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Discovery of an Optimal Drug Combination: Overcoming Resistance to Targeted Drugs for Liver Cancer
A KAIST research team presented a novel method for improving medication treatment for liver cancer using Systems Biology, combining research from information technology and the life sciences. Professor Kwang-Hyun Cho in the Department of Bio and Brain Engineering at KAIST conducted the research in collaboration with Professor Jung-Hwan Yoon in the Department of Internal Medicine at Seoul National University Hospital. This research was published in Hepatology in September 2017 (available online from August 24, 2017).
Liver cancer is the fifth and seventh most common cancer found in men and women throughout the world, which places it second in the cause of cancer deaths. In particular, Korea has 28.4 deaths from liver cancer per 100,000 persons, the highest death rate among OECD countries and twice that of Japan.
Each year in Korea, 16,000 people get liver cancer on average, yet the five-year survival rate stands below 12%. According to the National Cancer Information Center, lung cancer (17,399) took the highest portion of cancer-related deaths, followed by liver cancer (11,311) based on last year data.
Liver cancer is known to carry the highest social cost in comparison to other cancers and it causes the highest fatality in earlier age groups (40s-50s). In that sense, it is necessary to develop a new treatment that mitigates side effects yet elevates the survival rate.
There are ways in which liver cancer can be cured, such as surgery, embolization, and medication treatments; however, the options become limited for curing progressive cancer, a stage in which surgical methods cannot be executed.
Among anticancer medications, Sorafenib, a drug known for enhancing the survival rate of cancer patients, is a unique drug allowed for use as a targeted anticancer medication for progressive liver cancer patients. Its sales reached more than ten billion KRW annually in Korea, but its efficacy works on only about 20% of the treated patients. Also, acquired resistance to Sorafenib is emerging. Additionally, the action mechanism and resistance mechanism of Sorafenib is only vaguely identified.Although Sorafenib only extends the survival rate of terminal cancer patients less than three months on average, it is widely being used because drugs developed by global pharmaceutical companies failed to outperform its effectiveness.
Professor Cho’s research team analyzed the expression changes of genes in cell lines in response to Sorafenib in order to identify the effect and the resistance mechanism of Sorafenib.
As a result, the team discovered the resistance mechanism of Sorafenib using Systems Biology analysis. By combining computer simulations and biological experiments, it was revealed that protein disulfide isomerase (PDI) plays a crucial role in the resistance mechanism of Sorafenib and that its efficacy can be improved significantly by blocking PDI.
The research team used mice in the experiment and discovered the synergic effect of PDI inhibition with Sorafenib for reducing liver cancer cells, known as hepatocellular carcinoma. Also, more PDIs are shown in tissue from patients who possess a resistance to Sorafenib. From these findings, the team could identify the possibility of its clinical applications. The team also confirmed these findings from clinical data through a retrospective cohort study.
“Molecules that play an important role in cell lines are mostly put under complex regulation. For this reason, the existing biological research has a fundamental limitations for discovering its underlying principles,” Professor Cho said. “This research is a representative case of overcoming this limitation of traditional life science research by using a Systems Biology approach, combining IT and life science. It suggests the possibility of developing a new method that overcomes drug resistance with a network analysis of the targeted drug action mechanism of cancer.”
The research was supported by the National Research Foundation of Korea (NRF) and funded by the Ministry of Science and ICT.
(Figure 1. Simulation results from cellular experiments using hepatocellular carcinoma)
(Figure 2. Network analysis and computer simulation by using the endoplasmic reticulum (ER) stress network)
(Figure 3. ER stress network model)
2017.08.30 View 10464 -
Professor Dan Keun Sung Endows Scholarship in Honor of His Retirement
Professor Dan Keun Sung in the School of Electrical Engineering contributed a 100 million KRW scholarship fund this month to KAIST to mark his retirement after more than three decades of work.
“As my retirement date comes closer, I have been thinking about what I could do for the school. I wanted to leave something behind, even though it’s small, for my lifelong school and students. I am hoping that this scholarship fund will benefit the members of KAIST.”
This isn’t his first time making a donation to KAIST. In 2013, Professor Sung donated ten million KRW, which was his cash prize from the 9th Haedong Academic Award of The Korean Institute of Communications and Information Sciences (KICS). At that time, Professor Sung had the chance to create a scholarship fund in his name; however, he wanted to highlight that the scholarship fund was for ‘someone,’ not created by ‘someone.’ In that sense, his scholarship fund was created with no name to benefit students in the School of Electrical Engineering. His colleagues and students supported his idea. Professor Seonghwan Cho, students, and alumni also participated in fund raising efforts, which reached 55 million KRW in total.
Professor Sung emphasized, “Donations should always be remembered, no matter how small they are.” He then explained his purpose for creating the scholarship fund by saying, “Fundraising can be truly meaningful to contributors, knowing that their money is going to supporting the school and students.”
Professor Sung, a fellow of the Institute of Electrical and Electronics Engineers (IEEE) Communication Society, started his post at KAIST in 1986. For the past 30 years, he has devoted himself to fostering young scholars and studying in the area of information and communication. He also participated in developing technologies for the resource management of various future cellular components, such as satellites, switchboards, and signaling networks.
2017.08.11 View 7958 -
Students from Science Academies Shed a Light on KAIST
Recent KAIST statistics show that graduates from science academies distinguish themselves not only by their academic performance at KAIST but also in various professional careers after graduation.
Every year, approximately 20% of newly-enrolled students of KAIST are from science academies. In the case of the class of 2017, 170 students from science academies accounted for 22% of the newly-enrolled students. Moreover, they are forming a top-tier student group on campus. As shown in the table below, the ratio of students graduating early for either enrolling in graduate programs or landing a job indicates their excellent performance at KAIST.
There are eight science academies in Korea: Korea Science Academy of KAIST located in Busan, Seoul Science High School, Gyeonggi Science High School, Gwangju Science High School, Daejeon Science High School, Sejong Academy of Science and Arts, and Incheon Arts and Sciences Academy.
Recently, KAIST analyzed 532 university graduates from the class of 2012. It was found that 23 out of 63 graduates with the alma mater of science academies finished their degree early; as a result, the early graduation ratio of the class of 2012 stood at 36.5%. This percentage was significantly higher than that of students from other high schools.
Among the notable graduates, there was a student who made headlines with donation of 30 million KRW to KAIST. His donation was the largest donation from an enrolled student on record. His story goes back when Android smartphones were about to be distributed. Seung-Gyu Oh, then a student in the School of Electrical Engineering felt that existing subway apps were inconvenient, so he invented his own subway app that navigated the nearest subway lines in 2015. His app hit the market and ranked second in the subway app category. It had approximately five million users, which led to it generating advertising revenue. After the successful launch of the app, Oh accepted the takeover offered by Daum Kakao. He then donated 30 million KRW to his alma mater. “Since high school, I’ve always been thinking that I have received many benefits from my country and felt heavily responsible for it,” the alumnus of Korea Science of Academy and KAIST said. “I decided to make a donation to my alma mater, KAIST because I wanted to return what I had received from my country.” After graduation, Oh is now working for the web firm, Daum Kakao.
In May 24, 2017, the 41st International Collegiate Programming Contest, hosted by Association for Computing Machinery (ACM) and sponsored by IBM, was held in Rapid City, South Dakota in the US. It is a prestigious contest that has been held annually since 1977. College students from around the world participate in this contest; and in 2017, a total of 50,000 students from 2,900 universities in 104 countries participated in regional competitions, and approximately 400 students made it to the final round, entering into a fierce competition. KAIST students also participated in this contest. The team was comprised of Ji-Hoon Ko, Jong-Won Lee, and Han-Pil Kang from the School of Computing. They are also alumni of Gyeonggi Science High School. They received the ‘First Problem Solver’ award and a bronze medal which came with a 3,000 USD cash prize.
Sung-Jin Oh, who also graduated from Korea Science Academy of KAIST, is a research professor at the Korea Institute of Advanced Study (KIAS). He is the youngest recipient of the ‘Young Scientist Award’, which he received by proving a hypothesis from Einstein’s Theory of General Relativity mathematically at the age of 27. After graduating from KAIST, Oh earned his master’s and doctorate degrees from Princeton University, completed his post-doctoral fellow at UC Berkeley, and is now immersing himself in research at KIAS.
Heui-Kwang Noh from the Department of Chemistry and Kang-Min Ahn from the School of Computing, who were selected to receive the presidential scholarship for science in 2014, both graduated from Gyeonggi Science High School. Noh was recognized for his outstanding academic capacity and was also chosen for the ‘GE Foundation Scholar-Leaders Program’ in 2015. The ‘GE Foundation Scholar-Leaders Program’, established in 1992 by the GE Foundation, aims at fostering talented students. This program is for post-secondary students who have both creativity and leadership. It selects five outstanding students and provides 3 million KRW per annum for a maximum of three years.
The grantees of this program have become influential people in various fields, including professors, executives, staff members of national/international firms, and researchers. And they are making a huge contribution to the development of engineering and science. Noh continues doing various activities, including the completion of his internship at ‘Harvard-MIT Biomedical Optics’ and the publication of a paper (3rd author) for the ACS Omega of American Chemical Society (ACS).
Ahn, a member of the Young Engineers Honor Society (YEHS) of the National Academy of Engineering of Korea, had an interest in startup businesses. In 2015, he founded DataStorm, a firm specializing in developing data solution, and merged with a cloud back-office, Jobis & Villains, in 2016. Ahn is continuing his business activities and this year he founded, and is successfully running, cocKorea.
“KAIST students whose alma mater are science academies form a top-tier group on campus and produce excellent performance,” said Associate Vice President for Admissions, Hayong Shin. “KAIST is making every effort to assist these students so that they can perform to the best of their ability.”
(Clockwise from top left: Seung-Gyu Oh, Sung-Jin Oh, Heui-Kwang Noh and Kang-Min Ahn)
2017.08.09 View 8002 -
Analysis of Gas Adsorption Properties for Amorphous Porous Materials
Professor Jihan Kim from the Department of Chemical and Biomolecular Engineering at KAIST has developed a method to predict gas adsorption properties of amorphous porous materials.
Metal-organic frameworks (MOFs) have large surface area and high density of pores, making them appropriate for various energy and environmental-related applications. And although most MOFs are crystalline, these structures can deform during synthesis and/or industrial processes, leading to loss in long-range order. Unfortunately, without the structural information, existing computer simulation techniques cannot be used to model these materials.
In this research, Professor Kim’s research team demonstrated that one can replace the material properties of structurally deformed MOFs with those of crystalline MOFs to indirectly analyze/model the material properties of amorphous materials. First, the team conducted simulations on methane gas adsorption properties for over 12,000 crystalline MOFs to obtain a large training set data, and created a resulting structure-property map. Upon mapping the experimental data of amorphous MOFs onto the structure-property map, results showed that regardless of crystallinity, the gas adsorption properties of MOFs showed congruence and consistency amongst one another.
Based on these findings, selected crystalline MOFs with the most similar gas adsorption properties as the collapsed structure from the 12,000 candidates. Then, the team verified that the adsorption properties of these similar MOFs can be successfully transferred to the deformed MOFs across different temperatures and even to different gas molecules (e.g. hydrogen), demonstrating transferability of properties.
These findings allow material property prediction in porous materials such as MOFs without structural information, and the techniques here can be used to better predict and understand optimal materials for various applications including, carbon dioxide capture, gas storage and separations.
This research was conducted in collaboration with Professor Dae-Woon Lim at Kyoto University, Professor Myunghyun Paik at Seoul National University, Professor Minyoung Yoon at Gachon University, and Aadesh Harale at Saudi Arabian Oil Company. The research was published in the Proceedings of the National Academy of Sciences (PNAS) online on 10 July and the co-first authors were Ph. D. candidate WooSeok Jeong and Professor Dae-Woon Lim.
This research was funded by the Saudi Aramco-KAIST CO2 Management Center.
(Figure 1. Trends in structure - material property map and in collapsed structures)
(Figure 2. Transferability between the experimental results of collapsed MOFs and the simulation results of crystalline MOFs)
2017.07.26 View 8547 -
Structural Insights into the Modulation of Synaptic Adhesion by MDGA for Synaptogenesis
Synapses connected by various synaptic adhesion molecules are communication spaces between neurons for transmitting information. Among various synaptic adhesion molecules, neuroligins are arguably the most widely studied class of postsynaptic adhesion molecules, which mainly interact with presynaptic neurexins to induce excitatory or inhibitory synapse development. Recently, the membrane-associated mucin (MAM) domain-containing GPI anchor protein 1 (MDGA1) has been characterized as a key suppressor of Neuroligin-2/Neurexin-1β-mediated inhibitory synapse development, but how it acts remains a mystery.
In a recent issue of Neuron, published on June 21, 2017, a research team led by Professor Ho Min Kim at the Graduate School of Medical Science and Engineering of KAIST reported the three-dimensional structure of MDGA1/Neuroligin-2 complex and mechanistic insights into how MDGAs negatively modulate synapse development governed by Neurexins/Neuroligins trans -synaptic adhesion complex.
MDGA1 consists of six Ig-like domains, fibronectin type III repeat domain, and MAM domain . The crystal structure of MDGA1/Neuroligin-2 complex reveals that they form the 2:2 hetero-tetrameric complex and only the Ig1-Ig2 domains of MDGA1 are involved in interactions with Neuroligin-2. The structural comparison between the MDGA1/Neuroligin-2 and Neurexin-1β/Neuroligin-1 complexes intriguingly indicates that the Neuroligin-2 region binding to MDGA1 largely overlaps with that of Neurexin-1β, but the interaction interface of the MDGA1/Neuroligin-2 complex is much larger than that of the Neurexin-1β/Neuroligin-1 complex. This explains why Neuroligin-2 binds stronger to MDGA1 than Neurexin-1β, and how the favored MDGA1 binding to Neuroligin-2 sterically blocks the interaction between Neuroligin-2 and Neurexin-1β, which is critical for the suppression of inhibitory synapse development.
“Although we found that MDGA Ig domains (Ig 1 and Ig 2) are sufficient to form a complex with NL2, other extracellular domains, including Ig 3–6, FN III, and MAM domains, may also contribute to stable cis-interactions between MDGA1 and Neuroligin-2 by providing conformational flexibility. Therefore, further structural analysis of full-length MDGA will be required,” Professor Kim said.
Neuroligin-2 specifically promotes the development of inhibitory synapses, whereas neuroligin-1 promotes the development of excitatory synapses. Recently, not only MDGA1, but also MDGA2 have emerged as synaptic regulators for the development of excitatory or inhibitory synapses. In vitro biochemical analysis in this research clearly demonstrates that Neuroligin-1 and Neuroligin-2 bind to both MDGA1 and MDGA2 with comparable affinity. However, pull-down assays using detergent-solubilized mouse brain membrane fractions show the specific interaction of MDGA1 with Neuroligin-2, but not with Neuroligin-1. “This suggests that unidentified processes may dictate the selective association of MDGA1 with Neuroligin-2 in vivo , ” explained Professor Jaewon Ko at the Daegu Gyeongbuk Institute of Science and Technology (DGIST).
A balance between excitatory and inhibitory synapses is crucial to healthy cognition and behavior. Mutations in neuroligins, neurexins, and MDGAs, which can disrupt the excitatory/inhibitory balance, are associated with neuropsychiatric diseases such as autism and schizophrenia. Jung A Kim at KAIST, first author in this study, said, “Our discovery from integrative investigations are an important first step both for a better understanding of Neuroligin/Neurexin synaptic adhesion pathways and MDGA-mediated regulation of synapse development as well as the development of potential new therapies for autism, schizophrenia, and epilepsy.”
2017.07.10 View 7931 -
Cooperative Tumor Cell Membrane-Targeted Phototherapy
A KAIST research team led by Professor Ji-Ho Park in the Bio and Brain Engineering Department at KAIST developed a technology for the effective treatment of cancer by delivering synthetic receptors throughout tumor tissue. The study, led by Ph.D. candidate Heegon Kim, was published online in Nature Communications on June 19.
Cancer targeted therapy generally refers to therapy targeting specific molecules that are involved in the growth and generation of cancer. The targeted delivery of therapeutics using targeting agents such as antibodies or nanomaterials has improved the precision and safety of cancer therapy.
However, the paucity and heterogeneity of identified molecular targets within tumors have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes.
To solve this problem, the team constructed a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumor cell membrane-selective localization of synthetic receptors to amplify the subsequent targeting of therapeutics. Here, synthetic and biological nanocomponents refer to liposomes and extracellular vesicles, respectively.
The synthetic receptors are first delivered selectively to tumor cell membranes in the perivascular region using liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the synthetic receptors are transferred to neighboring cells and further spread throughout the tumor tissues where the molecular targets are limited.
Hitchhiking extracellular vesicles for delivery of synthetic receptors was possible since extracellular vesicles, such as exosomes, mediate intercellular communications by transferring various biological components such as lipids, cytosolic proteins, and RNA through a membrane fusion process. They also play a supportive role in promoting tumor progression in that tumor-derived extracellular vesicles deliver oncogenic signals to normal host cells.
The team showed that this tumor cell membrane-targeted delivery of synthetic receptors led to a uniform distribution of synthetic receptors throughout a tumor and subsequently led to enhanced phototherapeutic efficacy of the targeted photosensitizer.
Professor Park said, “The cooperative tumor targeting system is expected to be applied in treating various diseases that are hard to target.”
The research was funded by the Basic Science Research Program through the National Research Foundation funded by the Ministry of Science, ICT & Future Planning, and the National R&D Program for Cancer Control funded by the Ministry for Health and Welfare.
(Ph.D. candidates Hee Gon Kim (left) and Chanhee Oh)
Figure 1. A schematic of a cooperative tumor targeting system via delivery of synthetic receptors.
Figure 2. A confocal microscopic image of a tumor section after cooperative targeting by synthetic receptor delivery. Green and magenta represent vessels and therapeutic agents inside a tumor respectively.
2017.07.07 View 9587 -
KAIST Professors Sweep the Best Science and Technology Award
(Distinguished Professors Sang Yup Lee (left) and Kyu-Young Whang)
Distinguished Professors Sang Yup Lee from the Department of Chemical and Biomolecular Engineering and Kyu-Young Whang of the College of Computing were selected as the winners of the "2017 Korea Best Science and Technology Award" by the Ministry of Science, ICT and Future Planning (MSIP) and the Korea Federation of Science and Technology Societies.
The award, which was established in 2003, is the highest honor bestowed to the two most outstanding scientists in Korea annually. This is the first time that KAIST faculty members have swept the award since its founding.
Distinguished Professor Lee is renowned for his pioneering studies of system metabolic engineering, which produces useful chemicals by utilizing microorganisms. Professor Lee has developed a number of globally-recognized original technologies such as gasoline production using micro-organisms, a bio-butanol production process, microbes for producing nylon and plastic raw materials, and making native-like spider silk produced in metabolically engineering bacterium which is stronger than steel but finer than human hair.
System metabolism engineering was also selected as one of the top 10 promising technologies in the world in 2016 by the World Economic Forum. Selected as one of the world’s top 20 applied bioscientists in 2014 by Nature Biotechnology, he has many ‘first’ titles in his academic and research careers. He was the first Asian to win the James Bailey Award (2016) and Marvin Johnson Award (2012), the first Korean elected to both the US National Academy of Science (NAS) and the National Academy of Engineering (NAE) this year. He is the dean of KAIST institutes, a multi and interdisciplinary research institute at KAIST. He serves as co-chair of the Global Council on Biotechnology and as a member of the Global Future Council on the Fourth Industrial Revolution at the World Economic Forum.
Distinguished Professor Whang, the first recipient in the field of computer science in this award, has been recognized for his lifetime achievement and contributions to the development of the software industry and the spreading of information culture. He has taken a pioneering role in presenting novel theories and innovative technologies in the field of database systems such as probabilistic aggregation, multidimensional indexing, query, and database and information retrieval. The Odysseus database management system Professor Hwang developed has been applied in many diverse fields of industry, while promoting the domestic software industry and its technical independence.
Professor Hwang is a fellow at the American Computer Society (ACM) and life fellow at IEEE. Professor Whang received the ACM SIGMOD Contributions Award in 2014 for his work promoting database research worldwide, the PAKDD Distinguished Contributions Award in 2014, and the DASFAA Outstanding Contributions Award in 2011 for his contributions to database and data mining research in the Asia-Pacific region. He is also the recipient of the prestigious Korea (presidential) Engineering Award in 2012.
2017.07.03 View 9130 -
2017 World Friends ICT KAIST Sets Off to Ethiopia, Tanzania
KAIST launched the ‘2017 World Friends ICT KAIST’ on 21 June at a ceremony held at the Faculty Club. The event was attended by 40 student volunteers and faculty members including President Sung-Chul Shin and student volunteers.
The ‘2017 World Friends ICT KAIST’ is an oversees volunteer program aimed at providing ICT education for students from developing countries and for cultural exchange. The program was organized by the KAIST Leadership Center and sponsored by the National Information Agency (NIA) since 2015.
President Sung-Chul Shin delivered words of encouragement to start the opening ceremony, followed by an oath-taking by the volunteer group, safety training, and a commemorative photoshoot. This year’s World Friends ICT volunteer group consisted of 32 students and 2 staff members to lead and to support the team.
The group was divided into eight teams including APP-frica, KAI-Tigers, and WITH (4 members per team) to volunteer in Addis Ababa Institute of Technology (AAIT) and Adama Science and Technology University in Ethiopia (ASTU), as well as Nelson Mandela African Institute of Science and Technology (NM-AIST) in Tanzania. The teams will educate local students on ICT and promote cultural exchanges. The volunteer period is from July 7 to August 5, lasting about a month.
KAIST conducted primary document examinations and interviews from April 27 to May 18 on volunteer candidates who registered to take part, and selected 32 student volunteers. A total of 68 students registered to volunteer, resulting in a 1:2.1 competition rate.
The volunteering program was customized to the local needs of Ethiopia and Tanzania and thus consisted of ICT education, cultural exchanges, volunteering at farms on the weekends, and science experiments. The area with the most focus by the volunteer team is ICT education, which accounts for 70% of the total volunteer activities. The aim is to educate Ethiopian students at AAIT and ASTU on Windows, MS Office, Adobe Photoshop, and using smartphones. In Tanzania, the team is to volunteer with students of NM-AIST to provide ICT application education such as water tank control using appropriate technology and Arduino to local high school students.
The team is also planning to promote cultural exchanges by preparing K-Pop dancing, traditional Korean games such as Korean shuttlecock game (jegichagi) and Korean wrestling (ssireum), traditional cooking such as bibimbab and half-moon-shaped rice cake (songpyeon), and teaching the Korean language, as well as preparing cultural performances with local university students. On the weekends, the team will visit local farms to volunteer, and local elementary schools and orphanages to conduct science experiments for children, as well as physical education and art activities.
(Photo caption: Volunteers poses with faculty and staff members including President Sung-Chul Shin at a ceremony on June 21.)
2017.06.29 View 9632 -
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.
2017.06.05 View 10402 -
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.
2017.06.02 View 8702 -
Extreme Materials for Fusion with Metal Cocktail
The research team under Professor Ryu Ho-jin of the Department of Nuclear and Quantum Engineering has developed a new material for facing fusion plasma environments using metal powder mixing technology. This technology is expected to extend the range of materials that can be designed for use in extreme environments such as in fusion power generators.
The durability of the tokamak vessel, which holds high-temperature plasma, is very important to create fusion power reactors, which are expected to be a future energy source. Currently, high-melting-point metals, such as tungsten, are considered plasma-facing materials to protect the tokamak vessel. However, high-energy thermal shocks, plasma ions, and neutrons are fatal to the plasma-facing material during high temperature fusion plasma operation. Therefore, it is necessary to develop new high-performance materials.
The ITER project, in which seven countries including the United States, the EU, and Korea participate jointly, is constructing a nuclear fusion experimental reactor in France with the goal of achieving the first plasma in 2025 and deuterium-tritium fusion operation in 2035. In Korea, the KSTAR tokamak at the National Fusion Research Institute has succeeded in maintaining high-performance plasma for 70 seconds.
Researchers in Europe, the United States, and China, who are leading the research on fusion plasma-facing materials, are studying the improvement of physical properties by adding a small amount of metal elements to tungsten. However, Professor Ryu’s team reported that by mixing various metals’ powders, including tungsten, they have succeeded in producing a new material that has twice the hardness and strength of tungsten. The difference in the atomic sizes of the well-mixed elements in the alloy is very significant because it makes it difficult to deform the alloy.
The team will continue its research to find alloying compositions that optimize mechanical properties as well as thermal conductivity, plasma interactions, neutron irradiation embrittlement, tritium absorption, and high-temperature oxidation properties.
Professor Ryu said, "Fusion plasma-facing materials are exposed to extreme environments and no metal is capable of withstanding thermal shock, plasma, and neutron damage simultaneously. As a result of this research, attempts to develop complex metallic materials for nuclear fusion and nuclear power are expected to become more active around the world. "
Ph.D. candidate Owais Ahmed Waseem is the first author of this project. The research is supported by the Ministry of Science, ICT and Future Planning, the Korea Research Foundation's Fusion Basic Research project, and the Engineering Research Center. The results were published in 'Scientific Report' on May 16.
Figure 1. Tungsten-based high strengh alloy sample
Figure 2. Fusion plasma facing material development by powder processing of refractory elements
2017.05.26 View 8585 -
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)
2017.05.23 View 8392