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A New Therapeutic Drug for Alzheimer’s Disease without Inflammatory Side Effects
Although Aduhelm, a monoclonal antibody targeting amyloid beta (Aβ), recently became the first US FDA approved drug for Alzheimer’s disease (AD) based on its ability to decrease Aβ plaque burden in AD patients, its effect on cognitive improvement is still controversial. Moreover, about 40% of the patients treated with this antibody experienced serious side effects including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H) that are likely related to inflammatory responses in the brain when the Aβ antibody binds Fc receptors (FCR) of immune cells such as microglia and macrophages. These inflammatory side effects can cause neuronal cell death and synapse elimination by activated microglia, and even have the potential to exacerbate cognitive impairment in AD patients. Thus, current Aβ antibody-based immunotherapy holds the inherent risk of doing more harm than good due to their inflammatory side effects. To overcome these problems, a team of researchers at KAIST in South Korea has developed a novel fusion protein drug, αAβ-Gas6, which efficiently eliminates Aβ via an entirely different mechanism than Aβ antibody-based immunotherapy. In a mouse model of AD, αAβ-Gas6 not only removed Aβ with higher potency, but also circumvented the neurotoxic inflammatory side effects associated with conventional antibody treatments. Their findings were published on August 4 in Nature Medicine. Schematic of a chimeric Gas6 fusion protein. A single chain variable fragment (scFv) of an Amyloid β (Aβ)-targeting monoclonal antibody is fused with a truncated receptor binding domain of Gas6, a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL, and MERTK) receptors, which are expressed by microglia and astrocytes. “FcR activation by Aβ targeting antibodies induces microglia-mediated Aβ phagocytosis, but it also produces inflammatory signals, inevitably damaging brain tissues,” said paper authors Chan Hyuk Kim and Won-Suk Chung, associate professors in the Department of Biological Sciences at KAIST. “Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Aβ in the brain,” Prof. Kim and Chung said. “Efferocytosis is accompanied by anti-inflammatory responses to maintain tissue homeostasis. To exploit this process, we engineered Gas6, a soluble adaptor protein that mediates efferocytosis via TAM phagocytic receptors in such a way that its target specificity was redirected from dead cells to Aβ plaques.” The professors and their team demonstrated that the resulting αAβ-Gas6 induced Aβ engulfment by activating not only microglial but also astrocytic phagocytosis since TAM phagocytic receptors are highly expressed by these two major phagocytes in the brain. Importantly, αAβ-Gas6 promoted the robust uptake of Aβ without showing any signs of inflammation and neurotoxicity, which contrasts sharply with the treatment using an Aβ monoclonal antibody. Moreover, they showed that αAβ-Gas6 substantially reduced excessive synapse elimination by microglia, consequently leading to better behavioral rescues in AD model mice. “By using a mouse model of cerebral amyloid angiopathy (CAA), a cerebrovascular disorder caused by the deposition of Aβ within the walls of the brain’s blood vessels, we also showed that the intrathecal administration of Gas6 fusion protein significantly eliminated cerebrovascular amyloids, along with a reduction of microhemorrhages. These data demonstrate that aAb-Gas6 is a potent therapeutic agent in eliminating Aβ without exacerbating CAA-related microhemorrhages.” The resulting αAβ-Gas6 clears Aβ oligomers and fibrils without causing neurotoxicity (a-b, neurons: red, and fragmented axons: yellow) and proinflammatory responses (c, TNF release), which are conversely exacerbated by the treatment of an Aβ-targeting monoclonal antibody (Aducanumab). Professors Kim and Chung noted, “We believe our approach can be a breakthrough in treating AD without causing inflammatory side effects and synapse loss. Our approach holds promise as a novel therapeutic platform that is applicable to more than AD. By modifying the target-specificity of the fusion protein, the Gas6-fusion protein can be applied to various neurological disorders as well as autoimmune diseases affected by toxic molecules that should be removed without causing inflammatory responses.” The number and total area of Aβ plaques (Thioflavin-T, green) were significantly reduced in αAβ-Gas6-treated AD mouse brains compared to Aducanumab-treated ones (a, b). The cognitive functions of AD model mice were significantly rescued by αAβ-Gas6 treatment, whereas Aducanumab-treated AD mice showed partial rescue in these cognitive tests (c-e). Professors Kim and Chung founded “Illimis Therapeutics” based on this strategy of designing chimeric Gas6 fusion proteins that would remove toxic aggregates from the nervous system. Through this company, they are planning to further develop various Gas6-fusion proteins not only for Ab but also for Tau to treat AD symptoms. This work was supported by KAIST and the Korea Health Technology R&D Project that was administered by the Korea Health Industry Development Institute (KHIDI) and the Korea Dementia Research Center (KDRC) funded by the Ministry of Health & Welfare (MOHW) and the Ministry of Science and ICT (MSIT), and KAIST. Other contributors include Hyuncheol Jung and Se Young Lee, Sungjoon Lim, Hyeong Ryeol Choi, Yeseong Choi, Minjin Kim, Segi Kim, the Department of Biological Sciences, and the Korea Advanced Institute of Science and Technology (KAIST). To receive more up-to-date information on this new development, follow “Illimis Therapeutics” on twitter @Illimistx.
2022.08.05
View 8210
KAIST Research Team Proves How a Neurotransmitter may be the Key in Controlling Alzheimer’s Toxicity
With nearly 50 million dementia patients worldwide, and Alzheimers’s disease is the most common neurodegenerative disease. Its main symptom is the impairment of general cognitive abilities, including the ability to speak or to remember. The importance of finding a cure is widely understood with increasingly aging population and the life expectancy being ever-extended. However, even the cause of the grim disease is yet to be given a clear definition. A KAIST research team in the Department of Chemistry led by professor Mi Hee Lim took on a lead to discovered a new role for somatostatin, a protein-based neurotransmitter, in reducing the toxicity caused in the pathogenic mechanism taken towards development of Alzheimer’s disease. The study was published in the July issue of Nature Chemistry under the title, “Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β”. According to the amyloid hypothesis, the abnormal deposition of Aβ proteins causes death of neuronal cells. While Aβ agglomerations make up most of the aged plaques through fibrosis, in recent studies, high concentrations of transitional metal were found in the plaques from Alzheimer’s patients. This suggests a close interaction between metallic ions and Aβ, which accelerates the fibrosis of proteins. Copper in particular is a redox-activating transition metal that can produce large amounts of oxygen and cause serious oxidative stress on cell organelles. Aβ proteins and transition metals can closely interact with neurotransmitters at synapses, but the direct effects of such abnormalities on the structure and function of neurotransmitters are yet to be understood. Figure 1. Functional shift of somatostatin (SST) by factors in the pathogenesis of Alzheimer's disease. Figure 2. Somatostatin’s loss-of-function as neurotransmitter. a. Schematic diagram of SST auto-aggregation due to Alzheimer's pathological factors. b. SST’s aggregation by copper ions. c. Coordination-prediction structure and N-terminal folding of copper-SST. d. Inhibition of SST receptor binding specificity by metals. In their research, Professor Lim’s team discovered that when somatostatin, the protein-based neurotransmitter, is met with copper, Aβ, and metal-Aβ complexes, self-aggregates and ceases to perform its innate function of transmitting neural signals, but begins to attenuate the toxicity and agglomeration of metal-Aβ complexes. Figure 3. Gain-of-function of somatostatin (SST) in the dementia setting. a. Prediction of docking of SST and amyloid beta. b. SST making metal-amyloid beta aggregates into an amorphous form. c. Cytotoxic mitigation effect of SST. d. SST mitigating the interaction between amyloid beta protein with the cell membrane. This research, by Dr. Jiyeon Han et al. from the KAIST Department of Chemistry, revealed the coordination structure between copper and somatostatin at a molecular level through which it suggested the agglomeration mechanism, and discovered the effects of somatostatin on Aβ agglomeration path depending on the presence or absence of metals. The team has further confirmed somatostatin’s receptor binding, interactions with cell membranes, and effects on cell toxicity for the first time to receive international attention. Professor Mi Hee Lim said, “This research has great significance in having discovered a new role of neurotransmitters in the pathogenesis of Alzheimer’s disease.” “We expect this research to contribute to defining the pathogenic network of neurodegenerative diseases caused by aging, and to the development of future biomarkers and medicine,” she added. This research was conducted jointly by Professor Seung-Hee Lee’s team of KAIST Department of Biological Sciences, Professor Kiyoung Park’s Team of KAIST Department of Chemistry, and Professor Yulong Li’s team of Peking University. The research was funded by Basic Science Research Program of the National Research Foundation of Korea and KAIST. For more information about the research team, visit the website: https://sites.google.com/site/miheelimlab/1-professor-mi-hee-lim.
2022.07.29
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New Polymer Mesophase Structure Discovered
Bilayer-folded lamellar mesophase induced by random polymer sequence Polymers, large molecules made up of repeating smaller molecules called monomers, are found in nearly everything we use in our day-to-day lives. Polymers can be natural or created synthetically. Natural polymers, also called biopolymers, include DNA, proteins, and materials like silk, gelatin, and collagen. Synthetic polymers make up many different kinds of materials, including plastic, that are used in constructing everything from toys to industrial fiber cables to brake pads. As polymers are formed through a process called polymerization, the monomers are connected through a chain. As the chain develops, the structure of the polymer determines its unique physical and chemical properties. Researchers are continually studying polymers, how they form, how they are structured, and how they develop these unique properties. By understanding this information, scientists can develop new uses for polymers and create new materials that can be used in a wide variety of industries. In a paper published in Nature Communications on May 4, researchers describe a new structure found in an aqueous solution of an amphiphilic copolymer, called a bilayer-folded lamellar mesophase, that has been discovered through a random copolymer sequence. “A new mesophase is an important discovery as it shows a new way for molecules to self-organize,” said Professor Myungeun Seo at the Department of Chemistry at KAIST. “We were particularly thrilled to identify this bilayer-folded lamellar phase because pure bilayer membranes are difficult to fold thermodynamically.” Researchers think that this mesophase structure comes from the sequence of the monomers within the copolymer. The way the different monomers arrange themselves in the chain that makes up a copolymer is important and can have implications for what the copolymer can do. Many copolymers are random, which means that their structure relies on how the monomers interact with each other. In this case, the interaction between the hydrophobic monomers associates the copolymer chains to conceal the hydrophobic domain from water. As the structure gets more complex, researchers have found that a visible order develops so that monomers can be matched up with the right pair. “While we tend to think random means disorder, here we showed that a periodic order can spontaneously arise from the random copolymer sequence based on their collective behavior,” said Professor Seo. “We believe this comes from the sequence matching problem: finding a perfectly complementary pair for a long sequence is nearly impossible.” This is what creates the unique structure of this newly discovered mesophase. The copolymer spontaneously folds and creates a multilamellar structure that is separated by water. A multilamellar structure refers to plate-like folds and the folded layers stack on top of each other. The resulting mesophase is birefringent, meaning light refracts through it, it is similar to liquid crystalline, and viscoelastic, which means that it is both viscous and elastic at the same time. Looking ahead, researchers hope to learn more about this new mesophase and figure out how to control the outcome. Once more is understood about the mesophase and how it is formed, it’s possible that new mesophases could be discovered as more sequences are researched. “One of the obvious questions for us is how to control the folding frequency and adjust the folded height, which we are currently working to address. Ultimately, we want to understand how different multinary sequences can associate with another to create order and apply the knowledge to develop new materials,” said Professor Seo. The National Research Foundation, the Ministry of Education, and the Ministry of Science and ICT of Korea funded this research. -PublicationMinjoong Shin, Hayeon Kim, Geonhyeong Park, Jongmin Park, Hyungju Ahn, Dong Ki Yoon, Eunji Lee, Myungeun Seo, “Bilayer-folded lamellar mesophase induced by random polymersequence,” May 4, 2022, Nature Communications (https://doi.org/10.1038/s41467-022-30122-z) -ProfileProfessor Myungeun SeoMacromolecular Materials Chemistry Lab (https://nanopsg.kaist.ac.kr/)Department of ChemistryCollege of Natural SciencesKAIST
2022.06.17
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Distinguished Professor Sukbok Chang Named the 2022 Ho-Am Laureate
Distinguished Professor Sukbok Chang from the Department of Chemistry was named the awardee of the Ho-Am Prize in the fields of chemistry and life sciences. The award has recognized the most distinguished scholars, individuals, and organizations in physics and mathematics, chemistry and life sciences, engineering, medicine, arts, and community service in honor of the late founder of Samsung Group Byong-Chul Lee, whose penname is Ho-Am. The awards ceremony will be held on May 31 and awardees will receive 300 million KRW in prize money. Professor Chang became the fourth KAIST Ho-Am laureate following Distinguished Professor Sang Yup Lee in engineering in 2014, Distinguished Professor Jun Ho Oh in engineering in 2016, and Distinguished Professor Gou Young Koh in medicine in 2018. Professor Chang is a renowned chemist who has made pioneering research in the area of transition metal catalysis for organic transformations. Professor Chang is also one of the Highly Cited Researchers who rank in the top 1% of citations by field and publication year in the Web of Science citation index. He has made the list seven years in a row from 2016. Professor Chang has developed a range of new and impactful C-H bond functionalization reactions. By using his approaches, value-added molecules can be readily produced from chemical feedstocks, representatively hydrocarbons and (hetero)arenes. His research team elucidated fundamental key mechanistic aspects in the course of the essential C-H bond activation process of unreactive starting materials. He was able to utilize the obtained mechanistic understanding for the subsequent catalyst design to develop more efficient and highly (stereo)selective catalytic reactions. Among the numerous contributions he made, the design of new mechanistic approaches toward metal nitrenoid transfers are of especially high impact to the chemical community. Indeed, a series of important transition metal catalyst systems were developed by Professor Chang to enable the direct and selective C-H amidation of unreactive organic compounds, thereby producing aminated compounds that have important applicability in synthetic, medicinal, and materials science. He has also pioneered in the area of asymmetric C-H amination chemistry by creatively devising various types of chiral transition metal catalyst systems, and his team proved for the first time that chiral lactam compounds can be obtained at an excellent level of stereoselectivity. Another significant contribution of Professor. Chang was the introduction of dioxazolones as a robust but highly reactive source of acyl nitrenoids for the catalytic C-H amidation reactions, and this reagent is now broadly utilized in synthetic chemistry worldwide. Professor Chang also leads a research group in the Center for Catalytic Hydrocarbon Functionalizations at the Institute for Basic Science.
2022.04.06
View 5440
Mathematicians Identify a Key Source of Cell-to-Cell Variability in Cell Signaling
Systematic inferences identify a major source of heterogeneity in cell signaling dynamics Why do genetically identical cells respond differently to the same external stimuli, such as antibiotics? This long-standing mystery has been solved by KAIST and IBS mathematicians who have developed a new framework for analyzing cell responses to some stimuli. The team found that the cell-to-cell variability in antibiotic stress response increases as the effective length of the cell signaling pathway (i.e., the number of rate-limiting steps) increases. This finding could identify more effective chemotherapies to overcome the fractional killing of cancer cells caused by cell-to-cell variability. Cells in the human body contain signal transduction systems that respond to various external stimuli such as antibiotics and changes in osmotic pressure. When an external stimulus is detected, various biochemical reactions occur sequentially. This leads to the expression of relevant genes, allowing the cells to respond to the perturbed external environment. Furthermore, signal transduction leads to a drug response (e.g., antibiotic resistance genes are expressed when antibiotic drugs are given). However, even when the same external stimuli are detected, the responses of individual cells are greatly heterogeneous. This leads to the emergence of persister cells that are highly resistant to drugs. To identify potential sources of this cell-to cell variability, many studies have been conducted. However, most of the intermediate signal transduction reactions are unobservable with current experimental techniques. A group of researchers including Dae Wook Kim and Hyukpyo Hong and led by Professor Jae Kyoung Kim from the KAIST Department of Mathematical Sciences and IBS Biomedical Mathematics Group solved the mystery by exploiting queueing theory and Bayesian inference methodology. They proposed a queueing process that describes the signal transduction system in cells. Based on this, they developed Bayesian inference computational software using MBI (the Moment-based Bayesian Inference method). This enables the analysis of the signal transduction system without a direct observation of the intermediate steps. This study was published in Science Advances. By analyzing experimental data from Escherichia coli using MBI, the research team found that cell-to-cell variability increases as the number of rate-limiting steps in the signaling pathway increases. The rate-limiting steps denote the slowest steps (i.e., bottlenecks) in sequential biochemical reaction steps composing cell signaling pathways and thus dominates most of the signaling time. As the number of the rate-limiting steps increases, the intensity of the transduced signal becomes greatly heterogeneous even in a population of genetically identical cells. This finding is expected to provide a new paradigm for studying the heterogeneous antibiotic resistance of cells, which is a big challenge in cancer medicine. Professor Kim said, “As a mathematician, I am excited to help advance the understanding of cell-to-cell variability in response to external stimuli. I hope this finding facilitates the development of more effective chemotherapies.” This work was supported by the Samsung Science and Technology Foundation, the National Research Foundation of Korea, and the Institute for Basic Science. -Publication:Dae Wook Kim, Hyukpyo Hong, and Jae Kyoung Kim (2022) “Systematic inference identifies a major source of heterogeneity in cell signaling dynamics: the rate-limiting step number,”Science Advances March 18, 2022 (DOI: 10.1126/sciadv.abl4598) -Profile:Professor Jae Kyoung Kimhttp://mathsci.kaist.ac.kr/~jaekkim jaekkim@kaist.ac.kr@umichkim on TwitterDepartment of Mathematical SciencesKAIST
2022.03.29
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Tomographic Measurement of Dielectric Tensors
Dielectric tensor tomography allows the direct measurement of the 3D dielectric tensors of optically anisotropic structures A research team reported the direct measurement of dielectric tensors of anisotropic structures including the spatial variations of principal refractive indices and directors. The group also demonstrated quantitative tomographic measurements of various nematic liquid-crystal structures and their fast 3D nonequilibrium dynamics using a 3D label-free tomographic method. The method was described in Nature Materials. Light-matter interactions are described by the dielectric tensor. Despite their importance in basic science and applications, it has not been possible to measure 3D dielectric tensors directly. The main challenge was due to the vectorial nature of light scattering from a 3D anisotropic structure. Previous approaches only addressed 3D anisotropic information indirectly and were limited to two-dimensional, qualitative, strict sample conditions or assumptions. The research team developed a method enabling the tomographic reconstruction of 3D dielectric tensors without any preparation or assumptions. A sample is illuminated with a laser beam with various angles and circularly polarization states. Then, the light fields scattered from a sample are holographically measured and converted into vectorial diffraction components. Finally, by inversely solving a vectorial wave equation, the 3D dielectric tensor is reconstructed. Professor YongKeun Park said, “There were a greater number of unknowns in direct measuring than with the conventional approach. We applied our approach to measure additional holographic images by slightly tilting the incident angle.” He said that the slightly tilted illumination provides an additional orthogonal polarization, which makes the underdetermined problem become the determined problem. “Although scattered fields are dependent on the illumination angle, the Fourier differentiation theorem enables the extraction of the same dielectric tensor for the slightly tilted illumination,” Professor Park added. His team’s method was validated by reconstructing well-known liquid crystal (LC) structures, including the twisted nematic, hybrid aligned nematic, radial, and bipolar configurations. Furthermore, the research team demonstrated the experimental measurements of the non-equilibrium dynamics of annihilating, nucleating, and merging LC droplets, and the LC polymer network with repeating 3D topological defects. “This is the first experimental measurement of non-equilibrium dynamics and 3D topological defects in LC structures in a label-free manner. Our method enables the exploration of inaccessible nematic structures and interactions in non-equilibrium dynamics,” first author Dr. Seungwoo Shin explained. -PublicationSeungwoo Shin, Jonghee Eun, Sang Seok Lee, Changjae Lee, Herve Hugonnet, Dong Ki Yoon, Shin-Hyun Kim, Jongwoo Jeong, YongKeun Park, “Tomographic Measurement ofDielectric Tensors at Optical Frequency,” Nature Materials March 02, 2022 (https://doi.org/10/1038/s41563-022-01202-8) -ProfileProfessor YongKeun ParkBiomedical Optics Laboratory (http://bmol.kaist.ac.kr)Department of PhysicsCollege of Natural SciencesKAIST
2022.03.22
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Scientist Discover How Circadian Rhythm Can Be Both Strong and Flexible
Study reveals that master and slave oscillators function via different molecular mechanisms From tiny fruit flies to human beings, all animals on Earth maintain their daily rhythms based on their internal circadian clock. The circadian clock enables organisms to undergo rhythmic changes in behavior and physiology based on a 24-hour circadian cycle. For example, our own biological clock tells our brain to release melatonin, a sleep-inducing hormone, at night time. The discovery of the molecular mechanism of the circadian clock was bestowed the Nobel Prize in Physiology or Medicine 2017. From what we know, no one centralized clock is responsible for our circadian cycles. Instead, it operates in a hierarchical network where there are “master pacemaker” and “slave oscillator”. The master pacemaker receives various input signals from the environment such as light. The master then drives the slave oscillator that regulates various outputs such as sleep, feeding, and metabolism. Despite the different roles of the pacemaker neurons, they are known to share common molecular mechanisms that are well conserved in all lifeforms. For example, interlocked systems of multiple transcriptional-translational feedback loops (TTFLs) composed of core clock proteins have been deeply studied in fruit flies. However, there is still much that we need to learn about our own biological clock. The hierarchically-organized nature of master and slave clock neurons leads to a prevailing belief that they share an identical molecular clockwork. At the same time, the different roles they serve in regulating bodily rhythms also raise the question of whether they might function under different molecular clockworks. Research team led by Professor Kim Jae Kyoung from the Department of Mathematical Sciences, a chief investigator at the Biomedical Mathematics Group at the Institute for Basic Science, used a combination of mathematical and experimental approaches using fruit flies to answer this question. The team found that the master clock and the slave clock operate via different molecular mechanisms. In both master and slave neurons of fruit flies, a circadian rhythm-related protein called PER is produced and degraded at different rates depending on the time of the day. Previously, the team found that the master clock neuron (sLNvs) and the slave clock neuron (DN1ps) have different profiles of PER in wild-type and Clk-Δ mutant Drosophila. This hinted that there might be a potential difference in molecular clockworks between the master and slave clock neurons. However, due to the complexity of the molecular clockwork, it was challenging to identify the source of such differences. Thus, the team developed a mathematical model describing the molecular clockworks of the master and slave clocks. Then, all possible molecular differences between the master and slave clock neurons were systematically investigated by using computer simulations. The model predicted that PER is more efficiently produced and then rapidly degraded in the master clock compared to the slave clock neurons. This prediction was then confirmed by the follow-up experiments using animal. Then, why do the master clock neurons have such different molecular properties from the slave clock neurons? To answer this question, the research team again used the combination of mathematical model simulation and experiments. It was found that the faster rate of synthesis of PER in the master clock neurons allows them to generate synchronized rhythms with a high level of amplitude. Generation of such a strong rhythm with high amplitude is critical to delivering clear signals to slave clock neurons. However, such strong rhythms would typically be unfavorable when it comes to adapting to environmental changes. These include natural causes such as different daylight hours across summer and winter seasons, up to more extreme artificial cases such as jet lag that occurs after international travel. Thanks to the distinct property of the master clock neurons, it is able to undergo phase dispersion when the standard light-dark cycle is disrupted, drastically reducing the level of PER. The master clock neurons can then easily adapt to the new diurnal cycle. Our master pacemaker’s plasticity explains how we can quickly adjust to the new time zones after international flights after just a brief period of jet lag. It is hoped that the findings of this study can have future clinical implications when it comes to treating various disorders that affect our circadian rhythm. Professor Kim notes, “When the circadian clock loses its robustness and flexibility, the circadian rhythms sleep disorders can occur. As this study identifies the molecular mechanism that generates robustness and flexibility of the circadian clock, it can facilitate the identification of the cause of and treatment strategy for the circadian rhythm sleep disorders.” This work was supported by the Human Frontier Science Program. -PublicationEui Min Jeong, Miri Kwon, Eunjoo Cho, Sang Hyuk Lee, Hyun Kim, Eun Young Kim, and Jae Kyoung Kim, “Systematic modeling-driven experiments identify distinct molecularclockworks underlying hierarchically organized pacemaker neurons,” February 22, 2022, Proceedings of the National Academy of Sciences of the United States of America -ProfileProfessor Jae Kyoung KimDepartment of Mathematical SciencesKAIST
2022.02.23
View 6433
A Mathematical Model Shows High Viral Transmissions Reduce the Progression Rates for Severe Covid-19
The model suggests a clue as to when a pandemic will turn into an endemic A mathematical model demonstrated that high transmission rates among highly vaccinated populations of COVID-19 ultimately reduce the numbers of severe cases. This model suggests a clue as to when this pandemic will turn into an endemic. With the future of the pandemic remaining uncertain, a research team of mathematicians and medical scientists analyzed a mathematical model that may predict how the changing transmission rate of COVID-19 would affect the settlement process of the virus as a mild respiratory virus. The team led by Professor Jae Kyoung Kim from the Department of Mathematical Science and Professor Eui-Cheol Shin from the Graduate School of Medical Science and Engineering used a new approach by dividing the human immune responses to SARS-CoV-2 into a shorter-term neutralizing antibody response and a longer-term T-cell immune response, and applying them each to a mathematical model. Additionally, the analysis was based on the fact that although breakthrough infection may occur frequently, the immune response of the patient will be boosted after recovery from each breakthrough infection. The results showed that in an environment with a high vaccination rate, although COVID-19 cases may rise temporarily when the transmission rate increases, the ratio of critical cases would ultimately decline, thereby decreasing the total number of critical cases and in fact settling COVID-19 as a mild respiratory disease more quickly. Conditions in which the number of cases may spike include relaxing social distancing measures or the rise of variants with higher transmission rates like the Omicron variant. This research did not take the less virulent characteristic of the Omicron variant into account but focused on the results of its high transmission rate, thereby predicting what may happen in the process of the endemic transition of COVID-19. The research team pointed out the limitations of their mathematical model, such as the lack of consideration for age or patients with underlying diseases, and explained that the results of this study must be applied with care when compared against high-risk groups. Additionally, as medical systems may collapse when the number of cases rises sharply, this study must be interpreted with prudence and applied accordingly. The research team therefore emphasized that for policies that encourage a step-wise return to normality to succeed, the sustainable maintenance of public health systems is indispensable. Professor Kim said, “We have drawn a counter-intuitive conclusion amid the unpredictable pandemic through an adequate mathematical model,” asserting the importance of applying mathematical models to medical research. Professor Shin said, “Although the Omicron variant has become the dominant strain and the number of cases is rising rapidly in South Korea, it is important to use scientific approaches to predict the future and apply them to policies rather than fearing the current situation.” The results of the research were published on medRxiv.org on February 11, under the title “Increasing viral transmission paradoxically reduces progression rates to severe COVID-19 during endemic transition.” This research was funded by the Institute of Basic Science, the Korea Health Industry Development Institute, and the National Research Foundation of Korea. -PublicationHyukpyo Hong, Ji Yun Noh, Hyojung Lee, Sunhwa Choi, Boseung Choi, Jae Kyung Kim, Eui-Cheol Shin, “Increasing viral transmission paradoxically reduces progression rates to severe COVID-19 during endemic transition,” medRxiv, February 9, 2022 (doi.org/10.1101/2022.02.09.22270633) -ProfileProfessor Jae Kyung KimDepartment of Mathematical SciencesKAIST Professor Eui-Cheol ShinGraduate School of Medical Science and EngineeringKAIST
2022.02.22
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Label-Free Multiplexed Microtomography of Endogenous Subcellular Dynamics Using Deep Learning
AI-based holographic microscopy allows molecular imaging without introducing exogenous labeling agents A research team upgraded the 3D microtomography observing dynamics of label-free live cells in multiplexed fluorescence imaging. The AI-powered 3D holotomographic microscopy extracts various molecular information from live unlabeled biological cells in real time without exogenous labeling or staining agents. Professor YongKeum Park’s team and the startup Tomocube encoded 3D refractive index tomograms using the refractive index as a means of measurement. Then they decoded the information with a deep learning-based model that infers multiple 3D fluorescence tomograms from the refractive index measurements of the corresponding subcellular targets, thereby achieving multiplexed micro tomography. This study was reported in Nature Cell Biology online on December 7, 2021. Fluorescence microscopy is the most widely used optical microscopy technique due to its high biochemical specificity. However, it needs to genetically manipulate or to stain cells with fluorescent labels in order to express fluorescent proteins. These labeling processes inevitably affect the intrinsic physiology of cells. It also has challenges in long-term measuring due to photobleaching and phototoxicity. The overlapped spectra of multiplexed fluorescence signals also hinder the viewing of various structures at the same time. More critically, it took several hours to observe the cells after preparing them. 3D holographic microscopy, also known as holotomography, is providing new ways to quantitatively image live cells without pretreatments such as staining. Holotomography can accurately and quickly measure the morphological and structural information of cells, but only provides limited biochemical and molecular information. The 'AI microscope' created in this process takes advantage of the features of both holographic microscopy and fluorescence microscopy. That is, a specific image from a fluorescence microscope can be obtained without a fluorescent label. Therefore, the microscope can observe many types of cellular structures in their natural state in 3D and at the same time as fast as one millisecond, and long-term measurements over several days are also possible. The Tomocube-KAIST team showed that fluorescence images can be directly and precisely predicted from holotomographic images in various cells and conditions. Using the quantitative relationship between the spatial distribution of the refractive index found by AI and the major structures in cells, it was possible to decipher the spatial distribution of the refractive index. And surprisingly, it confirmed that this relationship is constant regardless of cell type. Professor Park said, “We were able to develop a new concept microscope that combines the advantages of several microscopes with the multidisciplinary research of AI, optics, and biology. It will be immediately applicable for new types of cells not included in the existing data and is expected to be widely applicable for various biological and medical research.” When comparing the molecular image information extracted by AI with the molecular image information physically obtained by fluorescence staining in 3D space, it showed a 97% or more conformity, which is a level that is difficult to distinguish with the naked eye. “Compared to the sub-60% accuracy of the fluorescence information extracted from the model developed by the Google AI team, it showed significantly higher performance,” Professor Park added. This work was supported by the KAIST Up program, the BK21+ program, Tomocube, the National Research Foundation of Korea, and the Ministry of Science and ICT, and the Ministry of Health & Welfare. -Publication Hyun-seok Min, Won-Do Heo, YongKeun Park, et al. “Label-free multiplexed microtomography of endogenous subcellular dynamics using generalizable deep learning,” Nature Cell Biology (doi.org/10.1038/s41556-021-00802-x) published online December 07 2021. -Profile Professor YongKeun Park Biomedical Optics Laboratory Department of Physics KAIST
2022.02.09
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KAIST and KNUA to Collaborate on Culture Technology
Distinguished Visiting Scholar Soprano Sumi Jo Accompanied by AI pianist ‘VirtuosoNet’ during the Special Concert at KAIST KAIST will expand the convergence of arts education and culture technology research in collaboration with the Korea National University of Arts (KNUA), the nation’s top arts university. KAIST President Kwang Hyung Lee signed an MOU with President Daejin Kim of the Korea National University of Art on January 6 at KAIST’s Daejeon campus for collaborations in arts education and research. KAIST and KNUA will expand educational programs such as student exchanges and co-credit programs. The two universities will team up for cooperation focusing on research centers and academic conferences for the creation of culture technology and convergence arts. Minister of Culture, Sports, and Tourism Hee Hwang also attended the ceremony. Minister Hwang said that the Ministry will invest 132 billion KRW in R&D for developing metaverse and content technologies. He added that this collaboration will be a very meaningful turning point for creating a new culture combining high-level technologies. President Kim also expressed his expectations saying, “The collaboration of our two universities will generate a huge synergistic impact for nurturing talents and the creation of convergence arts. President Lee said that the collaboration with KNUA will take KAIST another step forward as it aims to foster well-rounded talents. “We look forward to proactive collaborative research that will expand the new chapter of convergence arts and future stage performances.” Right after the signing ceremony, world renowned soprano Sumi Jo, who was named a Distinguished Visiting Scholar, took the KAIST auditorium stage for a special concert. AI pianist ‘VirtuosoNet’, developed by Professor Juhan Nam at the Graduate School of Culture Technology, made its debut at the concert by playing Mozart’s Turkish March arranged by Arcardi Volrodos. VirtuosoNet also accompanied Soprano Jo on one of her songs. The concert by Sumi Jo and AI pianist VirtuosoNet heralds what KAIST is pursuing for education and research in culture technology. The Graduate School of Culture Technology plans to conduct research on future culture industries combined with technologies for the metaverse. The Sumi Jo Performing Arts Research Center will conduct research on performing technologies together with virtual artists. Head of the Graduate School of Culture Technology Woontack Woo said that KAIST will expand the sphere of the culture industry including tourism in collaboration with KNUA by incorporating technology into arts.
2022.01.10
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A Genetic Change for Achieving a Long and Healthy Life
Researchers identified a single amino acid change in the tumor suppressor protein in PTEN that extends healthy periods while maintaining longevity Living a long, healthy life is everyone’s wish, but it is not an easy one to achieve. Many aging studies are developing strategies to increase health spans, the period of life spent with good health, without chronic diseases and disabilities. Researchers at KAIST presented new insights for improving the health span by just regulating the activity of a protein. A research group under Professor Seung-Jae V. Lee from the Department of Biological Sciences identified a single amino acid change in the tumor suppressor protein phosphatase and tensin homolog (PTEN) that dramatically extends healthy periods while maintaining longevity. This study highlights the importance of the well-conserved tumor suppressor protein PTEN in health span regulation, which can be targeted to develop therapies for promoting healthy longevity in humans. The research was published in Nature Communications on September 24, 2021. Insulin and insulin-like growth factor-1 (IGF-1) signaling (IIS) is one of the evolutionarily conserved aging-modulatory pathways present in life forms ranging from tiny roundworms to humans. The proper reduction of IIS leads to longevity in animals but often causes defects in multiple health parameters including impaired motility, reproduction, and growth. The research team found that a specific amino acid change in the PTEN protein improves health status while retaining the longevity conferred by reduced IIS. They used the roundworm C. elegans, an excellent model animal that has been widely used for aging research, mainly because of its very short normal lifespan of about two to three weeks. The PTEN protein is a phosphatase that removes phosphate from lipids as well as proteins. Interestingly, the newly identified amino acid change delicately recalibrated the IIS by partially maintaining protein phosphatase activity while reducing lipid phosphatase activity. As a result, the amino acid change in the PTEN protein maintained the activity of the longevity-promoting transcription factor Forkhead Box O (FOXO) protein while restricting the detrimental upregulation of another transcription factor, NRF2, leading to long and healthy life in animals with reduced IIS. Professor Lee said, “Our study raises the exciting possibility of simultaneously promoting longevity and health in humans by slightly tweaking the activity of one protein, PTEN.” This work was supported by the MInistry of Science and ICT through the National Research Foundation of Korea. -Publication:Hae-Eun H. Park, Wooseon Hwang, Seokjin Ham, Eunah Kim, Ozlem Altintas, Sangsoon Park, Heehwa G. Son, Yujin Lee, Dongyeop Lee, Won Do Heo, and Seung-Jae V. Lee. 2021. “A PTEN variant uncouples longevity from impaired fitness in Caenorhabditis elegans with reduced insulin/IGF-1 signaling,” Nature Communications, 12(1), 5631. (https://doi.org/10.1038/s41467-021-25920-w) -ProfileProfessor Seung-Jae V. LeeMolecular Genetics of Aging LaboratoryDepartment of Biological Sciences KAIST
2021.11.19
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Two Researchers Designated as SUHF Fellows
Professor Taeyun Ku from the Graduate School of Medical Science and Engineering and Professor Hanseul Yang from the Department of Biological Sciences were nominated as 2021 fellows of the Suh Kyungbae Foundation (SUHF). SUHF selected three young promising scientists from 53 researchers who are less than five years into their careers. A panel of judges comprised of scholars from home and abroad made the final selection based on the candidates’ innovativeness and power to influence. Professor You-Bong Hyun from Seoul National University also won the fellowship. Professor Ku’s main topic is opto-connectomics. He will study ways to visualize the complex brain network using innovative technology that transforms neurons into optical elements. Professor Yang will research the possibility of helping patients recover from skin diseases or injuries without scars by studying spiny mouse genes. SUHF was established by Amorepacific Group Chairman Suh Kyungbae in 2016 with 300 billion KRW of his private funds. Under the vision of ‘contributing to humanity by supporting innovative discoveries of bioscience researchers,’ the foundation supports promising Korean scientists who pioneer new fields of research in biological sciences. From 2017 to this year, SUHF has selected 20 promising scientists in the field of biological sciences. Selected scientists are provided with up to KRW 500 million each year for five years. The foundation has provided a total of KRW 48.5 billion in research funds to date.
2021.09.15
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