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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 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.
KAIST's Mathematician Reveals the Mechanism for Sustaining Biological Rhythms
Our bodies have a variety of biological clocks that follow rhythms or oscillations with periods ranging from seconds to days. For example, our hearts beat every second, and cells divide periodically. The circadian clock located in the hypothalamus generates twenty-four hour rhythms, timing our sleep and hormone release. How do these biological clocks or circuits generate and sustain the stable rhythms that are essential to life? Jae Kyoung Kim, who is an assistant professor in the Department of Mathematical Sciences at KAIST, has predicted how these biological circuits generate rhythms and control their robustness, utilizing mathematical modeling based on differential equations and stochastic parameter sampling. Based on his prediction, using synthetic biology, a research team headed by Matthew Bennett of Rice University constructed a novel biological circuit that spans two genetically engineered strains of bacteria, one serves as an activator and the other as a repressor to regulate gene expression across multiple cell types, and found that the circuit generates surprisingly robust rhythms under various conditions. The results of the research conducted in collaboration with KAIST (Korea Institute of Science and Technology), Rice University, and the University of Houston were published in Science (August 28, 2015 issue). The title of the paper is "Emergent Genetic Oscillations in a Synthetic Microbial Consortium" . The top-down research approach, which focuses on identifying the components of biological circuits, limits our understanding of the mechanisms in which the circuits generate rhythms. Synthetic biology, a rapidly growing field at the interface of biosciences and engineering, however, uses a bottom-up approach. Synthetic biologists can create complex circuits out of simpler components, and some of these new genetic circuits are capable of fluctuation to regulate gene production. In the same way that electrical engineers understand how an electrical circuit works as they construct batteries, resistors, and wires, synthetic biologists can understand better about biological circuits if they put them together using genes and proteins. However, due to the complexity of biological systems, both experiments and mathematical modeling need to be applied hand in hand to design these biological circuits and understand their function. In this research, an interdisciplinary approach proved that a synthetic intercellular singling circuit generates robust rhythms to create a cooperative microbial system. Specifically, Kim's mathematical analysis suggested, and experiments confirmed, that the presence of negative feedback loops in addition to a core transcriptional negative feedback loop can explain the robustness of rhythms in this system. This result provides important clues about the fundamental mechanism of robust rhythm generation in biological systems. Furthermore, rather than constructing the entire circuit inside a single bacterial strain, the circuit was split among two strains of Escherichia coli bacterium. When the strains were grown together, the bacteria exchanged information, completing the circuit. Thus, this research also shows how, by regulating individual cells within the system, complex biological systems can be controlled, which in turn influences each other (e.g., the gut microbiome in humans). ### Ye Chen, a graduate student in Bennett's laboratory at Rice University, and Jae Kyoung Kim, an assistant professor at KAIST and a former postdoctoral fellow at Ohio State University, are the lead authors of the paper. The co-authors are Rice graduate student Andrew Hirning and Krešimir Josic?, a professor of mathematics at the University of Houston. Bennett is the Assistant Professor of the Biochemistry and Cell Biology Department at Rice University. About the researcher: While Jae Kyoung Kim is a mathematician, he has also solved various biological puzzles in collaboration with various experimental laboratories of Matthew Bennett at Rice University, David Virshup at Duke and the National University of Singapore, Carla Finkielstein at Virginia Polytechnic Institute and State University, Choo-Gon Lee at the Florida State University, Seung-Hee Yoo at the Medical School of the University of Texas, Toru Takumi at RIKEN Brain Science Institute, and Travis Wager at Pfizer Inc. He has used non-linear dynamics and stochastic analysis to understand the function of biochemical networks in biological systems. In particular, he is interested in mechanisms generating and regulating biological rhythms. Picture 1: This schematic image is the design of a biological circuit between two strains of bacteria and the part of differential equations used to understand the function of the biological circuit. Picture 2: The core transcriptional negative feedback loop and additional negative feedback loop in the biological circuit (picture 1) generate robust rhythms. The snapshots correspond the red dots in the time series graph.
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