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Afternoon chemotherapy proved to deliver more desirable results for female lymphoma patients
Chemotherapy is a commonly used regimen for cancer treatment, but it is also a double-edged sword. While the drugs are highly effective at killing cancer cells, they are also notorious for killing healthy cells in the body. As such, minimizing the drug’s damage to the patient’s body is necessary for improving the prognosis of chemotherapy. Recently, “chrono-chemotherapy” have been gaining interest in the research community. As the name suggests, the aim is timing the delivery of the drugs when the body is least vulnerable to their harmful effects and while the cancer cells are at their most vulnerable. < Figure 1. Chrono-chemotherapy considering circadian rhythm > Chrono-chemotherapy exploits the fact that human physiological processes, including cell proliferation and differentiation, are regulated by an endogenous timer called the circadian clock. However, this has not been widely exploited in real-world clinical settings because, as of now, there is no systematic method for finding the optimal chemotherapy delivery time. This problem was tackled by an interdisciplinary team of researchers from South Korea. They were led by principal investigators Jae Kyoung Kim (a mathematician from the Biomedical Mathematics Group, Institute for Basic Science) and Youngil Koh (an oncologist at Seoul National University Hospital). The researchers studied a group of patients suffering from diffuse large B-cell lymphoma (DLBCL). Terminology * Diffuse large B-cell lymphoma (DLBCL): Lymphoma is a type of blood cancer caused by the malignant transformation of lymphoid tissue cells. Lymphoma is divided into Hodgkin's lymphoma and non-Hodgkin's lymphoma (malignant lymphoma), and diffuse large B-cell lymphoma accounts for about 30 to 40% of non-Hodgkin's lymphoma. The research team noticed that DLBCL patients at Seoul National University Hospital received chemotherapy on two different schedules, with some patients receiving morning treatment (8:30 a.m.) and others taking the drugs in the afternoon (2:30 p.m.). All patients received the same cancer treatment (R-CHOP), which is a combination of targeted therapy and chemotherapy, four to six times in the morning or afternoon at intervals of about three weeks. They analyzed 210 patients to investigate whether there was any difference between morning and afternoon treatments. It was found that female patients who received the afternoon treatment had a 12.5 times reduced mortality rate (25% to 2%), while the cancer recurrence after 60 months decreased by 2.8 times (37% to 13%). In addition, chemotherapy side effects such as neutropenia were more common in female patients who received the morning treatment. Surprisingly, there was no differences found in treatment efficiency depending on the treatment schedule in the cases of male patients. To understand the cause of the gender differences, the research team analyzed upto 14,000 blood samples from the Seoul National University Hospital Health Examination Center. It was found that in females, white blood cell counts tended to decrease in the morning and increase in the afternoon. This indicates that the bone marrow proliferation rate was higher in the morning than in the afternoon because there is a upto 12 hour delay between bone marrow proliferation and blood cell production. This means that if a female patient receives chemotherapy in the morning when bone marrow is actively producing blood cells, the possibility of adverse side effects becomes greater. These results are consistent with the findings from recent randomized clinical trials that showed female colorectal cancer patients treated with irinotecan in the morning suffered from higher drug toxicities. One confounding variable was the drug dose. Since the morning female patients suffered from greater adverse side effects, oftentimes the dose had to be reduced for these patients. On average, the drug dose was reduced by upto 10% compared to the dose intensity given to female patients receiving the afternoon treatment. Unlike the female patients, it was found that male patients did not show a significant difference in white blood cell count and bone marrow cell proliferation activity throughout the day, which explains why the timing of the treatment had no impact. Professor Youngil Koh said, “We plan to verify the conclusions of this study again with a large-scale follow-up study that completely controls for the confounding variables, and to confirm whether chrono-chemotherapy has similar effects on other cancers.” CI Jae Kyoung Kim said, “Because the time of the internal circadian clock can vary greatly depending on the individual's sleep-wake patterns, we are currently developing a technology to estimate a patient’s circadian clock from their sleep pattern. We hope that this can be used to develop an individualized anti-cancer chronotherapy schedule.” < Figure 2. Chemotherapy in the afternoon can improve treatment outcomes. > The daily fluctuation of proliferative activity of bone marrow is larger in females than in males, and it becomes higher in the morning (left). Thus, chemotherapy in the morning strongly inhibits proliferative activity in female lymphoma patients, resulting in a higher incidence of adverse events such as neutropenia and infections. This forced the clinicians to reduce the dose intensity (center). Consequently, female patients undergoing the morning treatment showed a lower survival probability than those undergoing the afternoon treatment (right). Specifically, only ~13% of female patients treated in the afternoon had a worse outcome and ~2% of them died while ~37% of female patients treated in the morning had a worse outcome and ~25% of them died. Male patients did not show any difference in treatment outcomes depending on the chemotherapy delivery time.
Scientists re-writes FDA-recommended equation to improve estimation of drug-drug interaction
Drugs absorbed into the body are metabolized and thus removed by enzymes from several organs like the liver. How fast a drug is cleared out of the system can be affected by other drugs that are taken together because added substance can increase the amount of enzyme secretion in the body. This dramatically decreases the concentration of a drug, reducing its efficacy, often leading to the failure of having any effect at all. Therefore, accurately predicting the clearance rate in the presence of drug-drug interaction* is critical in the process of drug prescription and development of a new drug in order to ensure its efficacy and/or to avoid unwanted side-effects. *Drug-drug interaction: In terms of metabolism, drug-drug interaction is a phenomenon in which one drug changes the metabolism of another drug to promote or inhibit its excretion from the body when two or more drugs are taken together. As a result, it increases the toxicity of medicines or causes loss of efficacy. Since it is practically impossible to evaluate all interactions between new drug candidates and all marketed drugs during the development process, the FDA recommends indirect evaluation of drug interactions using a formula suggested in their guidance, first published in 1997, revised in January of 2020, in order to evaluate drug interactions and minimize side effects of having to use more than one type of drugs at once. The formula relies on the 110-year-old Michaelis-Menten (MM) model, which has a fundamental limit of making a very broad and groundless assumption on the part of the presence of the enzymes that metabolizes the drug. While MM equation has been one of the most widely known equations in biochemistry used in more than 220,000 published papers, the MM equation is accurate only when the concentration of the enzyme that metabolizes the drug is almost non-existent, causing the accuracy of the equation highly unsatisfactory – only 38 percent of the predictions had less than two-fold errors. “To make up for the gap, researcher resorted to plugging in scientifically unjustified constants into the equation,” Professor Jung-woo Chae of Chungnam National University College of Pharmacy said. “This is comparable to having to have the epicyclic orbits introduced to explain the motion of the planets back in the days in order to explain the now-defunct Ptolemaic theory, because it was 'THE' theory back then.” < (From left) Ph.D. student Yun Min Song (KAIST, co-first authors), Professor Sang Kyum Kim (Chungnam National University, co-corresponding author), Jae Kyoung Kim, CI (KAIST, co-corresponding author), Professor Jung-woo Chae (Chungnam National University, co-corresponding author), Ph.D. students Quyen Thi Tran and Ngoc-Anh Thi Vu (Chungnam National University, co-first authors) > A joint research team composed of mathematicians from the Biomedical Mathematics Group within the Institute for Basic Science (IBS) and the Korea Advanced Institute of Science and Technology (KAIST) and pharmacological scientists from the Chungnam National University reported that they identified the major causes of the FDA-recommended equation’s inaccuracies and presented a solution. When estimating the gut bioavailability (Fg), which is the key parameter of the equation, the fraction absorbed from the gut lumen (Fa) is usually assumed to be 1. However, many experiments have shown that Fa is less than 1, obviously since it can’t be expected that all of the orally taken drugs to be completely absorbed by the intestines. To solve this problem, the research team used an “estimated Fa” value based on factors such as the drug’s transit time, intestine radius, and permeability values and used it to re-calculate Fg. Also, taking a different approach from the MM equation, the team used an alternative model they derived in a previous study back in 2020, which can more accurately predict the drug metabolism rate regardless of the enzyme concentration. Combining these changes, the modified equation with re-calculated Fg had a dramatically increased accuracy of the resulting estimate. The existing FDA formula predicted drug interactions within a 2-fold margin of error at the rate of 38%, whereas the accuracy rate of the revised formula reached 80%. “Such drastic improvement in drug-drug interaction prediction accuracy is expected to make great contribution to increasing the success rate of new drug development and drug efficacy in clinical trials. As the results of this study were published in one of the top clinical pharmacology journal, it is expected that the FDA guidance will be revised according to the results of this study.” said Professor Sang Kyum Kim from Chungnam National University College of Pharmacy. Furthermore, this study highlights the importance of collaborative research between research groups in vastly different disciplines, in a field that is as dynamic as drug interactions. “Thanks to the collaborative research between mathematics and pharmacy, we were able to recify the formula that we have accepted to be the right answer for so long to finally grasp on the leads toward healthier life for mankind.,” said Professor Jae Kyung Kim. He continued, “I hope seeing a ‘K-formula’ entered into the US FDA guidance one day.” The results of this study were published in the online edition of Clinical Pharmacology and Therapeutics (IF 7.051), an authoritative journal in the field of clinical pharmacology, on December 15, 2022 (Korean time). Thesis Title: Beyond the Michaelis-Menten: Accurate Prediction of Drug Interactions through Cytochrome P450 3A4 Induction (doi: 10.1002/cpt.2824) < Figure 1. The formula proposed by the FDA guidance for predicting drug-drug interactions (top) and the formula newly derived by the researchers (bottom). AUCR (the ratio of substrate area under the plasma concentration-time curve) represents the rate of change in drug concentration due to drug interactions. The research team more than doubled the accuracy of drug interaction prediction compared to the existing formula. > < Figure 2. Existing FDA formulas tend to underestimate the extent of drug-drug interactions (gray dots) than the actual measured values. On the other hand, the newly derived equation (red dot) has a prediction rate that is within the error range of 2 times (0.5 to 2 times) of the measured value, and is more than twice as high as the existing equation. The solid line in the figure represents the predicted value that matches the measured value. The dotted line represents the predicted value with an error of 0.5 to 2 times. > For further information or to request media assistance, please contact Jae Kyoung Kim at Biomedical Mathematics Group, Institute for Basic Science (IBS) (email@example.com) or William I. Suh at the IBS Communications Team (firstname.lastname@example.org). - About the Institute for Basic Science (IBS) IBS was founded in 2011 by the government of the Republic of Korea with the sole purpose of driving forward the development of basic science in South Korea. IBS has 4 research institutes and 33 research centers as of January 2023. There are eleven physics, three mathematics, five chemistry, nine life science, two earth science, and three interdisciplinary research centers.
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 email@example.com@umichkim on TwitterDepartment of Mathematical SciencesKAIST
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
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
Professor Jae Kyoung Kim to Lead a New Mathematical Biology Research Group at IBS
Professor Jae Kyoung Kim from the KAIST Department of Mathematical Sciences was appointed as the third Chief Investigator (CI) of the Pioneer Research Center (PRC) for Mathematical and Computational Sciences at the Institute for Basic Science (IBS). Professor Kim will launch and lead a new research group that will be devoted to resolving various biological conundrums from a mathematical perspective. His appointment began on March 1, 2021. Professor Kim, a rising researcher in the field of mathematical biology, has received attention from both the mathematical and biological communities at the international level. Professor Kim puts novel and unremitting efforts into understanding biological systems such as cell-to-cell interactions mathematically and designing mathematical models for identifying causes of diseases and developing therapeutic medicines. Through active joint research with biologists, mathematician Kim has addressed many challenges that have remained unsolved in biology and published papers in a number of leading international journals in related fields. His notable works based on mathematical modelling include having designed a biological circuit that can maintain a stable circadian rhythm (Science, 2015) and unveiling the principles of how the biological clock in the body maintains a steady speed for the first time in over 60 years (Molecular Cell, 2015). Recently, through a joint research project with Pfizer, Professor Kim identified what causes the differences between animal and clinical test results during drug development explaining why drugs have different efficacies in different people (Molecular Systems Biology, 2019). The new IBS biomedical mathematics research group led by Professor Kim will further investigate the causes of unstable circadian rhythms and sleeping patterns. The team will aim to present a new paradigm in treatments for sleep disorders. Professor Kim said, “We are all so familiar with sleep behaviors, but the exact mechanisms behind how such behaviors occur are still unknown. Through cooperation with biomedical scientists, our group will do its best to discover the complicated, fundamental mechanisms of sleep, and investigate the causes and cures of sleep disorders.” Every year, the IBS selects young and promising researchers and appoints them as CIs. A maximum of five selected CIs can form each independent research group within the IBS PRC, and receive research funds of 1 billion to 1.5 billion KRW over five years. (END)
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 firstname.lastname@example.org 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 email@example.com https://med.fsu.edu/biosci/lee-lab Department of Biomedical Sciences Florida State University Florida, USA (END)
A Mathematical Model Reveals Long-Distance Cell Communication Mechanism
How can tens of thousands of people in a large football stadium all clap together with the same beat even though they can only hear the people near them clapping? A combination of a partial differential equation and a synthetic circuit in microbes answers this question. An interdisciplinary collaborative team of Professor Jae Kyoung Kim at KAIST, Professor Krešimir Josić at the University of Houston, and Professor Matt Bennett at Rice University has identified how a large community can communicate with each other almost simultaneously even with very short distance signaling. The research was reported at Nature Chemical Biology. Cells often communicate using signaling molecules, which can travel only a short distance. Nevertheless, the cells can also communicate over large distances to spur collective action. The team revealed a cell communication mechanism that quickly forms a network of local interactions to spur collective action, even in large communities. The research team used an engineered transcriptional circuit of combined positive and negative feedback loops in E. coli, which can periodically release two types of signaling molecules: activator and repressor. As the signaling molecules travel over a short distance, cells can only talk to their nearest neighbors. However, cell communities synchronize oscillatory gene expression in spatially extended systems as long as the transcriptional circuit contains a positive feedback loop for the activator. Professor Kim said that analyzing and understanding such high-dimensional dynamics was extremely difficult. He explained, “That’s why we used high-dimensional partial differential equation to describe the system based on the interactions among various types of molecules.” Surprisingly, the mathematical model accurately simulates the synthesis of the signaling molecules in the cell and their spatial diffusion throughout the chamber and their effect on neighboring cells. The team simplified the high-dimensional system into a one-dimensional orbit, noting that the system repeats periodically. This allowed them to discover that cells can make one voice when they lowered their own voice and listened to the others. “It turns out the positive feedback loop reduces the distance between moving points and finally makes them move all together. That’s why you clap louder when you hear applause from nearby neighbors and everyone eventually claps together at almost the same time,” said Professor Kim. Professor Kim added, “Math is a powerful as it simplifies complex thing so that we can find an essential underlying property. This finding would not have been possible without the simplification of complex systems using mathematics." The National Institutes of Health, the National Science Foundation, the Robert A. Welch Foundation, the Hamill Foundation, the National Research Foundation of Korea, and the T.J. Park Science Fellowship of POSCO supported the research. (Figure: Complex molecular interactions among microbial consortia is simplified as interactions among points on a limit cycle (right).)
Professor Baik Awarded Sangsan Young Mathematician Prize
(Professor Hyungryul Baik) Professor Hyungryul Baik from the Department of Mathematical Sciences was honored as the recipient of the 2018 Sangsan Prize for Young Mathematicians by the Korean Mathematical Society (KMS). The Sangsan Prize recognizes young mathematicians who finished their degree within the previous five years and have begun an outstanding research career. Professor Baik was recognized for his studies in the fields of low-dimensional topology, geophysical mathematics, and geometric theory. In particular, his Ph.D. dissertation presented a new criterion that completely identifies the hyperbolic surface group, making an inference about the nature of the hyperbolic manifold group. Recently, Professor Baik co-published a paper entitled Spaces of Invariant Circular Orders of Groups with Professor Eric Samperton at the University of California Santa Barbara in the renowned academic journal Groups, Geometry, and Dynamics in 2018. Professor Baik earned his BS at KAIST and finished his MS and Ph.D. in mathematics in 2014 at Cornell University. He joined KAIST as a faculty member last year.
Professor Lee Recognized by the KMS as Best Paper Awardee
Professor Ji Oon Lee of the Department of Mathematical Sciences was selected as the 2017 Best Paper Awardee by the Korean Mathematical Society. The award will be presented during the KMS spring meeting on April 29. Dr. Lee is being honored for proving a necessary and sufficient condition for the Tracy-Wisdom law of Wigner matrices. In a paper titled ‘A Necessary and Sufficient Condition for Edge Universality of Wigner Matrices,’ he proposed a solution for one of the many unanswered problems in the field of random matrix theory that have existed for decades. The paper, co-authored with Professor Jun Yin at the University of Wisconsin – Madison, was published in the Duke Mathematical Journal in 2014. Professor Lee joined KAIST in 2010 after finishing his Ph.D. at Harvard University. He was named a ‘POSCI Science Fellow’ and received the ‘Young Scientist Award’ from the KMS in 2014.
Professor Jae Kyoung Kim Receives the 2017 HSFP Award
The Human Frontier Science Program (HSFP), one of the most competitive research grants in life sciences, has funded researchers worldwide across and beyond the field since 1990. Each year, the program selects a handful of recipients who push the envelope of basic research in biology to bring breakthroughs from novel approaches. Among its 7,000 recipients thus far, 26 scientists have received the Nobel Prize. For that reason, HSFP grants are often referred to as “Nobel Prize Grants.” Professor Jae Kyoung Kim of the Mathematical Sciences Department at KAIST and his international collaborators, Professor Robert Havekes from the University of Groningen, the Netherlands, Professor Sara Aton from the University of Michigan in Ann Arbor, the United States, and Professor Matias Zurbriggen from the University of Düsseldorf, Germany, won the Young Investigator Grants of the 2017 HSFP. The 30 winning teams of the 2017 competition (in 9 Young Investigator Grants and 21 Program Grants) went through a rigorous year-long review process from a total of 1,073 applications submitted from more than 60 countries around the world. Each winning team will receive financial support averaging 110,000-125,000 USD per year for three years. Although Professor Kim was trained as a mathematician, he has extended his research focus into biological sciences and attempted to solve some of the most difficult problems in biology by employing mathematical theories and applications including nonlinear dynamics, stochastic process, singular perturbation, and parameter estimation. The project that won the Young Investigator Grants was a study on how a molecular circadian clock may affect sleep-regulated neurophysiology in mammals. Physiological and metabolic processes such as sleep, blood pressure, and hormone secretion exhibit circadian rhythms in mammals. Professor Kim used mathematical modeling and analysis to explain that the mammalian circadian clock is a hierarchical system, in which the master clock in the superchiasmatic nucleus, a tiny region in the brain that controls circadian rhythms, functions as a pacemaker and synchronizer of peripheral clocks to generate coherent systematic rhythms throughout the body. Professor Kim said, “The mechanisms of our neuronal and hormonal activities regulating many of our bodily functions over a 24-hour cycle are not yet fully known. We go to sleep every night, but do not really know how it affects our brain functions. I hope my experience in mathematics, along with insights from biologists, can find meaningful answers to some of today’s puzzling problems in biological sciences, for example, revealing the complexities of our brains and showing how they work.” “In the meantime, I hope collaborations between the fields of mathematics and biology, as yet a rare phenomenon in the Korean scientific community, will become more popular in the near future.” Professor Kim received his doctoral degree in Applied and Interdisciplinary Mathematics in 2013 from the University of Michigan and joined KAIST in 2015. He has published numerous articles in reputable science journals such as Science, Molecular Cell, Proceedings of the National Academy of Sciences, and Nature Communications. Both the Program Grants and Young Investigator Grants support international teams with members from at least two countries for innovative and creative research. This year, the Program Grants were awarded to research topics ranging from the evolution of counting and the role of extracellular vesicles in breast cancer bone metastasis to the examination of obesity from a mechanobiological point of view. The Young Investigator Grants are limited to teams that established their independent research within the last five years and received their doctoral degrees within the last decade. Besides Professor Kim’s study, such topics as the use of infrasound for navigation by seabirds and protein formation in photochemistry and photophysics were awarded in 2017. Full lists of the 2017 HFSP winners are available at: http://www.hfsp.org/awardees/newly-awarded. About the Human Frontier Science Program (HFSP): The HFSP is a research funding program implemented by the International Human Frontier Science Program (HFSPO) based in Strasbourg, France. It promotes intercontinental collaboration and training in cutting-edge, interdisciplinary research specializing in life sciences. Founded in 1989, the HFSPO consists of the European Union and 14 other countries including the G7 nations and South Korea.
Professor Mikyoung Lim Receives the MediaV Young Researcher Award
Professor Mikyoung Lim of the Department of Mathematical Sciences at KAIST received the MediaV Young Researchers Award at the International Conference on Inverse Problems and Related Topics that took place at the National Taiwan University, Taiwan, on December 15-19, 2014. The Conference established the MediaV Young Researcher Award in 2010 to recognize distinguished scholars who are age 40 or younger and have made important contributions to the field of inverse problems. This year, two recipients were chosen for the award. Professor Lim has focused her research on the incremental reading of incomprehensible materials’ imaging and the effect of invisibility cloaking. The other awardee was Kui Ren, a professor at the University of Texas at Austin.
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