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A Mathematical Model Reveals Long-Distance Cell Communication Mechanism
How can tens of thousands of people in a large football stadium all clap together with the same beat even though they can only hear the people near them clapping? A combination of a partial differential equation and a synthetic circuit in microbes answers this question. An interdisciplinary collaborative team of Professor Jae Kyoung Kim at KAIST, Professor Krešimir Josić at the University of Houston, and Professor Matt Bennett at Rice University has identified how a large community can communicate with each other almost simultaneously even with very short distance signaling. The research was reported at Nature Chemical Biology. Cells often communicate using signaling molecules, which can travel only a short distance. Nevertheless, the cells can also communicate over large distances to spur collective action. The team revealed a cell communication mechanism that quickly forms a network of local interactions to spur collective action, even in large communities. The research team used an engineered transcriptional circuit of combined positive and negative feedback loops in E. coli, which can periodically release two types of signaling molecules: activator and repressor. As the signaling molecules travel over a short distance, cells can only talk to their nearest neighbors. However, cell communities synchronize oscillatory gene expression in spatially extended systems as long as the transcriptional circuit contains a positive feedback loop for the activator. Professor Kim said that analyzing and understanding such high-dimensional dynamics was extremely difficult. He explained, “That’s why we used high-dimensional partial differential equation to describe the system based on the interactions among various types of molecules.” Surprisingly, the mathematical model accurately simulates the synthesis of the signaling molecules in the cell and their spatial diffusion throughout the chamber and their effect on neighboring cells. The team simplified the high-dimensional system into a one-dimensional orbit, noting that the system repeats periodically. This allowed them to discover that cells can make one voice when they lowered their own voice and listened to the others. “It turns out the positive feedback loop reduces the distance between moving points and finally makes them move all together. That’s why you clap louder when you hear applause from nearby neighbors and everyone eventually claps together at almost the same time,” said Professor Kim. Professor Kim added, “Math is a powerful as it simplifies complex thing so that we can find an essential underlying property. This finding would not have been possible without the simplification of complex systems using mathematics." The National Institutes of Health, the National Science Foundation, the Robert A. Welch Foundation, the Hamill Foundation, the National Research Foundation of Korea, and the T.J. Park Science Fellowship of POSCO supported the research. (Figure: Complex molecular interactions among microbial consortia is simplified as interactions among points on a limit cycle (right).)
Hydrogen-Natural Gas Hydrates Harvested by Natural Gas
A hydrogen-natural gas blend (HNGB) can be a game changer only if it can be stored safely and used as a sustainable clean energy resource. A recent study has suggested a new strategy for stably storing hydrogen, using natural gas as a stabilizer. The research proposed a practical gas phase modulator based synthesis of HNGB without generating chemical waste after dissociation for the immediate service. The research team of Professor Jae Woo Lee from the Department of Chemical and Biomolecular Engineering in collaboration with the Gwangju Institute of Science and Technology (GIST) demonstrated that the natural gas modulator based synthesis leads to significantly reduced synthesis pressure simultaneously with the formation of hydrogen clusters in the confined nanoporous cages of clathrate hydrates. This approach minimizes the environmental impact and reduces operation costs since clathrate hydrates do not generate any chemical waste in both the synthesis and decomposition processes. For the efficient storage and transportation of hydrogen, numerous materials have been investigated. Among others, clathrate hydrates offer distinct benefits. Clathrate hydrates are nanoporous inclusion compounds composed of a 3D network of polyhedral cages made of hydrogen-bonded ‘host’ water molecules and captured ‘guest’ gas or liquid molecules. In this study, the research team used two gases, methane and ethane, which have lower equilibrium conditions compared to hydrogen as thermodynamic stabilizers. As a result, they succeeded in stably storing the hydrogen-natural gas compound in hydrates. According to the composition ratio of methane and ethane, structure I or II hydrates can be formed, both of which can stably store hydrogen-natural gas in low-pressure conditions. The research team found that two hydrogen molecules are stored in small cages in tuned structure I hydrates, while up to three hydrogen molecules can be stored in both small and large cages in tuned structure II hydrates. Hydrates can store gas up to about 170-times its volume and the natural gas used as thermodynamic stabilizers in this study can also be used as an energy source. The research team developed technology to produce hydrates from ice, produced hydrogen-natural gas hydrates by substitution, and successfully observed that the tuning phenomenon only occurs when hydrogen is involved in hydrate formation from the start for both structures of hydrates. They expect that the findings can be applied to not only an energy-efficient gas storage material, but also a smart platform to utilize hydrogen natural gas blends, which can serve as a new alternative energy source with targeted hydrogen contents by designing synthetic pathways of mixed gas hydrates. The research was published online in Energy Storage Materials on June 6, with the title ‘One-step formation of hydrogen clusters in clathrate hydrates stabilized via natural gas blending’. Professor Lee said, “HNGB will utilize the existing natural gas infrastructure for transportation, so it is very likely that we can commercialize this hydrate system. We are investigating the kinetic performance through a follow-up strategy to increase the volume of gas storage. This study was funded by the National Research Foundation of Korea and BK21 plus program. (Figure1. Schematics showing the storage method for hydrogen in a natural gas hydrate using a substitution method and storage method directly from ice to a hydrogen-natural gas hydrate.) (Figure 2. Artificially synthesized and dissociated hydrogen-natural gas hydrates. The Raman spectra of tuned sI and sII hydrate showing the hydrogen clusters in each cage.)
Early Genome Catastrophes Can Cause Non-Smoking Lung Cancer
Some teenagers harbor catastrophic changes to their genomes that can lead to lung cancer later on in life, even if they never smoke (Professor Young Seok Ju at the Graduate School of Medical Science and Engineering) Catastrophic rearrangements in the genome occurring as early as childhood and adolescence can lead to the development of lung cancer in later years in non-smokers. This finding, published in Cell, helps explain how some non-smoking-related lung cancers develop. Researchers at KAIST, Seoul National University and their collaborators confirmed that gene fusions in non-smokers mostly occur early on, sometimes as early as childhood or adolescence, and on average about three decades before cancer is diagnosed. The study showed that these mutant lung cells, harboring oncogenic seeds, remain dormant for several decades until a number of further mutations accumulate sufficiently for progression into cancer. This is the first study to reveal the landscape of genome structural variations in lung adenocarcinoma. Lung cancer is the leading cause of cancer-related deaths worldwide, and lung adenocarcinoma is its most common type. Most lung adenocarcinomas are associated with chronic smoking, but about a fourth develop in non-smokers. Precisely what happens in non-smokers for this cancer to develop is not clearly understood. Researchers analyzed the genomes of 138 lung adenocarcinoma patients, including smokers and non-smokers, with whole-genome sequencing technologies. They explored DNA damage that induced neoplastic transformation. Lung adenocarcinomas that originated from chronic smoking, referred to as signature 4-high (S4-high) cancers in the study, showed several distinguishing features compared to smoking-unrelated cancers (S4-low). People in the S4-high group were largely older, men and had more frequent mutations in a cancer-related gene called KRAS. Cancer genomes in the S4-high group were hypermutated with simple mutational classes, such as the substitution, insertion, or deletion of a single base, the building block of DNA. But the story was very different in the S4-low group. Generally, mutational profiles in this group were much more silent than the S4-high group. However, all cancer-related gene fusions, which are abnormally activated from the merging of two originally separate genes, were exclusively observed in the S4-low group. The patterns of genomic structural changes underlying gene fusions suggest that about three in four cases of gene fusions emerged from a single cellular crisis causing massive genomic fragmentation and subsequent imprecise repair in normal lung epithelium. Most strikingly, these major genomic rearrangements, which led to the development of lung adenocarcinoma, are very likely to be acquired decades before cancer diagnosis. The researchers used genomic archaeology techniques to trace the timing of when the catastrophes took place. Researchers started this study seven years ago when they discovered the expression of the KIF5B-RET gene fusion in lung adenocarcinoma for the first time. Professor Young-Seok Ju, co-lead author from the Graduate School of Medical Science and Engineering at KAIST says, “It is remarkable that oncogenesis can begin by a massive shattering of chromosomes early in life. Our study immediately raises a new question: What induces the mutational catastrophe in our normal lung epithelium.” Professor Young Tae Kim, co-lead author from Seoul National University says, “We hope this work will help us get one step closer to precision medicine for lung cancer patients.” The research team plans to further focus on the molecular mechanisms that stimulate complex rearrangements in the body, through screening the genomic structures of fusion genes in other cancer types. This study was supported by the National Research Foundation of Korea (NRF), Korea Health Industry Development Institute (KHIDI), Suh Kyungbae Foundation, the College of Medicine Research Foundations at Seoul National University and others. Figure. (Smoking-unrelated oncogenesis of lung cancers by gene fusions) Publication. Jake June-Koo Lee, Seongyeol Park et al., Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma Cell 177, June 13 2019, online publication ahead of print at May 30, 2019 https://doi.org/10.1016/j.cell.2019.05.013 Profile: Prof Young Seok Ju, MD, PhD firstname.lastname@example.org http://julab.kaist.ac.kr Associate Professor Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST) Daejeon 34141, Korea Profile: Prof Young Tae Kim, MD, PhD email@example.com Professor Seoul National University Cancer Research Institute Department of Thoracic and Cardiovascular Surgery Seoul National University Hospital Seoul 03080, Korea
5 Biomarkers for Overcoming Colorectal Cancer Drug Resistance Identified
< Professor Kwang-Hyun Cho's Team > KAIST researchers have identified five biomarkers that will help them address resistance to cancer-targeting therapeutics. This new treatment strategy will bring us one step closer to precision medicine for patients who showed resistance. Colorectal cancer is one of the most common types of cancer worldwide. The number of patients has surpassed 1 million, and its five-year survival rate significantly drops to about 20 percent when metastasized. In Korea, the surge of colorectal cancer has been the highest in the last 10 years due to increasing Westernized dietary patterns and obesity. It is expected that the number and mortality rates of colorectal cancer patients will increase sharply as the nation is rapidly facing an increase in its aging population. Recently, anticancer agents targeting only specific molecules of colon cancer cells have been developed. Unlike conventional anticancer medications, these selectively treat only specific target factors, so they can significantly reduce some of the side-effects of anticancer therapy while enhancing drug efficacy. Cetuximab is the most well-known FDA approved anticancer medication. It is a biomarker that predicts drug reactivity and utilizes the presence of the ‘KRAS’ gene mutation. Cetuximab is prescribed to patients who don’t carry the KRAS gene mutation. However, even in patients without the KRAS gene mutation, the response rate of Cetuximab is only about fifty percent, and there is also resistance to drugs after targeted chemotherapy. Compared with conventional chemotherapy alone, the life expectancy only lasts five months on average. In research featured in the FEBS Journal as the cover paper for the April 7 edition, the KAIST research team led by Professor Kwang-Hyun Cho at the Department of Bio and Brain Engineering presented five additional biomarkers that could increase Cetuximab responsiveness using systems biology approach that combines genomic data analysis, mathematical modeling, and cell experiments. The experimental inhibition of newly discovered biomarkers DUSP4, ETV5, GNB5, NT5E, and PHLDA1 in colorectal cancer cells has been shown to overcome Cetuximab resistance in KRAS-normal genes. The research team confirmed that when suppressing GNB5, one of the new biomarkers, it was shown to overcome resistance to Cetuximab regardless of having a mutation in the KRAS gene. Professor Cho said, “There has not been an example of colorectal cancer treatment involving regulation of the GNB5 gene.” He continued, “Identifying the principle of drug resistance in cancer cells through systems biology and discovering new biomarkers that could be a new molecular target to overcome drug resistance suggest real potential to actualize precision medicine.” This study was supported by the National Research Foundation of Korea (NRF) and funded by the Ministry of Science and ICT (2017R1A2A1A17069642 and 2015M3A9A7067220). Image 1. The cover of FEBS Journal for April 2019
Scientist of October, Professor Haeshin Lee
(Professor Haeshin Lee from the Department of Chemistry) Professor Haeshin Lee from the Department of Chemistry received the ‘Science and Technology Award of October’ from the Ministry of Science and ICT and the National Research Foundation of Korea for his contribution to developing an antibleeding injection needle. This novel outcome will fundamentally prevent the problem of secondary infections of AIDS, Ebola and Hepatitis viruses transmitting from patients to medical teams. This needle’s surface is coated with hemostatic materials. Its concept is simple and the key to this technology is to make materials that are firmly coated on the needle so that they can endure frictional force when being injected into skin and blood vessels. Moreover, the materials should be adhesive to skin and the interior of blood vessels, but harmless to humans. Professor Lee found a solution from natural polymer ingredients. Catecholamine can be found in mussels. Professor Lee conjugated catechol groups on the chitosan backbone. He applied this mussel-inspired adhesive polymer Chitosan-catechol, which immediately forms an adhesive layer with blood, as a bioadhesion for the antibleeding injection needle. Professor Lee said, “Chitosan-catechol, which copies the adhesive mechanism of mussels, shows high solubility in physiological saline as well as great mucoadhesion. Hence, it is perfectly suitable for coating the injection needle. Combining it with proteins allows for efficient drug delivery to the heart, which is a challenging injection location, so it will be also useful for treating incurable heart disease.”
Center for Industrial Future Strategy Takes Off at KAIST
Professor Hee-Sung Park Named Scientist of May
(Professor Hee-Sung Park) Professor Hee-Sung Park from the Department of Chemistry was named ‘Scientist of May’ sponsored by the Ministry of Science and ICT and the National Research Foundation of Korea. Professor Park was honored in recognition of his developing a tool to engineer designer proteins via diverse chemical modifications. This approach provides a novel platform for investigating numerous diseases such as cancer and dementia. His research focuses on the production of synthetic proteins and the generation of diverse protein functions as well as the designing and engineering of new translation machinery for genetic code expansion, and the application of synthetic biology techniques for basic cell biology and applied medical science. Post-translational modifications (PTMs) are constantly taking place during or after protein biosynthesis. PTMs play a vital role in expanding protein functional diversity and, as a result, critically affect numerous biological processes. Abnormal PTMs have been known to trigger various diseases including cancer and dementia. Therefore, this technology enables proteins to reproduce with specific modifications at selected residues and will significantly help establish experimental strategies to investigate fundamental biological mechanisms including the development of targeted cancer therapies. Professor Park also received 10 million KRW in prize money.
Scientist of March, Professor Hee-Seung Lee
(Professor Hee-Seung Lee) Professor Hee-Seung Lee from the Department of Chemistry at KAIST received the ‘Science and Technology Award of the Month’ awarded by the Ministry of ICT and Science, and the National Research Foundation of Korea for March 2018. Professor Lee has been recognized for successfully producing peptide-based molecular machines, which used to be made of metals. The methodology can be translated into magnetotactic behavior at the macroscopic scale, which is reminiscent of magnetosomes in magnetotactic bacteria. The team employed foldectures, self-assembled molecular architectures of β-peptide foldamers, to develop the peptide-based molecular machines that uniformly align with respect to an applied static magnetic field. Professor Lee said, “Molecular machines are widely used in the field of medical engineering or material science; however, there were limitations for developing the machines using magnetic fields. By developing peptide-based molecular machines, we were able to develop body-friendly molecular machines.” Every month, the Ministry of ICT and Science and the National Research Foundation of Korea award a cash prize worth 10,000,000 KRW to a scientist who has contributed to science and technology with outstanding research and development performance.
Scientist of November, Professor Hyung Jin Sung
Professor Hyung Jin Sung from the Department of Mechanical Engineering at KAIST received a ‘Science and Technology Award of the Month’ given by the Ministry of ICT and Science and the National Research Foundation of Korea for November 2017. He developed technology that can exquisitely control a micrometer-scaled liquid drop on a dime-sized lab-on-a-chip. With his work, he was recognized for reinforcing research capability on microfluidics. Lab-on-a-chip is an emerging experiment and diagnostic technology in the form of a bio-microchip that facilitates complex and various experiments with only a minimal sample size required. This technology draws a lot of attention not only from medical and pharmaceutical areas, but also the health and environmental field. The biggest problem was that technology for the temperature control of a fluid sample, which is one of the core technologies in microfluidics, has low accuracy. This limit had to be overcome in order to use the lab-on-a-chip more widely. Professor Sung developed an acoustic and thermal method which controls the temperature of a droplet quickly and meticulously by using sound and energy. This is a thermal method that uses heat generated during the absorption of an acoustic wave into viscoelastic substances. It facilitates a rapid heating rate and spatial-temporal temperature control, allowing heating in desired areas. In addition, Professor Sung applied his technology to polymerase chain reactions, which are used to amplify DNA. Through this experiment, he successfully shortened the reaction time from 1-2 hours to only three minutes, making this a groundbreaking achievement. Professor Sung said, “My research is significant for enhancing the applicability of microfluidics. I expect that it will lead to technological innovations in healthcare fields including biochemistry, medical checkups, and new medicine development.”
Research Center for Smart Submerged Floating Tunnel Systems Opens
(Distinguished guests including President Shin (fourth from the right) and Director Lee (third from left) at the opening ceremony) The Research Center for a Smart Submerged Floating Tunnel Systems was recently established at KAIST with the purpose of taking the lead in developing fundamental and applicable technology for submerged floating tunnels as well as fostering creative and talented people. Haeng-Ki Lee, a professor in the Department of Civil & Environmental Engineering at KAIST is heading the center. KAIST held its opening ceremony on September 7, 2017 in the Applied Engineering Building located on the main campus. Distinguished guests, including KAIST president Sung-Chul Shin, the President of the Korea Institute of Ocean Science and Technology Gi-Hoon Hong, the President of the Korean Society of Civil Engineering Young-Seok Park, and the Director in the Division of Engineering at the National Research Foundation of Korea Joong-Kon Park attended the ceremony. The National Research Foundation of Korea provides Engineering Research Center (ERC) projects which find and foster groups with outstanding research performance in a field of engineering. The projects support these groups so that they can strengthen their global competitiveness while enhancing national competence in basic research. The ‘Research Center for Smart Submerged Floating Tunnel Systems’ was selected as one of the ERC projects in 2017. For the next seven years, the research center will work to develop a submerged floating tunnel system resistant depths greater than 100 meters. To achieve its goal, the center has defined crucial research topics including: i) a structural analysis program and integrated design technology specific for submerged floating tunnel systems, ii) high-durability marine construction materials and submerged construction integrated systems, and iii) safety and maintenance integrated technology for smart submerged floating tunnel systems. The ‘Research Center for Smart Submerged Floating Tunnel Systems’ will devote itself to developing a variety of fundamental and applicable technology that will be leading global maritime construction. Moreover, it will concentrate on fostering professional research manpower in related areas. The Director of the Center Lee said, “The center will cooperate with KAIST researchers who are experts in various fields, including structures, materials, construction, and maritime research. Based on this collaboration, the center will contribute to achieving autonomous technologies by developing fundamental and applicable technology related with submerged floating tunnel systems. It will also take the role of a leading global research hub in the field of submerged floating tunnels as well as construction technologies.”
Professor Won Do Heo Receives 'Scientist of the Month Award'
Professor Won Do Heo of the Department of Biological Sciences was selected as the “Scientist of the Month” for April 2017 by the Ministry of Science, ICT and Future Planning and the National Research Foundation of Korea. Professor Heo was recognized for his suggestion of a new biological research method developing various optogenetics technology which controls cell function by using light. He developed the technology using lasers or LED light, without the need for surgery or drug administration, to identify the cause of diseases related to calcium ions such as Alzheimer’s disease and cancer. The general technique used in optogenetics, that control cells in the body with light, is the simple activation and deactivation of neurons. Professor Heo developed a calcium ion channel activation technique (OptoSTIM1) to activate calcium ions in the body using light. He also succeeded in increasing calcium concentrations with light to enhance the memory capacity of mice two-fold. Using this technology, the desired amount and residing time of calcium ion influx can be controlled by changing light intensity and exposure periods, enabling the function of a single cell or various cells in animal tissue to be controlled remotely. The experimental results showed that calcium ion influx can be activated in cells that are affected by calcium ions, such as normal cells, cancer cells, and human embryonic stem cells. By controlling calcium concentrations with light, it is possible to control biological phenomena, such as cellular growth, neurotransmitter transmission, muscle contraction, and hormone control. Professor Heo said, “Until now, it was standard to use optogenetics to activate neurons using channelrhodopsin. The development of this new optogenetic technique using calcium ion channel activation can be applied to various biological studies, as well as become an essential research technique in neurobiology. The “Scientist of the Month Award” is given every month to one researcher who made significant contributions to the advancement of science and technology with their outstanding research achievement. The awardee will receive prize money of ten million won.
Professor Tae-Eog Lee Receives December's Scientist of the Month Award by the Korean Government
Professor Tae-Eog Lee of the Industrial and Systems Engineering at KAIST received the Scientist of the Month Award for December 2015. The award is sponsored by the Ministry of Science, ICT and Future Planning of Korea, which was hosted by the National Research Foundation of Korea. The award recognizes Professor Lee’s efforts to advance the field of semiconductor device fabrication processing. This includes the development of the most efficient scheduling and controlling of cluster tools. He also created mathematical solutions to optimize the complicated cycle time of cluster tools in semiconductor manufacturing and the process of robot task workload. Professor Lee contributed to the formation of various discrete event systems and automation systems based on his mathematical theories and solutions and advanced a scheduling technology for the automation of semiconductor production. He has published 18 research papers in the past three years and has pioneered to develop Korean tool schedulers through the private sector-university cooperation.
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