Figure 3. Energy-dispersive X-ray spectroscopy (EDS) mapping images for SAC, ENS, and NP, respectively (green, Eh; red, Ce)
Metabolic Engineering of E. coli for the Secretory Production of Free Haem
Researchers of KAIST have defined a novel strategy for the secretory production of free haem using engineered Escherichia coli (E. coli) strains. They utilized the C5 pathway, the optimized downstream pathways, and the haem exporter to construct a recombinant micro-organism producing extracellular haem using fed-batch fermentation. This is the first report to extracellularly produce haem using engineered E. coli. This strategy will expedite the efficient production of free haem to serve as a bioavailable iron-supplying agent and an important prosthetic group of multiple hemoproteins for medical uses. This study, led by Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering, was published in Nature Catalysis on Aug. 28. Haem, an organometallic compound complexed with a ferrous ion, is an essential molecule delivering oxygen in the blood of many animals. It is also a key component of electron transport chains responsible for the respiration of aerobic organisms including diverse bacteria. It is now being widely applied as a bioavailable iron-supplying agent in the healthcare and dietary supplement industries. The demand for haem and the need for the efficient production of this compound continue to grow. Many previous researchers have attempted to produce free haem using engineered E. coli. However, none of the studies was successful in producing free haem extracellularly, requiring an additional step to extract the accumulated haem from cells for subsequent uses. The secretion of haem in the form of haem peptides or proteins also requires an extraction step to isolate the free haem from the secreted products. Thus, the secretory production of free haem is an important task for the economical production of haem that is suitable for human consumption. Although some researchers could produce intracellular haem using recombinant E. coli strains, its final titer was extremely low, resulting from the use of sub-optimal metabolic pathways. Furthermore, the addition of the precursors L-glycine and succinate was deemed undesirable for massive industrial production. Thus, it is necessary to construct an optimized haem biosynthetic pathway to enable the efficient production of haem and examine the consequent secretion of free haem. To address this issue, the KAIST team used multiple strategies to produce extracellular free haem by enhancing its biosynthesis in E. coli. First, the capacities of the C4 and C5 pathways to produce aminolevulinate (ALA) without feeding precursors were examined. After confirming the superior performance of the C5 pathway over the C4 pathway, the metabolic genes of the C5 pathway and downstream pathways for haem biosynthesis were overexpressed. Then, the metabolic pathways were optimized by adjusting the expression levels of the relevant genes and disrupting the putative haem degradation enzyme encoded by the yfeX gene. Consequently, the resulting engineered strain secreted a significant amount of haem to the medium. Subsequent optimization of the cultivation conditions and the supplementation of nitrogen sources further increased both the titer of the total free haem and the amount of free haem secreted to the medium. Finally, the overexpression of the ccmABC genes encoding the haem exporter further enhanced the production and secretion of haem, producing the highest titer of haem both intracellularly and extracellularly from glucose. Professor Lee said, “The eco-friendly and sustainable chemical industry is a key global agenda every nation faces. We are conducting research to bio-synthesize high concentrations, high yields, and high productivity in natural products. This novel technology will serve as an opportunity to advance the biochemical industry moving forward.” This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (NRF-2012M1A2A2026556 and NRF-2012M1A2A2026557) from the Ministry of Science and ICT through the National Research Foundation (NRF) of Korea. Further Contact: Dr. Sang Yup Lee, Distinguished Professor, KAIST, Daejeon, Korea ( email@example.com+82-42-350-3930).
Enhanced PDT to Cure Cancer with Fewer Side Effects
(From left: PhD candidate Ilkoo Noh and Professor Yeu-Chun Kim) A KAIST research team developed near-infrared fluorophores-based photodynamic therapy (PDT) that reduced the downside of existing PDTs. PDT is a way to cure wounds with lasers instead of drug treatment. When a laser irradiates a targeted site, a photosensitizer (PS) absorbs light energy and then converts oxygen to singlet oxygen or free radicals, leading to programmed cell death. This treatment has been used widely in clinical fields, especially for skin disease because it allows noninvasive treatment. However, the existing PDTs have limitations for first-line therapy because PDT agents can cause genetic variations when they have low efficiency, hence reducing treatment effects. The key to enhancing the efficiency of PDTs is how much PS can be concentrated to a wanted site, which laser wavelength the PS is reacted to, and how fast the PS clears organelle after treatment. Professor Yeu-Chun Kim and his team from the Department of Chemical and Biomolecular Engineering, in collaboration with Professor Ji-Ho Park from the Department of Bio and Brain Engineering, developed a new PS called mitochondria targeting photodynamic therapeutic agent (MitDt) to maximize PDT effects while reducing unwanted side effects. Mitochondria has emerged as target sites to maximize the effects of PS since they play essential roles in metabolism and have high transmembrane potential. According to the team, when mitochondria is photodamaged by reactive oxygen species (ROS) generated after laser irradiation, they immediately lose their mitochondrial membrane potential and initiate apoptosis. Therefore, combining the PDT agent with the mitochondrial targeting agent can result in rapid damage to cancer cells, improving therapeutic efficacy and reducing unwanted side effects. To successfully apply mitochondria-targeting PS, the team developed near-infrared (NIR) region PDT agents, which can be used to treat deep-tissue level cancer due to the permeability of the NIR laser. Light scattering is also decreased, thus obtaining higher therapeutic efficacy. However, there is a problem of generating singlet oxygen when irradiating with an NIR laser. To address this issue, the team developed a novel PS that combines a functionalized NIR dye and a mitochondria-targeting agent to gain the benefit of rapid organelle clearance after treatment and also remain in cancer mitochondria for a long time, amplifying the amount of ROS to the target sites irradiated by the laser. To verify the efficacy, the team injected MitDt into tumor-bearing mice. They were irradiated with an NIR laser at 662 nm to induce cancer treatment and their cancer size was reduced up to three-fold. PhD candidate Ilkoo Noh, who led this research said, “This enhanced photodynamic cancer treatment has the advantage of treating a wanted site without any side effects because this PS stays longer in a mitochondrial cancer cell. We also confirmed that the PS did not cause cytotoxicity.” Professor Kim added, “This research outcome will reduce the danger of side effects and can be applied for treating various diseases”. This research was chosen as the cover page of Advanced Science on March 25. Figure 1. The cover of Advanced Science Figure 2. a) Chemical structure of MitDt compounds (above) b) mitochondria localization of designed PS (left) and ROS generation after 662nm laser irradiation (right)
Photonic Capsules for Injectable Laser Resonators
A KAIST research group presented photonic capsules for injectable laser resonators using microfluidic technology. The capsule’s diameter is comparable to a human hair and stable in gas and liquid media, so it is injectable into any target volume. The research group headed by Professor Shin-Hyun Kim in the Department of Chemical and Biomolecular Engineering applied an interesting optical property from nature. Professor Kim, who has dived deep into photonic materials research inspired from nature such as the Morpho butterfly, used a trait of beetles this time. Chrysina gloriosa, commonly known as the glorious beetle, shows a green color similar to leaves when illuminated by left-handed, circularly-polarized light while showing no color with right-handed, circularly-polarized light. This unique optical feature helps the beetles communicate with each other and protects them from predators. The principle behind this interesting optical property of the beetles relies on helical nanostructures with left-handedness that are present on the shell of the beetles. The helical structures reflect a circularly-polarized light with the same handedness of the helix at the wavelength selected by the helical pitch through optical interference. Such helical nanostructures can be artificially created using liquid crystals (LCs). LCs with a helical arrangement are referred to as cholesteric LCs (CLCs). The CLCs exhibit the polarization-dependent reflection of light in the same manner as the beetles and have been used for various photonic applications. In particular, CLCs have been cast to a film format that serves as mirrorless laser resonators, unlike conventional lasing systems. However, the film-type CLCs are large in size and show unidirectional emission, which restricts the use of CLC resonators in microenvironments. To overcome these limitations, Professor Kim’s group has encapsulated the CLCs with dual shells using microfluidic technology. The inner shell is a water layer that promotes the alignment of LC molecules and the outer shell is an elastic polymer layer that secures capsule stability and enables reversible mechanical deformation. The spherical symmetry of the capsules enables omnidirectional laser emissions. Moreover, laser intensity and lasing direction can be further controlled by deforming the capsules, while its wavelength remains tunable. This new type of CLC laser resonator is promising for laser treatments in various biomedical applications. Professor Kim said, “The helical nanostructure used in the laser resonator resembles that of the shell of chrysina gloriosa. Humans learn from nature and engineer materials to create something unprecedented.” This research was led by graduate student Sang Seok Lee and an article entitled “Wavelength-tunable and shape-reconfigurable photonic capsule resonators containing cholesteric liquid crystals” was published online on June 22, in Science Advances. Figure 1. Chrysina gloriosa illuminated by left-handed (left panel) and right-handed (right panel) circularly-polarized lights. (Image source: https://doi.org/10.1016/j.cub.2010.05.036 , permitted for reuse in news media) Figure 2. Composition (left panel) and optical microscopy image (right panel) of the capsule-type laser resonator
Recombinant E. Coli As a Biofactory for the Biosynthesis of Diverse Nanomaterials
(Distinguished Professor Lee and PhD candidate Choi) A metabolic research group at KAIST and Chung-Ang University in Korea has developed a recombinant E. coli strain that biosynthesizes 60 different nanomaterials covering 35 elements on the periodic table. Among the elements, the team could biosynthesize 33 novel nanomaterials for the first time, advancing the forward design of nanomaterials through the biosynthesis of various single and multi-elements. The study analyzed the nanomaterial biosynthesis conditions using a Pourbaix diagram to predict the producibility and crystallinity. Researchers studied a Pourbaix diagram to predict the stable chemical species of each element for nanomaterial biosynthesis at varying levels of reduction potential (Eh) and pH. Based on the Pourbaix diagram analyses, the initial pH of the reaction was changed from 6.5 to 7.5, resulting in the biosynthesis of various crystalline nanomaterials that were previously amorphous or not synthesized. This strategy was extended to biosynthesize multi-element nanomaterials. Various single and multi-element nanomaterials biosynthesized in this research can potentially serve as new and novel nanomaterials for industrial applications such as catalysts, chemical sensors, biosensors, bioimaging, drug delivery, and cancer therapy. A research group consisting of PhD candidate Yoojin Choi, Associate Professor Doh Chang Lee, and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST and Associate Professor Tae Jung Park of the Department of Chemistry at Chung-Ang University reported the synthesis. This study, entitled “Recombinant Escherichia coli as a biofactory for various single- and multi-element nanomaterials,” was published online in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) on May 21. A recent successful biosynthesis of nanomaterials under mild conditions without requiring physical and chemical treatments has triggered the exploration of the full biosynthesis capacity of a biological system for producing a diverse range of nanomaterials as well as for understanding biosynthesis mechanisms for crystalline versus amorphous nanomaterials. There has been increased interest in synthesizing various nanomaterials that have not yet been synthesized for various applications including semiconducting materials, enhanced solar cells, biomedical materials, and many others. This research reports the construction of a recombinant E. coli strain that co-expresses metallothionein, a metal binding protein, and phytochelatin synthase that synthesizes the metal-binding peptide phytochelatin for the biosynthesis of various nanomaterials. Subsequently, an E. coli strain was engineered to produce a diverse range of nanomaterials, including those never biosynthesized before, by using 35 individual elements from the periodic table and also by combining multi-elements. Distinguished Professor Lee said, “An environmentally-friendly and sustainable process is of much interest for producing nanomaterials by not only chemical and physical methods but biological synthesis. Moreover, there has been much attention paid to producing diverse and novel nanomaterials for new industrial applications. This is the first report to predict the biosynthesis of various nanomaterials, by far the largest number of various single- and multi-elements nanomaterials. The strategies used for nanomaterial biosynthesis in this research will be useful for further diversifying the portfolio of nanomaterials that can be manufactured.” Figure: The biosynthesis of diverse nanomaterials using recombinant E. coli. This schematic diagram shows the overall conceptualization of the biosynthesis of various single and multi-element nanomaterials using recombinant E. coli under incubation with corresponding elemental precursors. The 35 elements that were tested to biosynthesize nanomaterials are shown in black circles on the periodic table.
Cross-Generation Collaborative Labs Open
KAIST opened two cross-generation collaborative labs last month. This novel approach will pair up senior and junior faculty members for sustaining research and academic achievements even after the senior researcher retires. This is one of the Vision 2031 innovation initiatives established to extend the spectrum of knowledge and research competitiveness. The selected labs will be funded for five years and the funding will be extended if necessary. KAIST will continue to select new labs every year. A five-member selection committee including the Nobel Laureates Professor Klaus Von Klitzing at the Max-Planck Institute for Solid State Research and Dr. Kurt Wüthrich from ETH Zürich selected the first two labs with senior-junior pairs in March. (Two renowned scholars' Cross-Generation Collaborative Labs which opened last month. Distinguished Professor Lee's lab (above) andChair Professor Sung's lab) Both labs are run by world-renowned scholars: the Systems Metabolic Engineering and Systems Healthcare Laboratory headed by Distinguished Professor Sang-Yup Lee in the Department of Chemical and Biomolecular Engineering and the Acousto-Microfluidics Research Center for Next-Generation Healthcare led by Chair Professor Hyung Jin Sung in the Department of Mechanical Engineering. Distinguished Professor Lee will be teamed up with Professor Hyun Uk Kim, and their lab aims to mass produce new eco-friendly chemical materials as well as higher-value-added materials which will be used for medicine. The new platform technologies created in the lab are expected to provide information which will benefit human healthcare. Meanwhile, the Acousto-Microfluidics Research Center for Next-Generation Healthcare will team up with Professors Hyoungsoo Kim and Yeunwoo Cho under Chair Professor Sung. The lab will conduct research on controlling fluids and objects exquisitely on a micro-nano scale by using high-frequency acoustic waves. The lab plans to develop a next-generation healthcare platform for customized diagnoses as well as disease treatment. KAIST President Sung-Chul Shin, who introduced this novel idea in his research innovation initiative, said that he hopes the Cross-Generation Collaborative Labs will contribute to honoring senior scholars’ research legacies and passing knowledge down to junior researchers in order to further develop their academic achievements. He said, “I sincerely hope the labs will make numerous research breakthroughs in the very near future.”
Deep Learning Predicts Drug-Drug and Drug-Food Interactions
A Korean research team from KAIST developed a computational framework, DeepDDI, that accurately predicts and generates 86 types of drug-drug and drug-food interactions as outputs of human-readable sentences, which allows in-depth understanding of the drug-drug and drug-food interactions. Drug interactions, including drug-drug interactions (DDIs) and drug-food constituent interactions (DFIs), can trigger unexpected pharmacological effects, including adverse drug events (ADEs), with causal mechanisms often unknown. However, current prediction methods do not provide sufficient details beyond the chance of DDI occurrence, or require detailed drug information often unavailable for DDI prediction. To tackle this problem, Dr. Jae Yong Ryu, Assistant Professor Hyun Uk Kim and Distinguished Professor Sang Yup Lee, all from the Department of Chemical and Biomolecular Engineering at Korea Advanced Institute of Science and Technology (KAIST), developed a computational framework, named DeepDDI, that accurately predicts 86 DDI types for a given drug pair. The research results were published online in Proceedings of the National Academy of Sciences of the United States of America (PNAS) on April 16, 2018, which is entitled “Deep learning improves prediction of drug-drug and drug-food interactions.” DeepDDI takes structural information and names of two drugs in pair as inputs, and predicts relevant DDI types for the input drug pair. DeepDDI uses deep neural network to predict 86 DDI types with a mean accuracy of 92.4% using the DrugBank gold standard DDI dataset covering 192,284 DDIs contributed by 191,878 drug pairs. Very importantly, DDI types predicted by DeepDDI are generated in the form of human-readable sentences as outputs, which describe changes in pharmacological effects and/or the risk of ADEs as a result of the interaction between two drugs in pair. For example, DeepDDI output sentences describing potential interactions between oxycodone (opioid pain medication) and atazanavir (antiretroviral medication) were generated as follows: “The metabolism of Oxycodone can be decreased when combined with Atazanavir”; and “The risk or severity of adverse effects can be increased when Oxycodone is combined with Atazanavir”. By doing this, DeepDDI can provide more specific information on drug interactions beyond the occurrence chance of DDIs or ADEs typically reported to date. DeepDDI was first used to predict DDI types of 2,329,561 drug pairs from all possible combinations of 2,159 approved drugs, from which DDI types of 487,632 drug pairs were newly predicted. Also, DeepDDI can be used to suggest which drug or food to avoid during medication in order to minimize the chance of adverse drug events or optimize the drug efficacy. To this end, DeepDDI was used to suggest potential causal mechanisms for the reported ADEs of 9,284 drug pairs, and also predict alternative drug candidates for 62,707 drug pairs having negative health effects to keep only the beneficial effects. Furthermore, DeepDDI was applied to 3,288,157 drug-food constituent pairs (2,159 approved drugs and 1,523 well-characterized food constituents) to predict DFIs. The effects of 256 food constituents on pharmacological effects of interacting drugs and bioactivities of 149 food constituents were also finally predicted. All these prediction results can be useful if an individual is taking medications for a specific (chronic) disease such as hypertension or diabetes mellitus type 2. Distinguished Professor Sang Yup Lee said, “We have developed a platform technology DeepDDI that will allow precision medicine in the era of Fourth Industrial Revolution. DeepDDI can serve to provide important information on drug prescription and dietary suggestions while taking certain drugs to maximize health benefits and ultimately help maintain a healthy life in this aging society.” Figure 1. Overall scheme of Deep DDDI and prediction of food constituents that reduce the in vivo concentration of approved drugs
Producing 50x More Stable Adsorbent
A KAIST research team developed a technology to increase the stability of amine-containing adsorbents by fifty times, moving one step further toward commercializing stable adsorbents that last longer. Professor Minkee Choi from the Department of Chemical and Biomolecular Engineering and his team succeeded in developing amine-containing adsorbents that show high oxidative stability. The capture of the greenhouse gas carbon dioxide is an active ongoing research field, and some of the latest advancements point to amine-containing adsorbents as an efficient and environment-friendly way to capture carbon dioxide. However, existing amine-containing adsorbents are known to be unstable under oxidation, which chemically breaks down the adsorbent, thereby making it difficult to rely on amine-containing adsorbents for repeated and continued use. The researchers have discovered that the miniscule amount of iron and copper present in the amine accelerate the oxidative breakdown of the amine-containing adsorbent. Upon this discovery, they proposed the use of a chelator substance, which essentially suppresses the activation of the impurities. The team demonstrates that the proposed method renders the adsorbent up to 50 times slower in its deactivation rate due to oxidation, compared to conventional polyethyleneimine (PEI) / silica adsorbents. Figure 1 illustrates the superior performance of this oxidation-stable amine-containing adsorbent (shown in black squares), whose carbon dioxide-capturing capacity deteriorates by only a small amount (~8%). Meanwhile, the carbon dioxide-capturing capacity of the PEI/silica adsorbent (shown in red diamonds) degrades dramatically after being exposed to oxidative aging for 30 days. This stability under oxidation is expected to have brought amine-containing adsorbents one step closer to commercialization. As such, first author Woosung Choi describes the significance of this study as “having brought solid carbon dioxide adsorbents to commercializable standards”. In fact, Professor Choi explains that commercialization steps for his team’s carbon dioxide adsorbents are already underway. He further set forth his aim to “develop the world’s best carbon dioxide capture adsorbent”. This research, led by the PhD candidate Woosung Choi, was published online in Nature Communications on February 20. Figure 1. Carbon dioxide working capacity against oxidative aging time. Performance of the proposed method (black) degrades much more slowly (~50x) than that of existing methods. The novel adsorbent is thus shown to be more robust to oxidation.
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