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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 11776 -
KAIST Honors BMW and Hyundai with the 2022 Future Mobility of the Year Award
BMW ‘iVision Circular’, Commercial Vehicle-Hyundai Motors ‘Trailer Drone’ selected as winners of the international awards for concept cars established by KAIST Cho Chun Shik Graduate School of Mobility to honor car makers that strive to present new visions in the field of eco-friendly design of automobiles and unmanned logistics.
KAIST (President Kwang Hyung Lee) hosted the “2022 Future Mobility of the Year (FMOTY) Awards” at the Convention Hall of the BEXCO International Motor Show at Busan in the afternoon of the 14th.
The Future Mobility of the Year Awards is an award ceremony that selects a model that showcases useful transportation technology and innovative service concepts for the future society among the set of concept cars exhibited at the motor show.
As a one-of-a-kind international concept car awards established by KAIST's Cho Chun Shik Graduate School of Mobility (Headed by Professor Jang In-Gwon), the auto journalists from 11 countries were invited to be the jurors to select the winner. With the inaugural awards ceremony held in 2019, over the past three years, automakers from around the globe, including internationally renowned automakers, such as, Volvo/Toyota (2019), Honda/Hyundai (2020), and Renault (2021), even a new start-up car manufacturer like Canoo, the winner of last year’s award for commercial vehicles, were honored for their award-winning works.
At this year’s awards ceremony, the 4th of its kind, BMW's “iVision Circular” and Hyundai's “'Trailer Drone” were selected as the best concept cars of the year, the former from the Private Mobility category and the latter from the Public & Commercial Vehicles category.
The jury consisting of 16 domestic and foreign auto journalists, including BBC Top Gear's Paul Horrell and Car Magazine’s Georg Kacher, evaluated 53 concept car contestants that made their entry last year. The jurors’ general comment was that while the trend of the global automobile market flowing fast towards electric vehicles, this year's award-winning works presented a new vision in the field of eco-friendly design and unmanned logistics.
Private Mobility Categry Winner: BMW iVision Circular
BMW's 'iVision Circular', the winner of the Private Mobility category, is an eco-friendly compact car in which all parts of the vehicle are designed with recycled and/or natural materials. It has received favorable reviews for its in-depth implementation of the concept of a futuristic eco-friendly car by manufacturing the tires from natural rubber and adopting a design that made recycling of its parts very easily when the car is to be disposed of.
Public & Commercial Vehicles Categry Winner: Hyundai Trailer Drone
Hyundai Motor Company’s “Trailer Drone”, the winner of the Public & Commercial Vehicles category, is an eco-friendly autonomous driving truck that can transport large-scale logistics from a port to a destination without a human driver while two unmanned vehicles push and drag a trailer. The concept car won supports from a large number of judges for the blueprint it presented for a groundbreaking logistics service that applied both eco-friendly hydrogen fuel cell and fully autonomous driving technology.
Jurors from overseas congratulated the development team of BMW and Hyundai Motor Company via a video message for providing a new direction for the global automobile industry as it strives to transform in line with the changes in the post-pandemic era.
Professor Bo-won Kim, the Vice President for Planning and Budget of KAIST, who presented the awards, said, “It is time for the K-Mobility wave to sweep over the global mobility industry.” “KAIST will lead in the various fields of mobility technologies to support global automakers,” he added.
Splitting the center are KAIST Vice President Bo-Won Kim on the right, and Seong-Kwon Lee,
the Deputy Mayor of the City of Busan on the left. To Kim's left is the Senior VP of BMW Asia-Pacific, Eastern Europe, Middle East, Africa, Jean-Philippe Parain, and to Lee's Right is Sangyup Lee,
the Head of Hyundai Motor Design Center and the Executive VP of Hyundai Motors.
At the ceremony, along with KAIST officials, including Vice President Bo-Won Kim and Professor In-Gwon Jang, the Head of Cho Chun Shik Graduate School of Mobility, are the Deputy Mayor Seong-Kwon Lee of the City of Busan and the figures from the automobile industry, including Jean-Philippe Parain, the Senior Vice President of BMW Asia-Pacific, Eastern Europe, Middle East, Africa, who is visiting Korea to receive the '2022 Future Mobility' award, and Sangyup Lee, the Head of Hyundai Motor Design Center and the Executive Vice President of Hyundai Motor Company, were in the attendance.
More information about the awards ceremony and winning works are available at the official website of this year's Future Mobility Awards (www.fmoty.org).
Profile:In-Gwon Jang, Ph.D.Presidentthe Organizing Committeethe Future Mobility of the Year Awardshttp://www.fmoty.org/
Head ProfessorKAIST Cho Chun Shik Graduate School of Mobilityhttps://gt.kaist.ac.kr
2022.07.14 View 13520 -
Atomically-Smooth Gold Crystals Help to Compress Light for Nanophotonic Applications
Highly compressed mid-infrared optical waves in a thin dielectric crystal on monocrystalline gold substrate investigated for the first time using a high-resolution scattering-type scanning near-field optical microscope.
KAIST researchers and their collaborators at home and abroad have successfully demonstrated a new platform for guiding the compressed light waves in very thin van der Waals crystals. Their method to guide the mid-infrared light with minimal loss will provide a breakthrough for the practical applications of ultra-thin dielectric crystals in next-generation optoelectronic devices based on strong light-matter interactions at the nanoscale.
Phonon-polaritons are collective oscillations of ions in polar dielectrics coupled to electromagnetic waves of light, whose electromagnetic field is much more compressed compared to the light wavelength. Recently, it was demonstrated that the phonon-polaritons in thin van der Waals crystals can be compressed even further when the material is placed on top of a highly conductive metal. In such a configuration, charges in the polaritonic crystal are “reflected” in the metal, and their coupling with light results in a new type of polariton waves called the image phonon-polaritons. Highly compressed image modes provide strong light-matter interactions, but are very sensitive to the substrate roughness, which hinders their practical application.
Challenged by these limitations, four research groups combined their efforts to develop a unique experimental platform using advanced fabrication and measurement methods. Their findings were published in Science Advances on July 13.
A KAIST research team led by Professor Min Seok Jang from the School of Electrical Engineering used a highly sensitive scanning near-field optical microscope (SNOM) to directly measure the optical fields of the hyperbolic image phonon-polaritons (HIP) propagating in a 63 nm-thick slab of hexagonal boron nitride (h-BN) on a monocrystalline gold substrate, showing the mid-infrared light waves in dielectric crystal compressed by a hundred times.
Professor Jang and a research professor in his group, Sergey Menabde, successfully obtained direct images of HIP waves propagating for many wavelengths, and detected a signal from the ultra-compressed high-order HIP in a regular h-BN crystals for the first time. They showed that the phonon-polaritons in van der Waals crystals can be significantly more compressed without sacrificing their lifetime.
This became possible due to the atomically-smooth surfaces of the home-grown gold crystals used as a substrate for the h-BN. Practically zero surface scattering and extremely small ohmic loss in gold at mid-infrared frequencies provide a low-loss environment for the HIP propagation. The HIP mode probed by the researchers was 2.4 times more compressed and yet exhibited a similar lifetime compared to the phonon-polaritons with a low-loss dielectric substrate, resulting in a twice higher figure of merit in terms of the normalized propagation length.
The ultra-smooth monocrystalline gold flakes used in the experiment were chemically grown by the team of Professor N. Asger Mortensen from the Center for Nano Optics at the University of Southern Denmark.
Mid-infrared spectrum is particularly important for sensing applications since many important organic molecules have absorption lines in the mid-infrared. However, a large number of molecules is required by the conventional detection methods for successful operation, whereas the ultra-compressed phonon-polariton fields can provide strong light-matter interactions at the microscopic level, thus significantly improving the detection limit down to a single molecule. The long lifetime of the HIP on monocrystalline gold will further improve the detection performance.
Furthermore, the study conducted by Professor Jang and the team demonstrated the striking similarity between the HIP and the image graphene plasmons. Both image modes possess significantly more confined electromagnetic field, yet their lifetime remains unaffected by the shorter polariton wavelength. This observation provides a broader perspective on image polaritons in general, and highlights their superiority in terms of the nanolight waveguiding compared to the conventional low-dimensional polaritons in van der Waals crystals on a dielectric substrate.
Professor Jang said, “Our research demonstrated the advantages of image polaritons, and especially the image phonon-polaritons. These optical modes can be used in the future optoelectronic devices where both the low-loss propagation and the strong light-matter interaction are necessary. I hope that our results will pave the way for the realization of more efficient nanophotonic devices such as metasurfaces, optical switches, sensors, and other applications operating at infrared frequencies.”
This research was funded by the Samsung Research Funding & Incubation Center of Samsung Electronics and the National Research Foundation of Korea (NRF). The Korea Institute of Science and Technology, Ministry of Education, Culture, Sports, Science and Technology of Japan, and The Villum Foundation, Denmark, also supported the work.
Figure. Nano-tip is used for the ultra-high-resolution imaging of the image phonon-polaritons in hBN launched by the gold crystal edge.
Publication:
Menabde, S. G., et al. (2022) Near-field probing of image phonon-polaritons in hexagonal boron nitride on gold crystals. Science Advances 8, Article ID: eabn0627. Available online at https://science.org/doi/10.1126/sciadv.abn0627.
Profile:
Min Seok Jang, MS, PhD
Associate Professor
jang.minseok@kaist.ac.kr
http://janglab.org/
Min Seok Jang Research Group
School of Electrical Engineering
http://kaist.ac.kr/en/
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, Republic of Korea
2022.07.13 View 12738 -
VP Sang Yup Lee Receives Honorary Doctorate from DTU
Vice President for Research, Distinguished Professor Sang Yup Lee at the Department of Chemical & Biomolecular Engineering, was awarded an honorary doctorate from the Technical University of Denmark (DTU) during the DTU Commemoration Day 2022 on April 29. The event drew distinguished guests, students, and faculty including HRH The Crown Prince Frederik Andre Henrik Christian and DTU President Anders Bjarklev.
Professor Lee was recognized for his exceptional scholarship in the field of systems metabolic engineering, which led to the development of microcell factories capable of producing a wide range of fuels, chemicals, materials, and natural compounds, many for the first time.
Professor Lee said in his acceptance speech that KAIST’s continued partnership with DTU in the field of biotechnology will lead to significant contributions in the global efforts to respond to climate change and promote green growth.
DTU CPO and CSO Dina Petronovic Nielson, who heads DTU Biosustain, also lauded Professor Lee saying, “It is not only a great honor for Professor Lee to be induced at DTU but also great honor for DTU to have him.”
Professor Lee also gave commemorative lectures at DTU Biosustain in Lingby and the Bio Innovation Research Institute at the Novo Nordisk Foundation in Copenhagen while in Denmark.
DTU, one of the leading science and technology universities in Europe, has been awarding honorary doctorates since 1921, including to Nobel laureate in chemistry Professor Frances Arnold at Caltech. Professor Lee is the first Korean to receive an honorary doctorate from DTU.
2022.05.03 View 10090 -
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 View 9864 -
Baemin CEO Endows a Scholarship in Honor of the Late Professor Chwa
CEO Beom-Jun Kim of Woowa Brothers also known as ‘Baemin,’ a leading meal delivery app company, made a donation of 100 million KRW in honor of the late Professor Kyong-Yong Chwa from the School of Computing who passed away last year. The fund will be established for the “Kyong-Yong Chwa - Beom-Jun Kim Scholarship” to provide scholarships for four students over five years.
Kim finished his BS in 1997 and MS in 1999 at the School of Computing and Professor Chwa was his advisor. The late Professor Chwa was a pioneering scholar who brought the concept of computer algorithms to Korea. After graduating from Seoul National University in electric engineering, Professor Chwa earned his PhD at Northwestern University and began teaching at KAIST in 1980. Professor Chwa served as the President of the Korean Institute of Information Scientists and Engineers and a fellow emeritus at the Korean Academy of Science and Technology.
Professor Chwa encouraged younger students to participate in international computer programming contests. Under his wing, Team Korea, which was comprised of four high school students, including Kim, placed fourth in the International Olympiad Informatics (IOI). Kim, who participated in the contest as high school junior, won an individual gold medal in the fourth IOI competition in 1992. Since then, Korean students have actively participated in many competitions including the International Collegiate Programming Contest (ICPC) hosted by the Association for Computing Machinery.
Kim said, “I feel fortunate to have met so many good friends and distinguished professors. With them, I had opportunities to grow. I would like to provide such opportunities to my juniors at KAIST. Professor Chwa was a larger than life figure in the field of computer programming. He was always caring and supported us with a warm heart. I want this donation to help carry on his legacy for our students and for them to seek greater challenges and bigger dreams.”
2022.03.25 View 8065 -
KAA Recognizes 4 Distinguished Alumni of the Year
The KAIST Alumni Association (KAA) recognized four distinguished alumni of the year during a ceremony on February 25 in Seoul. The four Distinguished Alumni Awardees are Distinguished Professor Sukbok Chang from the KAIST Department of Chemistry, Hyunshil Ahn, head of the AI Economy Institute and an editorial writer at The Korea Economic Daily, CEO Hwan-ho Sung of PSTech, and President Hark Kyu Park of Samsung Electronics.
Distinguished Professor Sukbok Chang who received his MS from the Department of Chemistry in 1985 has been a pioneer in the novel field of ‘carbon-hydrogen bond activation reactions’. He has significantly contributed to raising Korea’s international reputation in natural sciences and received the Kyungam Academic Award in 2013, the 14th Korea Science Award in 2015, the 1st Science and Technology Prize of Korea Toray in 2018, and the Best Scientist/Engineer Award Korea in 2019. Furthermore, he was named as a Highly Cited Researcher who ranked in the top 1% of citations by field and publication year in the Web of Science citation index for seven consecutive years from 2015 to 2021, demonstrating his leadership as a global scholar.
Hyunshil Ahn, a graduate of the School of Business and Technology Management with an MS in 1985 and a PhD in 1987, was appointed as the first head of the AI Economy Institute when The Korea Economic Daily was the first Korean media outlet to establish an AI economy lab. He has contributed to creating new roles for the press and media in the 4th industrial revolution, and added to the popularization of AI technology through regulation reform and consulting on industrial policies.
PSTech CEO Hwan-ho Sung is a graduate of the School of Electrical Engineering where he received an MS in 1988 and a PhD in EMBA in 2008. He has run the electronics company PSTech for over 20 years and successfully localized the production of power equipment, which previously depended on foreign technology. His development of the world’s first power equipment that can be applied to new industries including semiconductors and displays was recognized through this award.
Samsung Electronics President Hark Kyu Park graduated from the School of Business and Technology Management with an MS in 1986. He not only enhanced Korea’s national competitiveness by expanding the semiconductor industry, but also established contract-based semiconductor departments at Korean universities including KAIST, Sungkyunkwan University, Yonsei University, and Postech, and semiconductor track courses at KAIST, Sogang University, Seoul National University, and Postech to nurture professional talents. He also led the national semiconductor coexistence system by leading private sector-government-academia collaborations to strengthen competence in semiconductors, and continues to make unconditional investments in strong small businesses.
KAA President Chilhee Chung said, “Thanks to our alumni contributing at the highest levels of our society, the name of our alma mater shines brighter. As role models for our younger alumni, I hope greater honours will follow our awardees in the future.”
2022.03.03 View 7727 -
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 9625 -
Thermal Superconductor Lab Becomes the 7th Cross-Generation Collaborative Lab
The Thermal Superconductor Lab led by Senior Professor Sung Jin Kim from the Department of Mechanical Engineering will team up with Junior Professor Youngsuk Nam to develop next-generation superconductors. The two professor team was selected as the 7th Cross-Generation Collaborative Lab last week and will sustain the academic legacy of Professor Kim’s three decades of research on superconductors. The team will continue to develop thin, next-generation superconductors that carry super thermal conductivity using phase transition control technology and thin film packaging.
Thin-filmed, next-generation superconductors can be used in various high-temperature flexible electronic devices. The superconductors built inside of the semiconductor device packages will also be used for managing the low-powered but high-performance temperatures of semiconductor and electronic equipment.
Professor Kim said, “I am very pleased that my research, know-how, and knowledge from over 30 years of work will continue through the Cross-Generation Collaborative Lab system with Professor Nam. We will spare no effort to advance superconductor technology and play a part in KAIST leading global technology fields.” Junior Professor Nam also stressed that the team is excited to continue its research on crucial technology for managing the temperatures of semiconductors and other electronic equipment.
KAIST started this innovative research system in 2018, and in 2021 it established the steering committee to select new labs based on: originality, differentiation, and excellence; academic, social, economic impact; the urgency of cross-generation research; the senior professor’s academic excellence and international reputation; and the senior professor’s research vision. Selected labs receive 500 million KRW in research funding over five years.
2022.01.27 View 6261 -
AI Weather Forecasting Research Center Opens
The Kim Jaechul Graduate School of AI in collaboration with the National Institute of Meteorological Sciences (NIMS) under the National Meteorological Administration launched the AI Weather Forecasting Research Center last month.
The KAIST AI Weather Forecasting Research Center headed by Professor Seyoung Yoon was established with funding from from the AlphaWeather Development Research Project of the National Institute of Meteorological Sciences. KAIST was finally selected asas the project facilitator.
AlphaWeather is an AI system that utilizes and analyzes approximately approximately 150,000 ,000 pieces of weather information per hour to help weather forecasters produce accurate weather forecasts. The research center is composed of three research teams with the following goals: (a) developdevelop AI technology for precipitation nowcasting, (b) developdevelop AI technology for accelerating physical process-based numerical models, and (c) develop dAI technology for supporting weather forecasters. The teams consist of 15 staff member members from NIMS and 61 researchers from the Kim Jaechul Graduate School of AI at KAIST.
The research center is developing an AI algorithm for precipitation nowcasting (with up to six hours of lead time), which uses satellite images, radar reflectivity, and data collected from weather stations. It is also developing an AI algorithm for correcting biases in the prediction results from multiple numerical models. Finally, it is Finally, it is developing AI technology that supports weather forecasters by standardizing and automating repetitive manual processes. After verification, the the results obtained will be used by by the Korean National Weather Service as a next-generation forecasting/special-reporting system intelligence engine from 2026.
2022.01.10 View 6218 -
Connecting the Dots to Find New Treatments for Breast Cancer
Systems biologists uncovered new ways of cancer cell reprogramming to treat drug-resistant cancers
Scientists at KAIST believe they may have found a way to reverse an aggressive, treatment-resistant type of breast cancer into a less dangerous kind that responds well to treatment. The study involved the use of mathematical models to untangle the complex genetic and molecular interactions that occur in the two types of breast cancer, but could be extended to find ways for treating many others. The study’s findings were published in the journal Cancer Research.
Basal-like tumours are the most aggressive type of breast cancer, with the worst prognosis. Chemotherapy is the only available treatment option, but patients experience high recurrence rates. On the other hand, luminal-A breast cancer responds well to drugs that specifically target a receptor on their cell surfaces, called estrogen receptor alpha (ERα).
KAIST systems biologist Kwang-Hyun Cho and colleagues analyzed the complex molecular and genetic interactions of basal-like and luminal-A breast cancers to find out if there might be a way to switch the former to the latter and give patients a better chance to respond to treatment.
To do this, they accessed large amounts of cancer and patient data to understand which genes and molecules are involved in the two types. They then input this data into a mathematical model that represents genes, proteins and molecules as dots and the interactions between them as lines. The model can be used to conduct simulations and see how interactions change when certain genes are turned on or off.
“There have been a tremendous number of studies trying to find therapeutic targets for treating basal-like breast cancer patients,” says Cho. “But clinical trials have failed due to the complex and dynamic nature of cancer. To overcome this issue, we looked at breast cancer cells as a complex network system and implemented a systems biological approach to unravel the underlying mechanisms that would allow us to reprogram basal-like into luminal-A breast cancer cells.”
Using this approach, followed by experimental validation on real breast cancer cells, the team found that turning off two key gene regulators, called BCL11A and HDAC1/2, switched a basal-like cancer signalling pathway into a different one used by luminal-A cancer cells. The switch reprograms the cancer cells and makes them more responsive to drugs that target ERα receptors. However, further tests will be needed to confirm that this also works in animal models and eventually humans.
“Our study demonstrates that the systems biological approach can be useful for identifying novel therapeutic targets,” says Cho.
The researchers are now expanding its breast cancer network model to include all breast cancer subtypes. Their ultimate aim is to identify more drug targets and to understand the mechanisms that could drive drug-resistant cells to turn into drug-sensitive ones.
This work was supported by the National Research Foundation of Korea, the Ministry of Science and ICT, Electronics and Telecommunications Research Institute, and the KAIST Grand Challenge 30 Project.
-Publication Sea R. Choi, Chae Young Hwang, Jonghoon Lee, and Kwang-Hyun Cho, “Network Analysis Identifies Regulators of Basal-like Breast Cancer Reprogramming and Endocrine TherapyVulnerability,” Cancer Research, November 30. (doi:10.1158/0008-5472.CAN-21-0621)
-ProfileProfessor Kwang-Hyun ChoLaboratory for Systems Biology and Bio-Inspired EngineeringDepartment of Bio and Brain EngineeringKAIST
2021.12.07 View 10538 -
Renault 5 EV and Canoo’s Pickup Truck Win the 2021 FMOTY Awards
KAIST Future Mobility of the Year Awards recognize the most innovative concept cars of the year
The Renault 5 EV from France and a pickup truck from the US startup Canoo won the 2021 Future Mobility of the Year Awards (FMOTY) hosted by the Cho Chun Shik Graduate School of Green Transportation at KAIST. The awards ceremony was held at Renault Samsung Motors in Seoul on November 25.
KAIST began the FMOTY in 2019 to advance future car technology and stimulate growth in the industry. The award recognizes the most innovative ideas for making the most futuristic concept car and improving the technological and social value of the industry.
The awards ceremony was attended by KAIST President Kwang Hyung Lee, the dean of the Cho Chun Shik Graduate School of Green Transportation In Gwun Jang, CEO of Renault Samsung Motors Dominique Signora, and CEO of Canoo Tony Aquila. President Lee said, “The new world order will be impacted by new technology developers who envision the future. Their innovation and creative ideas will open a new world of sustainable future transportation.”
Out of the 46 concept cars revealed at global motor exhibitions between last year and the first quarter of this year, models demonstrating transport technology useful for future society and innovative service were selected in the categories of passenger cars and commercial vehicles.
Sixteen automotive journalists from 11 countries, including the chief editor of Car Magazine in Germany Georg Kacher and editorial director of BBC Top Gear Charlie Turner, participated as judges.
This year’s award for the best concept car for a passenger vehicle went to an electric vehicle, the Renault 5 EV. The compact electric car was highly regarded for its practicality and environmental friendliness. A pickup truck by Canoo, an American EV manufacturing start-up, won the award in the commercial vehicle category. The pickup features an innovative design allowing for a variety of functions topped with a competitive price and it received overwhelming support from the judges.
While Hyundai Motors swept both prizes at the awards last year and demonstrated the potential of Korean concept cars, Canoo’s win in the commercial vehicle section as a young American venture company brought attention to the changing dynamics in the automotive market. This shows that young EV start-ups can compete with existing car companies as the automotive paradigm is shifting from those with internal combustion engines to EVs.
The awards organizers said that the Cho Chun Shik Graduate School of Green Transportation will continue to hold the FMOTY to lead the fast-changing global mobility market. For more information, please visit www.fmoty.org.
2021.11.26 View 7432