Biocomputing Approach to Modeling and Modulating Calcium Signaling

Authors

Sehee Sun, University of Nebraska-LincolnFollow

First Advisor

Sasitharan Balasubramaniam

Committee Members

Massimiliano Pierobon, Ashok Samal

Date of this Version

7-2025

Document Type

Thesis

Citation

A thesis presented to the faculty of the Graduate College at the University of Nebraska in partial fulfilment of requirements for the degree of Master of Science

Major: Computer Science

Under the supervision of Professor Sasitharan Balasubramaniam

Lincoln, Nebraska, July 2025

Comments

Copyright 2025, Sehee Sun. Used by permission

Abstract

Biocomputing is an emerging field that seeks to perform computational tasks using biological substrates and processes. Unlike conventional computing systems based on silicon hardware, biocomputing leverages the parallelism, energy efficiency, and complex dynamics of living systems. Among various cellular mechanisms, calcium (Ca2+) signaling stands out as a central regulator of diverse biological functions, offering a promising basis for programmable logic and control in living cells.

This thesis introduces a novel framework for modeling and modulating Ca2+ dynamics using biologically inspired Boolean logic circuits. Specifically, we propose the Ca2+ Boolean Logic (CaBL) model, in which Ca2+ fluxes and interactions are abstracted into logic gates constructed from the kinetic processes governing Ca2+ signaling. These logic gates—parameterized to reflect biochemical rates and reactions—are composed into sub-circuits, each representing a distinct physiological process such as membrane flux, buffering, and store release. Together, the sub-circuits form a digital circuit that replicates the behavior of a canonical Ca2+ signaling model.

To enable precise modulation of cytoplasmic Ca²⁺ concentration, we developed the Biosignal Modulation Engine (BME), an algorithmic framework that searches for gate configurations capable of generating a digital output corresponding to a desired Ca²⁺ level. Through circuit reconfiguration simulations, the BME identifies multiple configurations with suitable parameters that achieve the target behavior. Results show that its performance improves when the parameter search is limited to biologically realistic ranges.

A case study involving GPCR-mediated reduction of cytoplasmic Ca²⁺ concentration is also presented. By targeting a sub-circuit corresponding to Ca²⁺ channel activation, the BME identified a circuit configuration that achieves a reduction in the cytoplasmic Ca2+ level, thereby functionally replicating a downstream effect of GPCR-mediated signaling relevant to Ca²⁺ suppression for certain diseases.

Overall, this work contributes a logic-based abstraction of Ca²⁺ signaling that can be interpreted and manipulated within a digital framework. It establishes a foundation for programmable cellular systems, suggesting future applications in therapeutic biocomputing, synthetic biology, and the development of molecular-scale logic architectures.

Advisor: Sasitharan Balasubramaniam