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KAIST to Collaborate with AT&C to Take Dominance over Dementia < Photo 1. (From left) KAIST Dean of the College of Natural Sciences Daesoo Kim, KAIST President Kwang Hyung Lee, AT&C Chairman Ki Tae Lee, AT&C CEO Jong-won Lee > KAIST (President Kwang Hyung Lee) announced on January 9th that it signed a memorandum of understanding for a comprehensive mutual cooperation with AT&C (CEO Jong-won Lee) at its Seoul Dogok Campus to expand research investment and industry-academia cooperation in preparation for the future cutting-edge digital bio era. Senile dementia is a rapidly increasing brain disease that affects 10% of the elderly population aged 65 and older, and approximately 38% of those aged 85 and older suffer from dementia. Alzheimer's disease is the most common dementia in the elderly and its prevalence has been increasing rapidly in the population of over 40 years of age. However, an effective treatment is yet to be found. The Korean government is investing a total of KRW 1.1 trillion in dementia R&D projects from 2020 to 2029, with the goal of reducing the rate of increase of dementia patients by 50%. Since it takes a lot of time and money to develop effective and affordable medicinal dementia treatments, it is urgent to work on the development of digital treatments for dementia that can be applied more quickly. AT&C, a digital healthcare company, has already received approval from the Ministry of Food and Drug Safety (MFDS) for its device for antidepressant treatment based on transcranial magnetic stimulation (TMS) using magnetic fields and is selling it domestically and internationally. In addition, it has developed the first Alzheimer's dementia treatment device in Korea and received MFDS approval for clinical trials. After passing phase 1 to evaluate safety and phase 2 to test efficacy on some patients, it is currently conducting phase 3 clinical trials to test efficacy on a larger group of patients. This dementia treatment device is equipped with a system that combines non-invasive electronic stimulations (TMS electromagnetic stimulator) and digital therapeutic prescription (cognitive learning programs) to provide precise, automated treatment by applying AI image analysis and robotics technology. Through this agreement, KAIST and AT&C have agreed to cooperate with each other in the development of innovative digital treatment equipment for brain diseases. Through research collaboration with KAIST, AT&C will be able to develop technology that can be widely applied to Parkinson's disease, stroke, mild cognitive impairment, sleep disorders, etc., and will develop portable equipment that can improve brain function and prevent dementia at home by utilizing KAIST's wearable technology. To this end, AT&C plans to establish a digital healthcare research center at KAIST by supporting research personnel and research expenses worth approximately 3 billion won with the goal of developing cutting-edge digital equipment within 3 years. The digital equipment market is expected to grow at a compounded annual growth rate of 22.1% from 2023 to 2033, reaching a market size of $1.9209 trillion by 2033. < Photo 2. (From left) Dean of the KAIST College of Natural Sciences Daesoo Kim, Professor Young-joon Lee, Professor Minee Choi of the KAIST Department of Brain and Cognitive Sciences, KAIST President Kwang Hyung Lee, Chairman Ki Tae Lee, CEO Jong-won Lee, and Headquarters Director Ki-yong Na of AT&C > CEO Jong-won Lee said, “AT&C is playing a leading role in the treatment of Alzheimer’s disease using TMS (transcranial magnetic stimulation) technology. Through this agreement with KAIST, we will do our best to create a new paradigm for brain disease treatment and become a platform company that can lead future medical devices and medical technology.” Former Samsung Electronics Vice Chairman Ki Tae Lee, a strong supporter of this R&D project, said, “Through this agreement with KAIST, we plan to prepare for a new future by combining the technologies AT&C has developed so far with KAIST’s innovative and differentiated technologies.” KAIST President Kwang Hyung Lee emphasized, “Through this collaboration, KAIST expects to build a world-class digital therapeutics infrastructure for treating brain diseases and contribute greatly to further strengthening Korea’s competitiveness in the biomedical field.” The signing ceremony was attended by KAIST President Kwang Hyung Lee, the Dean of KAIST College of Natural Sciences Daesoo Kim, AT&C CEO Lee Jong-won, and the current Chairman of AT&C, Ki Tae Lee, former Vice Chairman of Samsung Electronics.
2025.01.09 View 10012
Mystery Solved with Math: Cytoplasmic Traffic Jam Disrupts Sleep-Wake Cycles KAIST mathematicians and their collaborators at Florida State University have identified the principle of how aging and diseases like dementia and obesity cause sleep disorders. A combination of mathematical modelling and experiments demonstrated that the cytoplasmic congestion caused by aging, dementia, and/or obesity disrupts the circadian rhythms in the human body and leads to irregular sleep-wake cycles. This finding suggests new treatment strategies for addressing unstable sleep-wake cycles. Human bodies adjust sleep schedules in accordance with the ‘circadian rhythms’, which are regulated by our time keeping system, the ‘circadian clock’. This clock tells our body when to rest by generating the 24-hour rhythms of a protein called PERIOD (PER) (See Figure 1). The amount of the PER protein increases for half of the day and then decreases for the remaining half. The principle is that the PER protein accumulating in the cytoplasm for several hours enters the cell nucleus all at once, hindering the transcription of PER genes and thereby reducing the amount of PER. However, it has remained a mystery how thousands of PER molecules can simultaneously enter into the nucleus in a complex cell environment where a variety of materials co-exist and can interfere with the motion of PER. This would be like finding a way for thousands of employees from all over New York City to enter an office building at the same time every day. A group of researchers led by Professor Jae Kyoung Kim from the KAIST Department of Mathematical Sciences solved the mystery by developing a spatiotemporal and probabilistic model that describes the motion of PER molecules in a cell environment. This study was conducted in collaboration with Professor Choogon Lee’s group from Florida State University, where the experiments were carried out, and the results were published in the Proceedings of the National Academy of Sciences (PNAS) last month. The joint research team’s spatial stochastic model (See Figure 2) described the motion of PER molecules in cells and demonstrated that the PER molecule should be sufficiently condensed around the cell nucleus to be phosphorylated simultaneously and enter the nucleus together (See Figure 3 Left). Thanks to this phosphorylation synchronization switch, thousands of PER molecules can enter the nucleus at the same time every day and maintain stable circadian rhythms. However, when aging and/or diseases including dementia and obesity cause the cytoplasm to become congested with increased cytoplasmic obstacles such as protein aggregates and fat vacuoles, it hinders the timely condensation of PER molecules around the cell nucleus (See Figure 3 Right). As a result, the phosphorylation synchronization switch does not work and PER proteins enter into the nucleus at irregular times, making the circadian rhythms and sleep-wake cycles unstable, the study revealed. Professor Kim said, “As a mathematician, I am excited to help enable the advancement of new treatment strategies that can improve the lives of so many patients who suffer from irregular sleep-wake cycles. Taking these findings as an opportunity, I hope to see more active interchanges of ideas and collaboration between mathematical and biological sciences.” This work was supported by the National Institutes of Health and the National Science Foundation in the US, and the International Human Frontiers Science Program Organization and the National Research Foundation of Korea. Publication: Beesley, S. and Kim, D. W, et al. (2020) Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis. Proceedings of the National Academy of Sciences (PNAS), Vol. 117, No. 45, 28402-28411. Available online at https://doi.org/10.1073/pnas.2003524117 Profile: Jae Kyoung Kim, Ph.D. Associate Professor jaekkim@kaist.ac.kr http://mathsci.kaist.ac.kr/~jaekkim @umichkim on Twitter Department of Mathematical Sciences Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Republic of Korea Profile: Choogon Lee, Ph.D. Associate Professor clee@neuro.fsu.edu https://med.fsu.edu/biosci/lee-lab Department of Biomedical Sciences Florida State University Florida, USA (END)
2020.12.11 View 16090
Mathematical Modeling Makes a Breakthrough for a New CRSD Medication PhD Candidate Dae Wook Kim (Left) and Professor Jae Kyoung Kim (Right) - Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy - Mathematicians’ new modeling has identified major sources of interspecies and inter-individual variations in the clinical efficacy of a clock-modulating drug: photosensitivity and PER2 level. This enabled precision medicine for circadian disruption. A KAIST mathematics research team led by Professor Jae Kyoung Kim, in collaboration with Pfizer, applied a combination of mathematical modeling and simulation tools for circadian rhythms sleep disorders (CRSDs) to analyze the animal data generated by Pfizer. This study was reported in Molecular Systems Biology as the cover article on July 8. Pharmaceutical companies have conducted extensive studies on animals to determine the candidacy of this new medication. However, the results of animal testing do not always translate to the same effects in human trials. Furthermore, even between humans, efficacy differs across individuals depending on an individual’s genetic and environmental factors, which require different treatment strategies. To overcome these obstacles, KAIST mathematicians and their collaborators developed adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions. A circadian rhythm is a 24-hour cycle in the physiological processes of living creatures, including humans. A biological clock in the hypothalamic suprachiasmatic nucleus in the human brain sets the time for various human behaviors such as sleep. A disruption of the endogenous timekeeping system caused by changes in one’s life pattern leads to advanced or delayed sleep-wake cycle phase and a desynchronization between sleep-wake rhythms, resulting in CRSDs. To restore the normal timing of sleep, timing of the circadian clock could be adjusted pharmacologically. Pfizer identified PF-670462, which can adjust the timing of circadian clock by inhibiting the core clock kinase of the circadian clock (CK1d/e). However, the efficacy of PF-670462 significantly differs between nocturnal mice and diurnal monkeys, whose sleeping times are opposite. The research team discovered the source of such interspecies variations in drug response by performing thousands of virtual experiments using a mathematical model, which describes biochemical interactions among clock molecules and PF-670462. The result suggests that the effect of PF-670462 is reduced by light exposure in diurnal primates more than in nocturnal mice. This indicates that the strong counteracting effect of light must be considered in order to effectively regulate the circadian clock of diurnal humans using PF-670462. Furthermore, the team also found the source of inter-patients variations in drug efficacy using virtual patients whose circadian clocks were disrupted due to various mutations. The degree of perturbation in the endogenous level of the core clock molecule PER2 affects the efficacy. This explains why the clinical outcomes of clock-modulating drugs are highly variable and certain subtypes are unresponsive to treatment. Furthermore, this points out the limitations of current treatment strategies tailored to only the patient’s sleep and wake time but not to the molecular cause of sleep disorders. PhD candidate Dae Wook Kim, who is the first author, said that this motivates the team to develop an adaptive chronotherapy, which identifies a personalized optimal dosing time of day by tracking the sleep-wake up time of patients via a wearable device and allows for a precision medicine approach for CRSDs. Professor Jae Kyoung Kim said, "As a mathematician, I am excited to help enable the advancement of a new drug candidate, which can improve the lives of so many patients. I hope this result promotes more collaborations in this translational research.” This research was supported by a Pfizer grant to KAIST (G01160179), the Human Frontiers Science Program Organization (RGY0063/2017), and a National Research Foundation (NRF) of Korea Grant (NRF-2016 RICIB 3008468 and NRF-2017-Fostering Core Leaders of the Future Basic Science Program/ Global Ph.D. Fellowship Program). Figure 1. Interspecies and Inter-patients Variations in PF-670462 Efficacy Figure 2. Journal Cover Page Publication: Dae Wook Kim, Cheng Chang, Xian Chen, Angela C Doran, Francois Gaudreault, Travis Wager, George J DeMarco, and Jae Kyoung Kim. 2019. Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy. Molecular Systems Biology. EMBO Press, Heidelberg, Germany, Vol. 15, Issue No. 7, Article, 16 pages. https://doi.org/10.15252/msb.20198838 Profile: Prof. Jae Kyoung Kim, PhD jaekkim@kaist.ac.kr http://mathsci.kaist.ac.kr/~jaekkim Associate Professor Department of Mathematical Sciences Korea Advanced Institute of Science and Technology (KAIST) http://kaist.ac.kr Daejeon 34141, Korea Profile: Dae Wook Kim, PhD Candidate 0308kdo@kaist.ac.kr http://mathsci.kaist.ac.kr/~jaekkim PhD Candidate Department of Mathematical Sciences Korea Advanced Institute of Science and Technology (KAIST) http://kaist.ac.kr Daejeon 34141, Korea Profile: Dr. Cheng Chang, PhD cheng.chang@pfizer.com Associate Director of Clinical Pharmacology Clinical Pharmacology, Global Product Development Pfizer https://www.pfizer.com/ Groton 06340, USA (END)
2019.07.09 View 41599