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Related Experiment Video

Updated: Sep 11, 2025

Irradiator Commissioning and Dosimetry for Assessment of LQ α and β Parameters, Radiation Dosing Schema, and in vivo Dose Deposition

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Published on: March 11, 2021

Cumulative dose responses for adapting biological systems.

Ankit Gupta¹, Eduardo Sontag^2,3,4

¹Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.

Journal of the Royal Society, Interface

|August 12, 2025

Summary

This study introduces the cumulative dose response (cDR) to explain biological adaptation. The integral feedback (IFB) motif, unlike incoherent feedforward loops, can generate the non-monotonic cDR observed in experiments.

Keywords:

area under the curve dose response immunology incoherent feedforward loops integral feedback perfect adaptation systems biology

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Area of Science:

Systems Biology
Immunology
Pharmacology

Background:

Physiological adaptation is crucial for biological systems, typically modeled as an asymptotic dose response (DR).
Existing models struggle to explain transient, cumulative dose responses (cDR) observed in biological systems like cytokine accumulation.

Purpose of the Study:

To develop the concept of a cumulative dose response (cDR) as a finite-time measure of adaptation.
To investigate network motifs capable of generating non-monotonic cDR, consistent with experimental data.

Main Methods:

Developed the cumulative dose response (cDR) by integrating the response variable over a fixed time interval.
Analyzed two types of incoherent feedforward loops and one integral feedback (IFB) motif for their cDR properties.

Main Results:

Incoherent feedforward loops, despite non-monotonic DR, consistently produce monotonic cDR.
The integral feedback (IFB) motif is shown to generate non-monotonic cDR, aligning with experimental observations.

Conclusions:

The IFB motif is a viable mechanism for explaining the non-monotonic cDR observed in T-cell cytokine accumulation.
Incoherent feedforward loops are inconsistent with experimental data exhibiting non-monotonic cDR.