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Microbial Production of a Natural Red Colorant Carminic Acid
Metabolic engineering and computer-simulated enzyme engineering led to the production of carminic acid, a natural red colorant, from bacteria for the first time
A research group at KAIST has engineered a bacterium capable of producing a natural red colorant, carminic acid, which is widely used for food and cosmetics. The research team reported the complete biosynthesis of carminic acid from glucose in engineered Escherichia coli. The strategies will be useful for the design and construction of biosynthetic pathways involving unknown enzymes and consequently the production of diverse industrially important natural products for the food, pharmaceutical, and cosmetic industries.
Carminic acid is a natural red colorant widely being used for products such as strawberry milk and lipstick. However, carminic acid has been produced by farming cochineals, a scale insect which only grows in the region around Peru and Canary Islands, followed by complicated multi-step purification processes. Moreover, carminic acid often contains protein contaminants that cause allergies so many people are unwilling to consume products made of insect-driven colorants. On that account, manufacturers around the world are using alternative red colorants despite the fact that carminic acid is one of the most stable natural red colorants.
These challenges inspired the metabolic engineering research group at KAIST to address this issue. Its members include postdoctoral researchers Dongsoo Yang and Woo Dae Jang, and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering. This study entitled “Production of carminic acid by metabolically engineered Escherichia coli” was published online in the Journal of the American Chemical Society (JACS) on April 2.
This research reports for the first time the development of a bacterial strain capable of producing carminic acid from glucose via metabolic engineering and computer simulation-assisted enzyme engineering. The research group optimized the type II polyketide synthase machinery to efficiently produce the precursor of carminic acid, flavokermesic acid.
Since the enzymes responsible for the remaining two reactions were neither discovered nor functional, biochemical reaction analysis was performed to identify enzymes that can convert flavokermesic acid into carminic acid. Then, homology modeling and docking simulations were performed to enhance the activities of the two identified enzymes. The team could confirm that the final engineered strain could produce carminic acid directly from glucose. The C-glucosyltransferase developed in this study was found to be generally applicable for other natural products as showcased by the successful production of an additional product, aloesin, which is found in aloe leaves.
“The most important part of this research is that unknown enzymes for the production of target natural products were identified and improved by biochemical reaction analyses and computer simulation-assisted enzyme engineering,” says Dr. Dongsoo Yang. He explained the development of a generally applicable C-glucosyltransferase is also useful since C-glucosylation is a relatively unexplored reaction in bacteria including Escherichia coli. Using the C-glucosyltransferase developed in this study, both carminic acid and aloesin were successfully produced from glucose.
“A sustainable and insect-free method of producing carminic acid was achieved for the first time in this study. Unknown or inefficient enzymes have always been a major problem in natural product biosynthesis, and here we suggest one effective solution for solving this problem. As maintaining good health in the aging society is becoming increasingly important, we expect that the technology and strategies developed here will play pivotal roles in producing other valuable natural products of medical or nutritional importance,” said Distinguished Professor Sang Yup Lee.
This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries of the Ministry of Science and ICT (MSIT) through the National Research Foundation (NRF) of Korea and the KAIST Cross-Generation Collaborative Lab project; Sang Yup Lee and Dongsoo Yang were also supported by Novo Nordisk Foundation in Denmark.
Publication:
Dongsoo Yang, Woo Dae Jang, and Sang Yup Lee. Production of carminic acid by metabolically engineered Escherichia coli. at the Journal of the American Chemical Society. https://doi.org.10.1021/jacs.0c12406
Profile:
Sang Yup Lee, PhD
Distinguished Professor
leesy@kaist.ac.kr
http://mbel.kaist.ac.kr
Metabolic &Biomolecular Engineering National Research Laboratory
Department of Chemical and Biomolecular Engineering
KAIST
2021.04.06 View 10360 -
Streamlining the Process of Materials Discovery
The materials platform M3I3 reduces the time for materials discovery by reverse engineering future materials using multiscale/multimodal imaging and machine learning of the processing-structure-properties relationship
Developing new materials and novel processes has continued to change the world. The M3I3 Initiative at KAIST has led to new insights into advancing materials development by implementing breakthroughs in materials imaging that have created a paradigm shift in the discovery of materials. The Initiative features the multiscale modeling and imaging of structure and property relationships and materials hierarchies combined with the latest material-processing data.
The research team led by Professor Seungbum Hong analyzed the materials research projects reported by leading global institutes and research groups, and derived a quantitative model using machine learning with a scientific interpretation. This process embodies the research goal of the M3I3: Materials and Molecular Modeling, Imaging, Informatics and Integration.
The researchers discussed the role of multiscale materials and molecular imaging combined with machine learning and also presented a future outlook for developments and the major challenges of M3I3. By building this model, the research team envisions creating desired sets of properties for materials and obtaining the optimum processing recipes to synthesize them.
“The development of various microscopy and diffraction tools with the ability to map the structure, property, and performance of materials at multiscale levels and in real time enabled us to think that materials imaging could radically accelerate materials discovery and development,” says Professor Hong.
“We plan to build an M3I3 repository of searchable structural and property maps using FAIR (Findable, Accessible, Interoperable, and Reusable) principles to standardize best practices as well as streamline the training of early career researchers.”
One of the examples that shows the power of structure-property imaging at the nanoscale is the development of future materials for emerging nonvolatile memory devices. Specifically, the research team focused on microscopy using photons, electrons, and physical probes on the multiscale structural hierarchy, as well as structure-property relationships to enhance the performance of memory devices.
“M3I3 is an algorithm for performing the reverse engineering of future materials. Reverse engineering starts by analyzing the structure and composition of cutting-edge materials or products. Once the research team determines the performance of our targeted future materials, we need to know the candidate structures and compositions for producing the future materials.”
The research team has built a data-driven experimental design based on traditional NCM (nickel, cobalt, and manganese) cathode materials. With this, the research team expanded their future direction for achieving even higher discharge capacity, which can be realized via Li-rich cathodes.
However, one of the major challenges was the limitation of available data that describes the Li-rich cathode properties. To mitigate this problem, the researchers proposed two solutions: First, they should build a machine-learning-guided data generator for data augmentation. Second, they would use a machine-learning method based on ‘transfer learning.’ Since the NCM cathode database shares a common feature with a Li-rich cathode, one could consider repurposing the NCM trained model for assisting the Li-rich prediction. With the pretrained model and transfer learning, the team expects to achieve outstanding predictions for Li-rich cathodes even with the small data set.
With advances in experimental imaging and the availability of well-resolved information and big data, along with significant advances in high-performance computing and a worldwide thrust toward a general, collaborative, integrative, and on-demand research platform, there is a clear confluence in the required capabilities of advancing the M3I3 Initiative.
Professor Hong said, “Once we succeed in using the inverse “property−structure−processing” solver to develop cathode, anode, electrolyte, and membrane materials for high energy density Li-ion batteries, we will expand our scope of materials to battery/fuel cells, aerospace, automobiles, food, medicine, and cosmetic materials.”
The review was published in ACS Nano in March. This study was conducted through collaborations with Dr. Chi Hao Liow, Professor Jong Min Yuk, Professor Hye Ryung Byon, Professor Yongsoo Yang, Professor EunAe Cho, Professor Pyuck-Pa Choi, and Professor Hyuck Mo Lee at KAIST, Professor Joshua C. Agar at Lehigh University, Dr. Sergei V. Kalinin at Oak Ridge National Laboratory, Professor Peter W. Voorhees at Northwestern University, and Professor Peter Littlewood at the University of Chicago (Article title: Reducing Time to Discovery: Materials and Molecular Modeling, Imaging, Informatics, and Integration).This work was supported by the KAIST Global Singularity Research Program for 2019 and 2020.
Publication:
“Reducing Time to Discovery: Materials and Molecular Modeling, Imaging, Informatics and Integration,” S. Hong, C. H. Liow, J. M. Yuk, H. R. Byon, Y. Yang, E. Cho, J. Yeom, G. Park, H. Kang, S. Kim, Y. Shim, M. Na, C. Jeong, G. Hwang, H. Kim, H. Kim, S. Eom, S. Cho, H. Jun, Y. Lee, A. Baucour, K. Bang, M. Kim, S. Yun, J. Ryu, Y. Han, A. Jetybayeva, P.-P. Choi, J. C. Agar, S. V. Kalinin, P. W. Voorhees, P. Littlewood, and H. M. Lee, ACS Nano 15, 3, 3971–3995 (2021) https://doi.org/10.1021/acsnano.1c00211
Profile:
Seungbum Hong, PhD
Associate Professor
seungbum@kaist.ac.kr
http://mii.kaist.ac.kr
Department of Materials Science and Engineering
KAIST
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2021.04.05 View 11206 -
Plasma Jets Stabilize Water to Splash Less
< High-speed shadowgraph movie of water surface deformations induced by plasma impingement. >
A study by KAIST researchers revealed that an ionized gas jet blowing onto water, also known as a ‘plasma jet’, produces a more stable interaction with the water’s surface compared to a neutral gas jet. This finding reported in the April 1 issue of Nature will help improve the scientific understanding of plasma-liquid interactions and their practical applications in a wide range of industrial fields in which fluid control technology is used, including biomedical engineering, chemical production, and agriculture and food engineering.
Gas jets can create dimple-like depressions in liquid surfaces, and this phenomenon is familiar to anyone who has seen the cavity produced by blowing air through a straw directly above a cup of juice. As the speed of the gas jet increases, the cavity becomes unstable and starts bubbling and splashing.
“Understanding the physical properties of interactions between gases and liquids is crucial for many natural and industrial processes, such as the wind blowing over the surface of the ocean, or steelmaking methods that involve blowing oxygen over the top of molten iron,” explained Professor Wonho Choe, a physicist from KAIST and the corresponding author of the study.
However, despite its scientific and practical importance, little is known about how gas-blown liquid cavities become deformed and destabilized.
In this study, a group of KAIST physicists led by Professor Choe and the team’s collaborators from Chonbuk National University in Korea and the Jožef Stefan Institute in Slovenia investigated what happens when an ionized gas jet, also known as a ‘plasma jet’, is blown over water. A plasma jet is created by applying high voltage to a nozzle as gas flows through it, which causes the gas to be weakly ionized and acquire freely-moving charged particles.
The research team used an optical technique combined with high-speed imaging to observe the profiles of the water surface cavities created by both neutral helium gas jets and weakly ionized helium gas jets. They also developed a computational model to mathematically explain the mechanisms behind their experimental discovery.
The researchers demonstrated for the first time that an ionized gas jet has a stabilizing effect on the water’s surface. They found that certain forces exerted by the plasma jet make the water surface cavity more stable, meaning there is less bubbling and splashing compared to the cavity created by a neutral gas jet.
Specifically, the study showed that the plasma jet consists of pulsed waves of gas ionization propagating along the water’s surface so-called ‘plasma bullets’ that exert more force than a neutral gas jet, making the cavity deeper without becoming destabilized.
“This is the first time that this phenomenon has been reported, and our group considers this as a critical step forward in our understanding of how plasma jets interact with liquid surfaces. We next plan to expand this finding through more case studies that involve diverse plasma and liquid characteristics,” said Professor Choe.
This work was supported by KAIST as part of the High-Risk and High-Return Project, the National Research Foundation of Korea (NRF), and the Slovenian Research Agency (ARRS).
Image Credit: Professor Wonho Choe, KAIST
Usage Restrictions: News organizations may use or redistribute these materials, with proper attribution, as part of news coverage of this paper only.
Publication: Park, S., et al. (2021) Stabilization of liquid instabilities with ionized gas jets. Nature, Vol. No. 592, Issue No. 7852, pp. 49-53. Available online at https://doi.org/10.1038/s41586-021-03359-9
Profile:
Wonho Choe, Ph.D.
Professor
wchoe@kaist.ac.kr
https://gdpl.kaist.ac.kr/
Gas Discharge Physics Laboratory (GDPL)
Department of Nuclear and Quantum Engineering
Department of Physics
Impurity and Edge Plasma Research Center (IERC)
http://kaist.ac.kr/en/
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, Republic of Korea
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2021.04.01 View 9779 -
Professor Jihee Kim Wins the Lucas Prize for Her Income Inequality Theory
Professor Jihee Kim from the School of Business and Technology Management at KAIST was announced as one of two winners of the 2021 Robert E. Lucas Jr. Prize. Professor Kim was recognized for having provided an empirical analysis on engines of income growth, sources of income inequality, and their rich interplay in her paper published in the Journal of Political Economy (JPE) in October 2018. The co-author of this study, Professor Charles I. Jones at Stanford University, was honored to be another awardee of this year’s Lucas Prize.
The Robert E. Lucas Jr. Prize, simply known as the Lucas Prize, is awarded biannually for the most interesting paper in the area of Dynamic Economics published in the leading economics journal JPE in the preceding two years. The prize was established in 2016 in celebration of the 1995 Nobel Prize in Economics Laureate Dr. Lucas’s seminal contributions to economics. The two former prizes were presented in 2019 and 2017 respectively.
Professor Kim and Professor Jones, in their award-winning paper titled 'A Schumpeterian Model of Top Income Inequality', observed that top income inequality was relatively low and stable between 1960 and 1980, but then rose sharply in some countries, including the United States and the United Kingdom.
The authors focused on entrepreneurial activities and the resulting income as the driving force of income inequality. They assumed that the forces that increased the efforts of fast-growing entrepreneurs to improve their products or increased productivity of their efforts could increase income inequality. On the other hand, the forces that enhanced creative destruction or that raised the rate at which high-growth entrepreneurs lost that status could decrease income inequality, according to the authors’ theory.
Professor Kim explained, “Various economic forces due to globalization, the advancement in AI and IT technologies, taxes, and policies related to innovation blocking may explain the varied patterns in income inequality.”
“Through follow-up research, I will continue developing economic theory models that can analyze the impact of changes such as income tax rates and salary negotiations on income inequality,” she added.
Professor Kim received her bachelor’s degree from the KAIST School of Computing in 2005 and pursued her graduates studies at Stanford University, acquiring a master’s degree in economics in 2011 and a doctoral degree in management science and engineering in 2013.
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2021.03.26 View 7024 -
Professor Jae Kyoung Kim to Lead a New Mathematical Biology Research Group at IBS
Professor Jae Kyoung Kim from the KAIST Department of Mathematical Sciences was appointed as the third Chief Investigator (CI) of the Pioneer Research Center (PRC) for Mathematical and Computational Sciences at the Institute for Basic Science (IBS). Professor Kim will launch and lead a new research group that will be devoted to resolving various biological conundrums from a mathematical perspective. His appointment began on March 1, 2021.
Professor Kim, a rising researcher in the field of mathematical biology, has received attention from both the mathematical and biological communities at the international level. Professor Kim puts novel and unremitting efforts into understanding biological systems such as cell-to-cell interactions mathematically and designing mathematical models for identifying causes of diseases and developing therapeutic medicines.
Through active joint research with biologists, mathematician Kim has addressed many challenges that have remained unsolved in biology and published papers in a number of leading international journals in related fields. His notable works based on mathematical modelling include having designed a biological circuit that can maintain a stable circadian rhythm (Science, 2015) and unveiling the principles of how the biological clock in the body maintains a steady speed for the first time in over 60 years (Molecular Cell, 2015). Recently, through a joint research project with Pfizer, Professor Kim identified what causes the differences between animal and clinical test results during drug development explaining why drugs have different efficacies in different people (Molecular Systems Biology, 2019).
The new IBS biomedical mathematics research group led by Professor Kim will further investigate the causes of unstable circadian rhythms and sleeping patterns. The team will aim to present a new paradigm in treatments for sleep disorders.
Professor Kim said, “We are all so familiar with sleep behaviors, but the exact mechanisms behind how such behaviors occur are still unknown. Through cooperation with biomedical scientists, our group will do its best to discover the complicated, fundamental mechanisms of sleep, and investigate the causes and cures of sleep disorders.”
Every year, the IBS selects young and promising researchers and appoints them as CIs. A maximum of five selected CIs can form each independent research group within the IBS PRC, and receive research funds of 1 billion to 1.5 billion KRW over five years.
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2021.03.18 View 8184 -
Acoustic Graphene Plasmons Study Paves Way for Optoelectronic Applications
- The first images of mid-infrared optical waves compressed 1,000 times captured using a highly sensitive scattering-type scanning near-field optical microscope. -
KAIST researchers and their collaborators at home and abroad have successfully demonstrated a new methodology for direct near-field optical imaging of acoustic graphene plasmon fields. This strategy will provide a breakthrough for the practical applications of acoustic graphene plasmon platforms in next-generation, high-performance, graphene-based optoelectronic devices with enhanced light-matter interactions and lower propagation loss.
It was recently demonstrated that ‘graphene plasmons’ – collective oscillations of free electrons in graphene coupled to electromagnetic waves of light – can be used to trap and compress optical waves inside a very thin dielectric layer separating graphene from a metallic sheet. In such a configuration, graphene’s conduction electrons are “reflected” in the metal, so when the light waves “push” the electrons in graphene, their image charges in metal also start to oscillate. This new type of collective electronic oscillation mode is called ‘acoustic graphene plasmon (AGP)’.
The existence of AGP could previously be observed only via indirect methods such as far-field infrared spectroscopy and photocurrent mapping. This indirect observation was the price that researchers had to pay for the strong compression of optical waves inside nanometer-thin structures. It was believed that the intensity of electromagnetic fields outside the device was insufficient for direct near-field optical imaging of AGP.
Challenged by these limitations, three research groups combined their efforts to bring together a unique experimental technique using advanced nanofabrication methods. Their findings were published in Nature Communications on February 19.
A KAIST research team led by Professor Min Seok Jang from the School of Electrical Engineering used a highly sensitive scattering-type scanning near-field optical microscope (s-SNOM) to directly measure the optical fields of the AGP waves propagating in a nanometer-thin waveguide, visualizing thousand-fold compression of mid-infrared light for the first time.
Professor Jang and a post-doc researcher in his group, Sergey G. Menabde, successfully obtained direct images of AGP waves by taking advantage of their rapidly decaying yet always present electric field above graphene. They showed that AGPs are detectable even when most of their energy is flowing inside the dielectric below the graphene.
This became possible due to the ultra-smooth surfaces inside the nano-waveguides where plasmonic waves can propagate at longer distances. The AGP mode probed by the researchers was up to 2.3 times more confined and exhibited a 1.4 times higher figure of merit in terms of the normalized propagation length compared to the graphene surface plasmon under similar conditions.
These ultra-smooth nanostructures of the waveguides used in the experiment were created using a template-stripping method by Professor Sang-Hyun Oh and a post-doc researcher, In-Ho Lee, from the Department of Electrical and Computer Engineering at the University of Minnesota.
Professor Young Hee Lee and his researchers at the Center for Integrated Nanostructure Physics (CINAP) of the Institute of Basic Science (IBS) at Sungkyunkwan University synthesized the graphene with a monocrystalline structure, and this high-quality, large-area graphene enabled low-loss plasmonic propagation.
The chemical and physical properties of many important organic molecules can be detected and evaluated by their absorption signatures in the mid-infrared spectrum. However, conventional detection methods require a large number of molecules for successful detection, whereas the ultra-compressed AGP fields can provide strong light-matter interactions at the microscopic level, thus significantly improving the detection sensitivity down to a single molecule.
Furthermore, the study conducted by Professor Jang and the team demonstrated that the mid-infrared AGPs are inherently less sensitive to losses in graphene due to their fields being mostly confined within the dielectric. The research team’s reported results suggest that AGPs could become a promising platform for electrically tunable graphene-based optoelectronic devices that typically suffer from higher absorption rates in graphene such as metasurfaces, optical switches, photovoltaics, and other optoelectronic applications operating at infrared frequencies.
Professor Jang said, “Our research revealed that the ultra-compressed electromagnetic fields of acoustic graphene plasmons can be directly accessed through near-field optical microscopy methods. I hope this realization will motivate other researchers to apply AGPs to various problems where strong light-matter interactions and lower propagation loss are needed.”
This research was primarily funded by the Samsung Research Funding & Incubation Center of Samsung Electronics. The National Research Foundation of Korea (NRF), the U.S. National Science Foundation (NSF), Samsung Global Research Outreach (GRO) Program, and Institute for Basic Science of Korea (IBS) also supported the work.
Publication:
Menabde, S. G., et al. (2021) Real-space imaging of acoustic plasmons in large-area graphene grown by chemical vapor deposition. Nature Communications 12, Article No. 938. Available online at https://doi.org/10.1038/s41467-021-21193-5
Profile:
Min Seok Jang, MS, PhD
Associate Professorjang.minseok@kaist.ac.krhttp://jlab.kaist.ac.kr/
Min Seok Jang Research GroupSchool of Electrical Engineering
http://kaist.ac.kr/en/Korea Advanced Institute of Science and Technology (KAIST)Daejeon, Republic of Korea
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2021.03.16 View 12338 -
A Self-Made Couple in Their 90s Donates to KAIST
A self-made elderly couple in their 90s made a 20 billion KRW donation to KAIST on March 13. Chairman of Samsung Brush Sung-Hwan Chang and his wife Ha-Ok Ahn gave away their two properties valued at 20 billion in Nonhyon-dong in Seoul to KAIST during a ceremony on March 13 in Seoul.
Chairman Chang, 92, made a huge fortune starting his business manufacturing cosmetic brushes. Building two factories in China, he expanded his business to export to high-end cosmetic companies. Chairman Chang, a native of North Korea, is a refugee who fled his hometown with his sister at age 18 during the Korean War. He said remembering his mother who was left behind in North Korea was the most painful thing.
“We always wanted to help out people in need when we would earn enough money. We were inspired by our friends at our retirement community who made a donation to KAIST several years ago. We believe this is the right time to make this decision,” said Chairman Chang.
The couple lives in same retirement community, a famous place for many successful businessmen and wealthy retired figures, located in Yongin, Kyonggi-do with Chairmen Beang-Ho Kim, Chun-Shik Cho, and Chang-Keun Son. With their gift, KAIST established Kim Beang-Ho & Kim Sam-Youl ITC Building as well as the Cho Chun-Shik Graduate School of Green Transportation. The four senior couples’ donations amount to 76.1 billion KRW.
“It would be the most meaningful way if we could invest in KAIST for the country’s future,” said Chairman Chang. “I talked a lot with Chairman Kim on how KAIST utilizes its donations and have developed a strong belief in the future of KAIST.”
Chairman and Mrs. Chang already toured the campus several times at the invitation of President Kwang-Hyung Lee and President Lee himself presented the vision of KAIST to the couple. The couple also attended President Lee’s inauguration ceremony on March 8.
President Lee thanked the couple for their donation, saying “I take my hat off to Chairman Chang and his wife for their generous donation that was amassed over their lifetime. They lived very fiscally responsible lives. We will efficiently utilize this fund for educating future global talents."
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2021.03.15 View 7178 -
Professor Mu-Hyun Baik Honored with the POSCO TJ Park Prize
Professor Mu-Hyun Baik at the Department of Chemistry was honored to be the recipient of the 2021 POSCO TJ Park Prize in Science. The POSCO TJ Park Foundation awards every year the individual or organization which made significant contribution in science, education, community development, philanthropy, and technology.
Professor Baik, a renowned computational chemist in analyzing complicated chemical reactions to understand how molecules behave and how they change. Professor Baik was awarded in recognition of his pioneering research in designing numerous organometallic catalysts with using computational molecular modelling. In 2016, he published in Science on the catalytic borylation of methane that showed how chemical reactions can be carried out using the natural gas methane as a substrate.
In 2020, he reported in Science that electrodes can be used as functional groups with adjustable inductive effects to change the chemical reactivity of molecules that are attached to them, closely mimicking the inductive effect of conventional functional groups. This constitutes a potentially powerful new way of controlling chemical reactions, offering an alternative to preparing derivatives to install electron-withdrawing functional groups.
Joined at KAIST in 2015, Professor Baik also serves as associate director at the Center for Catalytic Hydrocarbon Functionalization at the Institute for Basic Science (IBS) since 2015. Among the many recognitions and awards that he received include the Kavli Fellowship by the Kavli Foundation and the National Academy of Science in the US in 2019 and the 2018 Friedrich Wilhelm Bessel Award by the Alexander von Humboldt Foundation in Germany.
2021.03.11 View 7485 -
Rare Mutations May Have Big Impact on Schizophrenia Pathology
- Somatic mutations found only in brain cells disrupt synaptic function. -
Schizophrenia is a neurodevelopmental disorder that disrupts brain activity, producing hallucinations, delusions, and other cognitive disturbances. Researchers have long searched for genetic influences in the disease, but genetic mutations have been identified in only a small fraction—fewer than a quarter—of sequenced patients. Now a study shows that “somatic” gene mutations in brain cells could account for some of the disease’s neuropathology.
The results of the study, led by Professor Jeong Ho Lee at the Graduate School of Medical Science and Engineering in collaboration with the Stanley Medical Research Institute in the US, appeared in Biological Psychiatry.
Traditional genetic mutations, called germline mutations, occur in sperm or egg cells and are passed on to offspring by their parents. Somatic mutations, in contrast, occur in an embryo after fertilization, and they can show up throughout the body or in isolated pockets of tissues, making them much harder to detect from blood or saliva samples, which are typically used for such sequencing studies.
Recently, more-advanced genetic sequencing techniques have allowed researchers to detect somatic mutations and studies have shown that even mutations present at very low levels can have functional consequences. A previous study hinted that brain somatic mutations were associated with schizophrenia, but it was not powerful enough to cement an association between brain somatic mutations and schizophrenia.
In the current study, the researchers used deep whole-exome sequencing to determine the genetic code of all exomes, the parts of genes that encode proteins. The scientists sequenced postmortem samples from brain, liver, spleen, or heart tissue of 27 people with schizophrenia and 31 control participants allowing them to compare the sequences in the two tissues. Using a powerful analytic technique, the team identified an average of 4.9 somatic single-nucleotide variants, or mutations, in brain samples from people with schizophrenia, and 5.6 somatic single-nucleotide variants in brain samples from control subjects.
Although there were no significant quantitative differences in somatic single-nucleotide variants between schizophrenia and control tissue samples, the researchers found that the mutations in schizophrenia patients were found in genes already associated with schizophrenia. Of the germline mutations that had previously been associated with schizophrenia, the genes affected encode proteins associated with synaptic neural communication, particularly in a brain region called the dorsolateral prefrontal cortex.
In the new analysis, the researchers determined which proteins might be affected by the newly identified somatic mutations. Remarkably, a protein called GRIN2B emerged as highly affected and two patients with schizophrenia carried somatic mutations on the GRIN2B gene itself. GRIN2B is a protein component of NMDA-type glutamate receptors, which are critical for neural signaling. Faulty glutamate receptors have long been suspected of contributing to schizophrenia pathology; GRIN2B ranks among the most-studied genes in schizophrenia. The somatic mutations identified in the study had a variant allele frequency of only ~1%, indicating that the mutations were rare among brain cells as a whole. Nevertheless, they have the potential to create widespread cortical dysfunction.
Professor Lee said, “Besides the comprehensive genetic analysis of brain-only mutations in postmortem tissues from schizophrenia patients, this study experimentally showed the biological consequence of identified somatic mutations, which led to neuronal abnormalities associated with schizophrenia. Thus, this study suggests that brain somatic mutations can be a hidden major contributor to schizophrenia and provides new insights into the molecular genetic architecture of schizophrenia.
John Krystal, MD, editor of Biological Psychiatry, said of the work, "The genetics of schizophrenia has received intensive study for several decades. Now a new possibility emerges, that in some cases, mutations in the DNA of brain cells contributes to the biology of schizophrenia. Remarkably this new biology points to an old schizophrenia story: NMDA glutamate receptor dysfunction. Perhaps the path through which somatic mutations contribute to schizophrenia converges with other sources of abnormalities in glutamate signaling in this disorder."
Professor Lee and the team next want to assess the functional consequences of the somatic mutations. Because of the location of the GRIN2B mutations found in schizophrenia patients, the researchers hypothesized that they might interfere with the receptors’ localization on neurons. Experiments on the cortical neurons of mice showed that the mutations indeed disrupted the receptors’ usual localization to dendrites, the “listening” ends of neurons, which in turn prevented the formation of normal synapses in the neurons. This finding suggests that the somatic mutations could disrupt neural communication, contributing to schizophrenia pathology.
- Profile:
Professor Jeong Ho Lee
Translational Neurogenetics Laboratory ( https://tnl.kaist.ac.kr/)
The Graduate School of Medical Science and Engineering
KAIST
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2021.03.11 View 6858 -
Upbeat Message for a New Future at President Lee’s Inauguration
KAIST’s 17th President Kwang Hyung Lee reaffirmed his commitment to building a new future preparing for the post-AI era during his inauguration on March 8. The Board of Trustees selected the former provost and executive vice president as the new president, succeeding 16th President Sung-Chul Shin whose four-year term expired last month.
In his inaugural address, President Lee proposed a new culture strategy, ‘QAIST’ designed to foster more creative talents and ensure innovative research infrastructure. He said that the best way to stand out as a leading global university is to carve out our own distinctness.
The ceremony was live streamed via YouTube due to the social distancing guidelines, with a very limited number of distinguished guests attending. Among them were President Lee’s former student Jung-Ju Kim who started Nexon, now the world’s most popular online game company, and former Chairman of the Board of Trustees Moon-Soul Chung who President Lee worked with when he made the endowment for establishing the Department of Bio and Brain Engineering in 2001 and the Moon Soul Graduate School of Future Strategy in 2013.
In his induction speech, Chairman Woo Sik Kim of the Board of Trustees said that President Lee is a proven leader who has deep insight and passion and he will help KAIST make a new leap forward. “I believe that Professor Lee will be the right leader at this critical moment for the university, ushering in a new future for KAIST as it turns 50 this year.”
President Lee explained that for the next 50 years, KAIST should double down to identify the challenges humanity faces, then define and resolve them with unyielding innovations in education, research, technology commercialization, and internationalization.
“We definitely should pull together to produce sustainable global value that will serve the prosperity and happiness of all humanity, not only our nation. We will become one of the top 10 universities in the world when we realize all these goals. We can live up to the people’s expectations by producing creative global talent, staying ahead of new research topics, and producing corporations that will lead the nation’s industries.”
“To this end, I will continue to strive to help us achieve our mission of becoming a ‘Global Value Creative Leading University’ as described in KAIST Vision 2031. I will do my utmost to bring about the ‘KAIST New Culture Strategy, QAIST’ for a post-AI era.”
He added that he would like to inspire students and faculty to have more humanistic approaches in their education and learning. The ‘Q’ in “QAIST” refers to questioning. President Lee believes that the learning starts with questions and being curious about something. “We will innovate the educational system to have them question everything.”
Then, he said that he will focus on ‘A’dvanced research to prepare for the post AI-era. “We should be the first mover who can define and solve new problems. It’s more important to be the ‘first’ one than the ‘best’ one.” He also said he will create a new culture that failing would not be stigmatized, offering more chances after failing.
‘I’nternationalization is another vision the new president will continue to pursue. He plans to embrace greater diversity on the campus to achieve goals of 15% international faculty, 25% female faculty, and 15% international students by reshaping the recruiting policy. He will continue to expand KAIST campuses overseas.
‘S’tartup and technology commercialization will be the crucial areas where the president will make innovations. “I will fully support any startups at KAIST. I encourage every lab to start a startup,” he stressed. President Lee said he plans to increase KAIST’s annual revenue from technology commercialization fees to 100 billion KRW in 10 years, a step to secure financial independence. He plans to privatize the Institute of Technology Value Creation, which is responsible for technology commercialization at KAIST to enhance its competitiveness.
‘T’rust building is the prerequisite value for creating transparent and reliable management in finance and HR. President Lee said he would like to make a new organizational culture that will be more ethical, responsible, and autonomous with a high standard of integrity.
His predecessor, President Sung-Chul Shin lauded his successor in his congratulatory speech saying, “He is a president prepared for this job.”
“I have known him for more than 30 years. He is a man of action. With unparalleled ideas and prompt execution, he carried out all his duties efficiently for the Committee of Vision 2031 that he chaired, and played a central role in establishing the full vision of KAIST. First and foremost, he is a man of great passion, with a firm vision but a warm heart.”
Nexon founder and Chairman Jung-Ju Kim also made an emotional tribute to his former professor. Holding back tears, he said, “I was not a good student. I was struggling in my graduate courses so I had to drop out of my PhD course. But Professor Lee and his wife never gave up on me. They were so kind to me and were always encouraging despite my disappointing days. I am now ready to do something good for KAIST, for Professor Lee, and for the future of our society. I believe that President Lee will guide us down the new path for KAIST.” IDIS Holdings CEO Young-Dal Kim also attended the ceremony to congratulate his former professor on his inauguration.
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2021.03.09 View 7886 -
ACS Nano Special Edition Highlights Innovations at KAIST
- The collective intelligence and technological innovation of KAIST was highlighted with case studies including the Post-COVID-19 New Deal R&D Initiative Project. -
KAIST’s innovative academic achievements and R&D efforts for addressing the world’s greatest challenges such as the COVID-19 pandemic were featured in ACS Nano as part of its special virtual issue commemorating the 50th anniversary of KAIST. The issue consisted of 14 review articles contributed by KAIST faculty from five departments, including two from Professor Il-Doo Kim from the Department of Materials Science and Engineering, who serves as an associate editor of the ACS Nano.
ACS Nano, the leading international journal in nanoscience and nanotechnology, published a special virtual issue last month, titled ‘Celebrating 50 Years of KAIST: Collective Intelligence and Innovation for Confronting Contemporary Issues.’
This special virtual issue introduced KAIST’s vision of becoming a ‘global value-creative leading university’ and its progress toward this vision over the last 50 years. The issue explained how KAIST has served as the main hub for advanced scientific research and technological innovation in South Korea since its establishment in 1971, and how its faculty and over 69,000 graduates played a key role in propelling the nation’s rapid industrialization and economic development.
The issue also emphasized the need for KAIST to enhance global cooperation and the exchange of ideas in the years to come, especially during the post-COVID era intertwined with the Fourth Industrial Revolution (4IR). In this regard, the issue cited the first ‘KAIST Emerging Materials e-Symposium (EMS)’, which was held online for five days in September of last year with a global audience of over 10,000 participating live via Zoom and YouTube, as a successful example of what academic collaboration could look like in the post-COVID and 4IR eras.
In addition, the “Science & Technology New Deal Project for COVID-19 Response,” a project conducted by KAIST with support from the Ministry of Science and ICT (MSIT) of South Korea, was also introduced as another excellent case of KAIST’s collective intelligence and technological innovation. The issue highlighted some key achievements from this project for overcoming the pandemic-driven crisis, such as: reusable anti-virus filters, negative-pressure ambulances for integrated patient transport and hospitalization, and movable and expandable negative-pressure ward modules.
“We hold our expectations high for the outstanding achievements and progress KAIST will have made by its centennial,” said Professor Kim on the background of curating the 14 review articles contributed by KAIST faculty from the fields of Materials Science and Engineering (MSE), Chemical and Biomolecular Engineering (CBE), Nuclear and Quantum Engineering (NQE), Electrical Engineering (EE), and Chemistry (Chem).
Review articles discussing emerging materials and their properties covered photonic carbon dots (Professor Chan Beum Park, MSE), single-atom and ensemble catalysts (Professor Hyunjoo Lee, CBE), and metal/metal oxide electrocatalysts (Professor Sung-Yoon Chung, MSE).
Review articles discussing materials processing covered 2D layered materials synthesis based on interlayer engineering (Professor Kibum Kang, MSE), eco-friendly methods for solar cell production (Professor Bumjoon J. Kim, CBE), an ex-solution process for the synthesis of highly stable catalysts (Professor WooChul Jung, MSE), and 3D light-patterning synthesis of ordered nanostructures (Professor Seokwoo Jeon, MSE, and Professor Dongchan Jang, NQE).
Review articles discussing advanced analysis techniques covered operando materials analyses (Professor Jeong Yeong Park, Chem), graphene liquid cell transmission electron microscopy (Professor Jong Min Yuk, MSE), and multiscale modeling and visualization of materials systems (Professor Seungbum Hong, MSE).
Review articles discussing practical state-of-the-art devices covered chemiresistive hydrogen sensors (Professor Il-Doo Kim, MSE), patient-friendly diagnostics and implantable treatment devices (Professor Steve Park, MSE), triboelectric nanogenerators (Professor Yang-Kyu Choi, EE), and next-generation lithium-air batteries (Professor Hye Ryung Byon, Chem, and Professor Il-Doo Kim, MSE).
In addition to Professor Il-Doo Kim, post-doctoral researcher Dr. Jaewan Ahn from the KAIST Applied Science Research Institute, Dean of the College of Engineering at KAIST Professor Choongsik Bae, and ACS Nano Editor-in-Chief Professor Paul S. Weiss from the University of California, Los Angeles also contributed to the publication of this ACS Nano special virtual issue.
The issue can be viewed and downloaded from the ACS Nano website at https://doi.org/10.1021/acsnano.1c01101.
Image credit: KAIST
Image usage restrictions: News organizations may use or redistribute this image,with proper attribution, as part of news coverage of this paper only.
Publication:
Ahn, J., et al. (2021) Celebrating 50 Years of KAIST: Collective Intelligence and Innovation for Confronting Contemporary Issues. ACS Nano 15(3): 1895-1907. Available online at https://doi.org/10.1021/acsnano.1c01101
Profile:
Il-Doo Kim, Ph.D
Chair Professor
idkim@kaist.ac.kr
http://advnano.kaist.ac.kr
Advanced Nanomaterials and Energy Lab.
Department of Materials Science and Engineering
Membrane Innovation Center for Anti-Virus and Air-Quality Control
https://kaist.ac.kr/
Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Republic of Korea
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2021.03.05 View 25321 -
Deep-Learning and 3D Holographic Microscopy Beats Scientists at Analyzing Cancer Immunotherapy
Live tracking and analyzing of the dynamics of chimeric antigen receptor (CAR) T-cells targeting cancer cells can open new avenues for the development of cancer immunotherapy. However, imaging via conventional microscopy approaches can result in cellular damage, and assessments of cell-to-cell interactions are extremely difficult and labor-intensive. When researchers applied deep learning and 3D holographic microscopy to the task, however, they not only avoided these difficultues but found that AI was better at it than humans were.
Artificial intelligence (AI) is helping researchers decipher images from a new holographic microscopy technique needed to investigate a key process in cancer immunotherapy “live” as it takes place. The AI transformed work that, if performed manually by scientists, would otherwise be incredibly labor-intensive and time-consuming into one that is not only effortless but done better than they could have done it themselves. The research, conducted by the team of Professor YongKeun Park from the Department of Physics, appeared in the journal eLife last December.
A critical stage in the development of the human immune system’s ability to respond not just generally to any invader (such as pathogens or cancer cells) but specifically to that particular type of invader and remember it should it attempt to invade again is the formation of a junction between an immune cell called a T-cell and a cell that presents the antigen, or part of the invader that is causing the problem, to it. This process is like when a picture of a suspect is sent to a police car so that the officers can recognize the criminal they are trying to track down. The junction between the two cells, called the immunological synapse, or IS, is the key process in teaching the immune system how to recognize a specific type of invader.
Since the formation of the IS junction is such a critical step for the initiation of an antigen-specific immune response, various techniques allowing researchers to observe the process as it happens have been used to study its dynamics. Most of these live imaging techniques rely on fluorescence microscopy, where genetic tweaking causes part of a protein from a cell to fluoresce, in turn allowing the subject to be tracked via fluorescence rather than via the reflected light used in many conventional microscopy techniques.
However, fluorescence-based imaging can suffer from effects such as photo-bleaching and photo-toxicity, preventing the assessment of dynamic changes in the IS junction process over the long term. Fluorescence-based imaging still involves illumination, whereupon the fluorophores (chemical compounds that cause the fluorescence) emit light of a different color. Photo-bleaching or photo-toxicity occur when the subject is exposed to too much illumination, resulting in chemical alteration or cellular damage.
One recent option that does away with fluorescent labelling and thereby avoids such problems is 3D holographic microscopy or holotomography (HT). In this technique, the refractive index (the way that light changes direction when encountering a substance with a different density—why a straw looks like it bends in a glass of water) is recorded in 3D as a hologram.
Until now, HT has been used to study single cells, but never cell-cell interactions involved in immune responses. One of the main reasons is the difficulty of “segmentation,” or distinguishing the different parts of a cell and thus distinguishing between the interacting cells; in other words, deciphering which part belongs to which cell.
Manual segmentation, or marking out the different parts manually, is one option, but it is difficult and time-consuming, especially in three dimensions. To overcome this problem, automatic segmentation has been developed in which simple computer algorithms perform the identification.
“But these basic algorithms often make mistakes,” explained Professor YongKeun Park, “particularly with respect to adjoining segmentation, which of course is exactly what is occurring here in the immune response we’re most interested in.”
So, the researchers applied a deep learning framework to the HT segmentation problem. Deep learning is a type of machine learning in which artificial neural networks based on the human brain recognize patterns in a way that is similar to how humans do this. Regular machine learning requires data as an input that has already been labelled. The AI “learns” by understanding the labeled data and then recognizes the concept that has been labelled when it is fed novel data. For example, AI trained on a thousand images of cats labelled “cat” should be able to recognize a cat the next time it encounters an image with a cat in it. Deep learning involves multiple layers of artificial neural networks attacking much larger, but unlabeled datasets, in which the AI develops its own ‘labels’ for concepts it encounters.
In essence, the deep learning framework that KAIST researchers developed, called DeepIS, came up with its own concepts by which it distinguishes the different parts of the IS junction process. To validate this method, the research team applied it to the dynamics of a particular IS junction formed between chimeric antigen receptor (CAR) T-cells and target cancer cells. They then compared the results to what they would normally have done: the laborious process of performing the segmentation manually. They found not only that DeepIS was able to define areas within the IS with high accuracy, but that the technique was even able to capture information about the total distribution of proteins within the IS that may not have been easily measured using conventional techniques.
“In addition to allowing us to avoid the drudgery of manual segmentation and the problems of photo-bleaching and photo-toxicity, we found that the AI actually did a better job,” Professor Park added.
The next step will be to combine the technique with methods of measuring how much physical force is applied by different parts of the IS junction, such as holographic optical tweezers or traction force microscopy.
-Profile
Professor YongKeun Park
Department of Physics
Biomedical Optics Laboratory
http://bmol.kaist.ac.kr
KAIST
2021.02.24 View 10384