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Structural Insight into the Molecular Mechanism of PET Degradation
A KAIST metabolic engineering research team has newly suggested a molecular mechanism showing superior degradability of poly ethylene terephthalate (PET).
This is the first report to simultaneously determine the 3D crystal structure of Ideonella sakaiensis PETase and develop the new variant with enhanced PET degradation.
Recently, diverse research projects are working to address the non-degradability of materials. A poly ethylene terephthalate (PET)-degrading bacterium called Ideonella sakaiensis was recently identified for the possible degradation and recycling of PET by Japanese team in Science journal (Yoshida et al., 2016). However, the detailed molecular mechanism of PET degradation has not been yet identified.
The team under Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering and the team under Professor Kyung-Jin Kim of the Department of Biotechnology at Kyungpook National University conducted this research. The findings were published in Nature Communications on January 26.
This research predicts a special molecular mechanism based on the docking simulation between PETase and a PET alternative mimic substrate. Furthermore, they succeeded in constructing the variant for IsPETase with enhanced PET-degrading activity using structural-based protein engineering.
It is expected that the new approaches taken in this research can be background for further study of other enzymes capable of degrading not only PET but other plastics as well.
PET is very important source in our daily lives. However, PET after use causes tremendous contamination issues to our environment due to its non-biodegradability, which has been a major advantage of PET. Conventionally, PET is disposed of in landfills, using incineration, and sometimes recycling using chemical methods, which induces additional environmental pollution. Therefore, a new development for highly-efficient PET degrading enzymes is essential to degrade PET using bio-based eco-friendly methods.
Recently, a new bacterial species, Ideonella sakaiensis, which can use PET as a carbon source, was isolated. The PETase of I. sakaiensis (IsPETase) can degrade PET with relatively higher success than other PET-degrading enzymes. However, the detailed enzyme mechanism has not been elucidated, hindering further studies.
The research teams investigated how the substrate binds to the enzyme and which differences in enzyme structure result in significantly higher PET degrading activity compared with other cutinases and esterases, which make IsPETase highly attractive for industrial applications toward PET waste recycling.
Based on the 3D structure and related biochemical studies, they successfully predicted the reasons for extraordinary PET degrading activity of IsPETase and suggested other enzymes that can degrade PET with a newly-classified phylogenetic tree. The team proposed that 4 MHET moieties are the most properly matched substrates due to a cleft on structure even with the 10-20-mers for PET. This is meaningful in that it is the first docking simulation between PETase and PET, not its monomer.
Furthermore, they succeeded in developing a new variant with much higher PET-degrading activity using a crystal structure of this variant to show that the changed structure is better to accommodate PET substrates than wild type PETase, which will lead to developing further superior enzymes and constructing platforms for microbial plastic recycling.
Professor Lee said, “Environmental pollution from plastics remains one of the greatest challenges worldwide with the increasing consumption of plastics. We successfully constructed a new superior PET-degrading variant with the determination of a crystal structure of PETase and its degrading molecular mechanism. This novel technology will help further studies to engineer more superior enzymes with high efficiency in degrading. This will be the subject of our team’s ongoing research projects to address the global environmental pollution problem for next generation.”
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 of Korea. Further Contact: Dr. Sang Yup Lee, Distinguished Professor, KAIST, Daejeon, Korea (leesy@kaist.ac.kr, +82-42-350-3930)
(Figure: Structural insight into the molecular mechanism of poly(ethylene terephthalate) degradation and the phylogenetic tree of possible PET degrading enzymes. This schematic diagram shows the overall conceptualization for structural insight into the molecular mechanism of poly (ethylene terephthalate) degradation and the phylogenetic tree of possible PET degrading enzymes.)
2018.01.31 View 9176 -
Plasma, an Excellent Sterilizer to Remove Harmful Bacteria
(PhD candidate Joo Young Park, Professor Wonho Choe and PhD researcher Sanghoo Park)
KAIST researchers are using plasma to remove bacteria that are stuck to surfaces of plastic bottles and food. This novel technology will contribute to disinfection in medical settings as well as food and agricultural industries.
Professor Wonho Choe and his team from the Department of Physics developed a technology that removes biofilm, which is comprised of microorganisms, by using plasma as a non-thermal sterilization method.
Plasma contains multiple bactericidal agents, including reactive species. In particular, the chemicals formed in aqueous solution during plasma exposure have the potential for high antibacterial activity against various bacterial infections.
The team treated water with plasma to see how effectively bactericidal agents in the plasma water can remove biofilm comprised of harmful microorganism such as Escherichia coli, Salmonella, and Listeria.
The team identified that reactive species, including hydroxyl radical, hydrogen peroxide, ozone, nitrite, and superoxide produced during plasma treatment, showed considerable ability to remove the biofilm. Hydrogen peroxide showed the strongest effect removing the biofilm; however, the hydroxyl radical also played a significant role in removing biofilm. Despite having a concentration 100 to 10,000 times lower than other reactive species, the hydroxyl radical showed a high biofilm removal efficacy owing to its strong oxidative power.
These findings reveal that plasma can be used as a no-residual and safe sterilization process alternative to conventional methods. With these outcomes, the team is planning to develop and commercialize a technology that can produce hydroxyl radicals with plasma.
Professor Choe has registered a patent for flexible packaging materials that facilitate plasma and completed the technology transfer to the startup company, named ‘Plasmapp’, which focuses on commercializing bactericidal technology.
“This research outcome will be the foundation for understanding plasma control technology and physicochemical interactions between plasma and microorganisms. It will also become an accelerator for utilizing plasma technology in the medical, food, and agricultural fields,” said Professor Choe.
This research, led by PhD candidate Joo Young Park and PhD researcher Sanghoo Park in collaboration with Professor Cheorun Jo’s team from Seoul National University, was published in ACS Applied Materials and Interfaces on December 20, 2017.
Figure 1. Flexible packaging materials that facilitate plasma
Figure 2. Schematic diagram of biofilm treatment with plasma
Figure 3. Concept of plasma application and evaluation result of reactive species' efficacy
Figure 4. STERPACK, the product launched by Plasmapp
2018.01.25 View 9563 -
Cellular Mechanism for Severe Viral Hepatitis Identified
(Professor Shin(left) and Professor Jung)
KAIST medical scientists identified a cellular mechanism causing inflammatory changes in regulatory T cells that can lead to severe viral hepatitis. Research on this mechanism will help further understand the nature of various inflammatory diseases and lead to the development of relevant clinical treatments.
It is known that activated immune cells of patients with viral hepatitis destroy hepatocyte, but its regulatory mechanism has not yet been described.
Regulatory T cells inhibit activation of other immune cells and thus are important for homeostasis of the immune system. However, recent studies contradictorily show that immune inhibitory functions of regulatory T cells weaken in inflammatory conditions and the cells secrete inflammatory cytokines in response. Meanwhile, such a phenomenon was not observed in viral hepatitis including types A, B and C.
The team focused on changes in regulatory T cells in patients with viral hepatitis and discovered that regulatory T cells undergo inflammatory changes to secrete inflammatory cytokines (protein secreted by immune cells) called TNF. They also proved regulatory T cells that secrete TNF contribute to the progression of viral hepatitis.
The team confirmed that regulatory T cells of acute hepatitis A patients have reduced immune-inhibitory functions. Instead, their regulatory T cells secrete TNF. Through this research, the team identified a molecular mechanism for changes in regulatory T cells and identified the transcription factor regulating the process. Furthermore, the team found similar changes to be also present in hepatitis B and C patients.
A KAIST immunology research team led by Professors Eui-Cheol Shin and Min Kyung Jung at the Graduate School of Medical Science & Engineering conducted this translational research with teams from Chungnam National University and Yonsei University to identify the mechanism in humans, instead of using animal models. The research was described in Gastroenterology last December.
Professor Shin said, “This is the first research on regulatory T cells that contributes to hepatocyte damage in viral hepatitis.” He continued, “It is significant for identifying the cells and the molecules that can be used as effective treatment targets for viral hepatitis in the future. This research was funded by the Samsung Science and Technology Foundation.
(Figure1: Treg cells from acute hepatitis A (AHA) patients produce tumor necrosis factor (TNF) andhave reduced suppressive activity. These changes are due to a decrease in FoxP3 transcription factor and an increase in RORγt transcription factor. TNF-producing Treg cells are associated with severe liver injury in AHA patients.)
(Figure 2: A higher proportion of Treg cells from patients with acute hepatitis A, compared with healthy controls, produced TNF upon stimulation with anti-CD3 and anti-CD2. This study reports the presence and the significance of TNF-producing Treg cells for the first time in human patients.)
2018.01.18 View 8421 -
Three Professors Named KAST Fellows
(Professor Dan Keun Sung at the center)
(Professor Y.H. Cho at the center)
(Professor K.H. Cho at the center)
The Korean Academy of Science and Technology (KAST) inducted three KAIST professors as fellows at the New Year’s ceremony held at KAST on January 12. They were among the 24 newly elected fellows of the most distinguished academy in Korea. The new fellows are Professor Dan Keun Sung of the School of Electrical Engineering, Professor Kwang-Hyun Cho of the Department of Bio and Brain Engineering, and Professor Yong-Hoon Cho of the Department of Physics.
Professor Sung was recognized for his lifetime academic achievements in fields related with network protocols and energy ICT. He also played a crucial role in launching the Korean satellites KITSAT-1,2,3 and the establishment of the Satellite Technology Research Center at KAIST.
Professor Y.H.Cho has been a pioneer in the field of low-dimensional semiconductor-powered quantum photonics that enables quantum optical research in solid state. He has been recognized as a renowned scholar in this field internationally.
Professor K.H.Cho has conducted original research that combines IT and BT in systems biology and has applied novel technologies of electronic modeling and computer simulation analysis for investigating complex life sciences. Professor Cho, who is in his 40s, is the youngest fellow among the newly inducted fellows.
2018.01.16 View 13729 -
Harnessing the Strength of KAIST Alumni: New Head of KAA Inaugurated
KAIST alumni gathered in Seoul on January 13 to celebrate the New Year and the newly-elected leadership of the KAIST Alumni Association (KAA). More than 300 alumni, including President Sung-Chul Shin who is also an alumnus of KAIST, joined the gala event held at the Lotte Hotel.
Photo: Ki-Chul Cha(left) and Jung Sik Koh(right)
The KAA inaugurated its new president, Ki-Chul Cha, who was preceded by Jung Sik Koh, the former CEO at the Korea Resources Corporation. His term starts from January 2018 to December 2020.
Cha is the CEO of Inbody Co Ltd., a global company specializing in developing and selling medical instruments, such as a body composition analyzers, and medical solutions. He is also an adjunct professor in the Department of Mechanical Engineering at Yonsei University. Cha obtained a master’s degree in Mechanical Engineering at KAIST in 1980, and a Ph.D. in Bioengineering at the University of Utah, before finishing his post-doc fellowship at Harvard Medical School.
Cha plans to explore the idea that alumni engagement, saying, “KAIST stays as a home in the memories of 60,000 alumni. I will dedicate myself to stimulating the alumni association to make KAISTians proud.”
At the gala event, the KAA awarded the Alumni of the Year honor to six alumni who distinguished themselves in the areas of professional achievement, humanitarianism, and public service. They are the Director of Startup KAIST Professor Byoung Yoon Kim; President of LG Chem Ltd and Head of Battery Research and Development Myung Hwan Kim; Director of INNOX Advanced Materials Co., Ltd Kyung Ho Chang; Vice President of the Korea International Trade Association Jung-Kwan Kim; CEO of Samsung Electro-Mechanics Yun-Tae Lee; and CEO of ENF Technology Jinbae Jung.
Photo: President Shin(far right) poses with six awardees of the Distinguished Alumni Award and the former President of KAA, Koh(far left)
2018.01.16 View 10394 -
New Arylation Inducing Reaction Developed
(Professor Chang(left) and Professor Baik)
KAIST researchers have identified a reaction mechanism that selectively introduces aryl groups at the desired position of a molecule at room temperature. A team, co-led by Professor Sukbok Chang and Mu-Hyun Baik of the Department of Chemistry, used an iridium catalyst for the reaction. The team also proved that the reaction proceeds by an unusual mechanism by employing computer simulations that were substantiated with targeted experimental probes.
Hydrocarbon is an omnipresent material in nature. But its low reactivity makes it difficult to process to value-added products at the room temperature. Thus, designing catalysts that can accelerate the reaction remains an important challenge in chemistry.
In particular, since most chemicals used in medicine, pharmacy, or material chemistry contain aryl groups, an effective reaction to selectively introduce the aryl group has been an area of intensive research in organic chemistry.
In order to introduce an aryl group into stable carbon-hydrogen (C-H) bond, activation of the C-H bond with a halogen atom or organic metal is required prior to the introduction of the aryl group, or C-H functionalization directly on C-H bond is needed. Direct functionalization is more effective and economical, but most reactions require harsh reaction conditions such as high temperature or excess additives. And adding the aryl fragment selectively to only one among the many possible sites in the molecule is difficult. The new catalyst developed by these KAIST researchers is highly selective.
This work is the latest example of a successful teamwork between experimental and theoretical research groups: Computer simulations revealed that traditional approaches to arylation required high energies because the intermediates produced during the reaction are too low in energy. Based on this insight, the researchers thought of changing the character of the intermediate by oxidizing it, which was predicted to be a great way of increasing the reactivity of the catalyst. Subsequent experimental work showed that this design strategy is highly effective resulting in unprecedented chemical transformations.
Professor Chang said, “We have been able to carry out location-selective arylation at room temperature, as well as identifying a new reaction pathway, different from the conventionally suggested mechanism.” He continued, “This research is significant for identifying the reaction pathway and developing a novel selective reaction method that does not require high temperature or additives based on the mechanistic understanding. This work is a triumph of rational design, rather than fortuitous discovery.” The research findings were published online in Nature Chemistry on December 11, 2017.
(Figure 1: X-ray crystal structure transmetallation intermediate)
(Figure 2: Correlation between oxidation state of intermediate and energy barrier required for reductive elimination of intermediate as calculated using density function from computational chemistry )
(Figure 3: Arylation mechanism using iridium catalyst as suggested by the research team)
2018.01.11 View 5876 -
KAIST Students Invited to the BNL
Siheon Ryee and Taek Jung Kim, combined Masters and PhD students from the Department of Physics, have been invited to be visiting researchers at the Brookhaven National Laboratory (BNL).
The BNL, located in Long Island, New York, is one of the most esteemed institutes in the United States. Ryee and Kim received the invitation from the Center for Computational Design of Functional Strongly Correlated Materials and Theoretical Spectroscopy. This center was established by scholars who have been leading this field in the United States.
The two students will be participating in developing a methodology and code for calculating strongly correlated electronic materials, and a grant of 40,000 USD will be provided to each student. This amount of support is not often awarded to researchers outside of postdoctoral programs.
Moreover, they are guaranteed to continue their combined Masters and PhD program and write their dissertations under the supervision of their advisor, Professor Myung Joon Han from the Department of Physics.
Professor Han said, “I was impressed by how well-known scholars established the center in order to cooperate with each other to solve challenging problems. Also, I was surprised and happy that my students were invited to this outstanding institute.”
“I believe that doing research with leaders in their field will give valuable experience to the students. At the same time, my students will be a great help to the scholars of the institute,” he added.
2018.01.11 View 7794 -
Professor Jung Awarded the Pople Medal by the APATCC
(Professor Yousung Jung)
Professor Yousung Jung of the Graduate School of EEWS won the Pople Medal from the Asia-Pacific Association of Theoretical & Computational Chemists (APATCC).
The Pople Medal has been awarded annually since 2007 to recognize young scholars in the fields of theoretical/computational chemistry in honor of Sir John Anthony Pople, who passed away in 2004. Dr. Pople was a British theoretical chemist and a Nobel laureate in 1998 for his development of computational methods in quantum chemistry.
The Pople Medal is awarded to scientists at or under the age of 45 in the Asia-Pacific region who have distinguished themselves through pioneering and important contributions.
Professor Jung was honored for his outstanding contributions to developing efficient electronic structure methods and their applications to energy materials discovery. He has published more than 120 papers in prestigious academic journals. He also has an h-index of 44, and has been cited more than 8,000 times.
2018.01.10 View 7222 -
One-Step Production of Aromatic Polyesters by E. coli Strains
KAIST systems metabolic engineers defined a novel strategy for microbial aromatic polyesters production fused with synthetic biology from renewable biomass. The team of Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering produced aromatic polyesters from Escherichia coli (E. coli) strains by applying microbial fermentation, employing direct microbial fermentation from renewable feedstock carbohydrates.
This is the first report to determine a platform strain of engineered E. coli capable of producing environmentally friendly aromatic polyesters. This engineered E. coli strain, if desired, has the potential to be used as a platform strain capable of producing various high-valued aromatic polyesters from renewable biomass. This research was published in Nature Communications on January 8.
Conventionally, aromatic polyesters boast solid strength and heat stability so that there has been a great deal of interest in fermentative production of aromatic polyesters from renewable non-food biomass, but without success.
However, aromatic polyesters are only made by feeding the cells with corresponding aromatic monomers as substrates, and have not been produced by direct fermentation from renewable feedstock carbohydrates such as glucose.
To address this issue, the team prescribed the detailed procedure for aromatic polyester production through identifying CoA-transferase that activates phenylalkanoates into their corresponding CoA derivatives. In this process, researchers employed metabolic engineering of E. coli to produce phenylalkanoates from glucose based on genome-scale metabolic flux analysis. In particular, the KAIST team made a modulation of gene expression to produce various aromatic polyesters having different monomer fractions.
The research team successfully produced aromatic polyesters, a non-natural polymer using the strategy that combines systems metabolic engineering and synthetic biology. They succeeded in biosynthesis of various kinds of aromatic polyesters through the system, thus proving the technical excellence of the environmentally friendly biosynthetic system of this research. Furthermore, his team also proved the potential of expanding the range of aromatic polyesters from renewable resources, which is expected to play an important role in the bio-plastic industry.
Professor Lee said, “An eco-friendly and sustainable chemical industry is the key global agenda every nation faces. We are making a research focus to a biochemical industry free from petroleum dependence, and conducting diverse research activities to address the issue. This novel technology we are presenting will serve as an opportunity to advance the biochemical industry moving forward.”
This work was supported by the Intelligent Synthetic Biology Center through the Global Frontier Project (2011-0031963) and also 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 of Korea.
Figure: Biosynthesis of aromatic polyesters by metabolically engineered E. coli.This schematic diagram shows the overall conceptualization of how metabolically engineered E. coli produced aromatic polyesters from glucose.
2018.01.09 View 7354 -
Ultra-Low Power Flexible Memory Using 2D Materials
(Professor Choi and Ph.D. candidate Jang)
KAIST research team led by Professor Sung-Yool Choi at School of Electrical Engineering and Professor Sung Gap Im at the Department of Chemical and Biomolecular Engineering developed high-density, ultra-low power, non-volatile, flexible memory technology using 2D materials. The team used ultrathin molybdenum disulfide (MoS2) with atomic-scale thickness as the channel material and high-performance polymeric insulator film as the tunneling dielectric material. This research was published on the cover of Advanced Functional Materials on November 17. KAIST graduate Myung Hun Woo, a researcher at Samsung Electronics and Ph.D. candidate Byung Chul Jang are first authors.
The surge of new technologies such as Internet of Things (IoT), Artificial Intelligence (AI), and cloud server led to the paradigm shift from processor-centric computing to memory-centric computing in the industry, as well as the increase in demand of wearable devices. This led to an increased need for high-density, ultra-low power, non-volatile flexible memory. In particular, ultrathin MoS2 as semiconductor material has been recently regarded as post-silicon material. This is due to its ultrathin thickness of atomic-scale which suppresses short channel effect observed in conventional silicon material, leading to advantages in high- density and low-power consumption. Further, this thickness allows the material to be flexible, and thus the material is applicable to wearable devices.
However, due to the dangling-bond free surface of MoS2 semiconductor material, it is difficult to deposit the thin insulator film to be uniform and stable over a large area via the conventional atomic layer deposition process. Further, the currently used solution process makes it difficult to deposit uniformly low dielectric constant (k) polymeric insulator film with sub-10 nm thickness on a large area, thus indicating that the memory device utilizing the conventional solution-processed polymer insulator film cannot be operated at low-operating voltage and is not compatible with photolithography.
The research team tried to overcome the hurdles and develop high-density, ultra-low power, non-volatile flexible memory by employing a low-temperature, solvent-free, and all-dry vapor phase technique named initiated chemical vapor deposition (iCVD) process. Using iCVD process, tunneling polymeric insulator film with 10 nm thickness was deposited uniformly on MoS2 semiconductor material without being restricted by the dangling bond-free surface of MoS2. The team observed that the newly developed MoS2-based non-volatile memory can be operated at low-voltage (around 10V), in contrast to the conventional MoS2-based non-volatile memory that requires over 20V.
Professor Choi said, “As the basis for the Fourth Industrial revolution technologies including AI and IoT, semiconductor device technology needs to have characteristics of low-power and flexibility, in clear contrast to conventional memory devices.” He continued, “This new technology is significant in developing source technology in terms of materials, processes, and devices to contribute to achieve these characteristics.”
This research was supported by the Global Frontier Center for Advanced Soft Electronics and the Creative Materials Discovery Program by funded the National Research Foundation of Korea of Ministry of Science and ICT.
( Figure 1. Cover of Advanced Functional Materials)
(Figure 2. Concept map for the developed non-volatile memory material and high-resolution transmission electron microscopy image for material cross-section )
2018.01.02 View 9051 -
President Shin Reaffirms Innovation Initiatives in New Year Speech
(President Shin and representatives of faculty, students, staff celebrate the New Year in a reception held on January 2 at the auditorium.)
The KAIST community gathered to celebrate a fresh start for the year 2018. At the ceremony, held in the auditorium on January 2, members of KAIST community reaffirmed their commitment to be the trailblazers of Korea and beyond through unwavering innovations.
President Sung-Chul Shin presented his new vision and plan in his New Year speech, which focused on innovation for enhancing institutional competitiveness and global visibility. He said that as you are the future of KAIST, KAIST is the future of Korea. KAIST’s vision for a better future will have a significant impact on national progress and beyond. He stressed that innovation in the five pillars of education, research, technology commercialization, globalization, and future strategy will further advance the excellence of KAIST.
At the ceremony, President Shin also presented the award for ‘the KAISTian of the Year’ to Professor YongKeun Park of the Department of Physics. The annual award recognizes a distinguished professor whose academic accomplishments made the most significant impact.
In his New Year speech, President Shin said that the year 2018 will provide an opportunity to take a leap forward for becoming a ‘Global Value Creative, World-Leading University. The Vision 2031 Committee endorsed the five innovation initiatives to fulfill KAIST’s long-term vision and will open its recommendations to the public on March 20.
Educational innovation tops the initiatives. President Shin explained that the future of Korea is in the hands of talented individuals in science and technology, emphasizing the need to nurture creative, transdisciplinary talents with the capacity to enhance the social value of science and technology.
To this end, KAIST will establish a new undergraduate non-departmental program for transdisciplinary education. This plan will eventually provide students with more options in choosing their major, as well as help students build a strong foundation in basic science and engineering and encourage multidisciplinary approaches.
For creating an innovative institutional research infrastructure, KAIST plans to build a Network of Excellence for the Fourth Industrial Revolution (NExFire) for convergence research. The plan of ‘Cross-Generational Collaborative Labs,’ will bring out a new collaboration platform by pairing up senior and junior faculty. President Shin said it will be a stepping stone to extend the spectrum of knowledge without any cessation.
For technology commercialization, KAIST will maximize its intellectual property and economic value by stimulating technology-invested companies and startups. Close cooperation with venture capitalists at home and abroad will further accelerate the commercialization drive at KAIST.
Saying that the globalization is no long an option but a necessity, he stressed KAIST will strengthen its efforts to established a bilingual campus. “KAIST will make every effort to create a more welcoming and comfortable atmosphere for the international community and their families. We will expand benefits to our international community, such as access to the KAIST Child Care Center and collaboration with the Taejon Christian International School (TCIS),” he said. President Shin added he will further expand global networks and partnerships this year, participating in a diverse range of international events at home and abroad for increasing global visibility.
He also said that well-designed future strategies will complete innovation initiatives. The Future Strategy Research Center will serve as a think tank for identifying future agendas, establishing strategies and advocating for them.
In addition to the five innovation initiatives, President Shin emphasized a new organizational culture that embraces inclusiveness and mutual respect among all of the members of KAIST.
“So far, the ideal qualifications expected of KAISTians have included creativity and a challenging spirit. From now on, we will nurture talents with a focus on the 3Cs: Creativity, Challenge, and Caring. I would like to make a campus in which all members care for each other to help attain mutual growth with warmth and respect," he said.
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2018.01.02 View 8974 -
Technology to Find Optimum Drug Target for Cancer Developed
(Professor Kwang-Hyun Cho (right) and lead author Dr. Minsoo Choi)
A KAIST research team led by Professor Kwang-Hyun Cho of the Department of Bio and Brain Engineering developed technology to find the optimum drug target according to the type of cancer cell. The team used systems biology to analyze molecular network dynamics that reflect genetic mutations in cancer cells and to predict drug response. The technology could contribute greatly to future anti-cancer drug development.
There are many types of genetic variations found in cancer cells, including gene mutations and copy number variations. These variations differ in cancer cells even within the same type of cancer, and thus the drug response varies cell by cell. Cancer researchers worked towards identifying frequently occurring genetic variations in cancer patients and, in particular, the mutations that can be used as an index for specific drugs. Previous studies focused on identifying a single genetic mutation or creating an analysis of the structural characteristics of a gene network. However, this approach was limited in its inability to explain the biological properties of cancer which are induced by various gene and protein interactions in cancer cells, which result in differences in drug response.
Gene mutations in cancer cells not only affect the function of the affected gene, but also other genes that interact with the mutated gene and proteins. As a consequence, one mutation could lead to changes in the dynamical properties of the molecular network. Therefore, the responses to anti-cancer drugs by cancer cells differ. The current treatment approach that ignores molecular network dynamics and targets a few cancer-related genes is only effective on a fraction of patients, while many other patients exhibit resistance to the drug.
Professor Cho’s team integrated a large-scale computer simulation using super-computing and cellular experiments to analyze changes in molecular network dynamics in cancer cells.
This led to development of technology to find the optimum drug target according to the type of cancer cells by predicting drug response. This technology was applied to the molecular network of known tumor suppressor p53. The team used large-scale cancer cell genomic data available from The Cancer Cell Line Encyclopedia (CCLE) to construct different molecular networks specific to the characteristics of genetic variations.
Perturbation analysis on drug response in each molecular network was used to quantify changes in cancer cells from drug response and similar networks were clustered. Then, computer simulations were used to analyze the synergetic effects in terms of efficacy and combination to predict the level of drug response. Based on the simulation results from various cancer cell lines including lung, breast, bone, skin, kidney, and ovary cancers were used in drug response experiments for compare analysis.
This technique can be applied in any molecular network to identify the optimum drug target for personalized medicine.
The research team suggests that the technology can analyze varying drug response due to the heterogeneity of cancer cells by considering the overall modulatory interactions rather than focusing only on a specific gene or protein. Further, the technology aids the prediction of causes of drug resistance and thus the identification of the optimum drug target to inhibit the resistance. This could be core source technology that can be used in drug repositioning, a process of applying existing drugs to new disease targets.
Professor Cho said, “Genetic variations in cancer cells are the cause of diverse drug response, but a complete analysis had not yet been made.” He continued, “Systems biology allowed the simulation of drug responses by cancer cell molecular networks to identify fundamental principles of drug response and optimum drug targets using a new conceptual approach.”
This research was published in Nature Communications on December 5 and was funded by Ministry of Science and ICT and National Research Foundation of Korea.
(Figure 1. Drug response prediction for each cancer cell type from computer simulation and cellular experiment verification for comparison)
(Figure 2. Drug response prediction based on cancer cell molecular network dynamics and clustering of cancer cells by their molecular networks)
(Figure 3. Identification of drug target for each cancer cell type by cellular molecular network analysis and establishment for personalized medicine strategy for each cancer patient)
2017.12.15 View 6987