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Systematic inferences identify a major source of heterogeneity in cell signaling dynamics

< Figure: In a cell signaling pathway, the heterogeneity (i.e., cell-to-cell variability) in the signal response increases as the number of rate-limiting step number increases. >

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.

< From Left Dr.Dae Wook Kim, Professor Jae Kyoung Kim, and PhD candidate Hyukpyo Hong >

-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 Kim
http://mathsci.kaist.ac.kr/~jaekkim
jaekkim@kaist.ac.kr
@umichkim on Twitter
Department of Mathematical Sciences
KAIST