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Mathematicians Solve Cellular Noise, a Long-standing Challenge in Biology
< (From left) Researcher Dongju Lim, Researcher Seokhwan Moon, Professor Jae Kyoung Kim (KAIST), Professor Jinsu Kim (POSTECH), Professor Byung-Kwan Cho (KAIST) >
Why does cancer sometimes recur even after successful treatment, or why do some bacteria survive despite the use of powerful antibiotics? One of the key culprits identified is "Biological Noise"—random fluctuations occurring inside cells. Even when cells share the same genes, the amount of protein varies in each, creating "outliers" that evade drug treatments and survive. Until now, scientists could only control the average values of cell populations; controlling the irregular variability of individual cells remained a long-standing challenge.
A joint research team—led by Professor Jae Kyoung Kim (Department of Mathematical Sciences, KAIST), Professor Jinsu Kim (Department of Mathematics, POSTECH), and Professor Byung-Kwan Cho (Graduate School of Engineering Biology, KAIST)—has theoretically established a "Noise Control Principle." Through mathematical modeling, they have found a way to eliminate biological noise and precisely govern cellular destiny. This achievement in securing precision control technology at the single-cell level is expected to be a new milestone in solving challenges in cancer treatment and synthetic biology.
While cells in our bodies strive to maintain homeostasis for survival, their internal environments are constantly changing. Existing genetic circuit technologies could regulate the average protein levels of a cell population but often ended up amplifying the "noise"—the variance between individual cells. The research team compared this to a "shower that fluctuates between boiling and freezing." Even if the average water temperature is set to 40°C, a normal shower is impossible if the water alternates between scalding and icy. Similarly, a small number of cells that escape control due to this "trap of the average" become the primary cause of cancer recurrence or antibiotic resistance. To solve this, the team devised a new mathematical model called the "Noise Controller (NC)."
The researchers first investigated whether they could control the variance of outputs—which differs from cell to cell—using a "dimerization reaction," where the final products of a system bind together to form pairs. In the process, they confirmed that the dimerization reaction could act as a sensor to detect fluctuations (noise) in the cellular state. However, initial attempts showed that this method alone had limits in reducing differences between cells. Consequently, they determined that a device was needed to immediately reduce substances if they were overproduced. They combined this with a "degradation-based actuation" principle, which promptly breaks down proteins when they become excessive. As a result, they theoretically implemented "Noise Robust Perfect Adaptation (Noise RPA)," which maintains a constant noise level despite external environmental changes. Through this, they succeeded in suppressing cell-to-cell deviation to a Fano factor of 1—the minimum level achievable by universal biological systems.
< Figure 1. Conceptual Diagram of Noise Controller (NC) Effects: When no control technology is used (top, gray), the average value of the cell population changes due to external stimuli. With existing control technology (middle, blue), the average value is maintained, but the deviation between individual cells (noise) remains large. In contrast, using the Noise Controller (bottom, green) maintains the average while also reducing the noise level of individual cells. >
The research team proved the model's performance by virtually applying it to the DNA repair system of E. coli. In the existing system, the amount of DNA-repairing proteins varied so greatly between cells that approximately 20% of the cells failed to repair and died. However, by applying the Noise Controller (NC) to unify protein levels across all cells, the mortality rate was slashed to 7%. The team significantly boosted cell survival rates through sophisticated mathematical principles alone. This is highly significant as it moves beyond the "average control" paradigm to realize "single-cell control," dealing with each cell with precision.
< Figure 2. Structure of the Noise Controller (NC).In the conventional control scheme (left), the final output (X2) produces one of the controller proteins (Z2), and this protein is degraded together with the other controller protein (Z1) that generates the system input (X1).In contrast, the noise controller (NC) established in this study (right) has a largely similar structure, but is characterized by the production of the controller protein (Z4) through a dimerization reaction of the final output. This protein directly degrades the system input (X1).Through this mechanism, mathematical expressions for the mean of the final output (lower left equation) and its noise (lower right equation) can be derived >
Professor Jae Kyoung Kim, who led the research, stated, "The significance lies in bringing cellular noise—which was previously dismissed as luck or coincidence in biological phenomena—into the realm of controllable factors through mathematical design." He added, "It will play a vital role in fields requiring precise cellular control, such as overcoming cancer treatment resistance and developing high-efficiency smart microorganisms." Co-corresponding author Professor Jinsu Kim of POSTECH emphasized, "This research demonstrates the power of mathematical modeling, starting from theoretical formulas of intracellular noise using reaction network theory and leading to the design of actual biological mechanisms."
< Figure 3. Actual Biological Circuit Structure of the Noise Controller (NC): A representation of the mathematical model established by the research team implemented as a genetic circuit, which is an actual biological system. The existing control technology (left) consists of a reaction where the final product produces an anti-sigma factor (RsiW), which then binds with the sigma factor (SigW) that generates the system’s input value. The Noise Controller (NC) (right) similarly utilizes the binding reaction between an anti-sigma factor (RseA) and a sigma factor (ECF); however, the primary differences are that the anti-sigma factor (RseA) is produced through the dimerization reaction of the final product , and that the anti-sigma factor (RseA) directly degrades the system’s input value >
The results of this study were published on December 24 in the international academic journal Nature Communications (IF=15.7).
2025.12.29 View 2352 -
Professor Mikyoung Lim from Mathematical Sciences to Deliver Keynote at International Conference on Applied Inverse Problems
Professor Mikyoung Lim from KAIST Department of Mathematical Sciences gave a plenary talk on "Research on Inverse Problems based on Geometric Function Theory" at AIP 2025 (12th Applied Inverse Problems Conference). AIP is one of the leading international conferences in applied mathematics, organized biennially by the Inverse Problems International Association (IPIA). This year's conference was held from July 28 to August 1 in Rio de Janeiro, Brazil, and consisted of plenary talks, over 40 mini-symposia, and poster sessions. The IPIA began in 2007 and was re-established in 2022 as a non-profit international academic organization officially registered in Germany. At that time, Professor Lim served as an executive committee member for the re-establishment.
During the lecture, Professor Lim's research team introduced a new geometric solution and its applications to boundary value problems for electric/elastic equations, which they have been working on for the past 10 years. In particular, they presented a method for reconstructing partial differential equation boundary value problems into matrix equations and applying them to inverse problems using geometric function theory, a classical theory of complex analysis. A representative achievement was the formalization of the relationship between conformal mappings for simply connected domains in a plane and the measured values of solutions to equations of inhomogeneous conductors into a closed-form expression.
This research led to the plenary talk, as it was recognized for pioneering a new methodology for inverse problem research by connecting geometric function theory and layer potential theory.
2025.08.14 View 4272 -
13 KAIST Faculty Named as Inaugural Members of Y-KAST
The Korean Academy of Science and Technology (KAST) launched the Young Korean Academy of Science and Technology (Y-KAST) and selected 73 scientists as its inaugural members on February 24. Among them, 13 KAIST faculty were recognized as the inaugural members of Y-KAST.
Y-KAIST, made up of distinguished mid-career scientists under the age of 45, will take the leading role in international collaboration as well as innovative agenda-making in science and technology.
The inaugural members include Professor Hyotcherl Ihee of the Department of Chemistry and Dr. Sung-Jin Oh of the Center for Mathematical Challenges at the Korea Institute for Advanced Study (KIAS), affiliated with KAIST. Professor Ihee is gaining wide acclaim in the fields of physics and chemistry, and in 2016, Dr. Oh was the youngest ever awardee of the Presidential Award of Young Scientist.
The other Y-KAIST members are as follows: Professors Haeshin Lee of the Department of Chemistry; Mi Young Kim, Byung-Kwan Cho, and Ji-Joon Song of the Department of Biological Sciences; Song-Yong Kim of the Department of Mechanical Engineering; Sang-il Oum of the Department of Mathematical Sciences; Jung Kyoon Choi of the Department of Bio and Brain Engineering; Seokwoo Jeon, Sang Ouk Kim, and Il-Doo Kim of the Department of Materials Science and Engineering; Jang Wook Choi of the Graduate School of EEWS (Energy, Environment, Water and Sustainability); and Jeong Ho Lee of the Graduate School of Medical Science and Engineering.
The leading countries of the Academy of Science, which include Germany, Sweden, Belgium, Canada, and Japan, have established the Young Academy of Science since 2010 in order to encourage the research activities of their young scientists and to establish a global platform for collaborative research projects through their active networking at home and abroad.
President Myung-Chul Lee of KAST said, “We will spare no effort to connect these outstanding mid-career researchers for their future collaboration. Their networking will make significant impacts toward their own research activities as well as the global stature of Korea’s science and technology R&D.
(Photo caption: Members of Y-KAST pose at the inaugural ceremony of Y-KAST on February 24.)
2017.03.02 View 26493