MINAS TIRITH: a new tool for simulating radiation-induced DNA damage at the cell population level

Abstract

Objective: The mechanisms of radiation-induced DNA damage can be understood via the fundamental acquisition of knowledge through a combination of experiments and modeling. Currently, most biological experiments are performed by irradiating an entire cell population, whereas modeling of radiation-induced effects is usually performed via Monte Carlo simulations with track structure codes coupled to realistic DNA geometries of a single-cell nucleus. However, the difference in scale between the two methods hinders a direct comparison because the dose distribution in the cell population is not necessarily uniform owing to the stochastic nature of the energy deposition. Thus, this study proposed the MINAS TIRITH tool to model the distribution of radiation-induced DNA damage in a cell population. Approach: The proposed method is based on precomputed databases of microdosimetric parameters and DNA damage distributions generated using the Geant4-DNA Monte Carlo Toolkit. First, a specific energy z was assigned to each cell of an irradiated population for a particular absorbed dose D_abs, following microdosimetric formalism. Then, each cell was assigned a realistic number of DNA damage events according to the specific energy z, respecting the stochastic character of its occurrence. Main results: This study validated the MINAS TIRITH tool by comparing its results with those obtained using the Geant4-DNA track structure code and a Geant4-DNA based simulation chain for DNA damage calculation. The different elements of comparison indicated consistency between MINAS TIRITH and the Monte Carlo simulation in case of the dose distribution in the population and the calculation of the amount of DNA damage. Significance: MINAS TIRITH is a new approach for the calculation of radiation-induced DNA damage at the cell population level that facilitates reasonable simulation times compared to those obtained with track structure codes. Moreover, this tool enables a more direct comparison between modeling and biological experimentation.

Accessing radiation damage to biomolecules on the nanoscale by particle-scattering simulations

“…Hereby the prediction of cell-survival is the benchmark for testing new models [232]. Going beyond isolated cells to study phenomena such as the radiation induced bystander effect [222] or the radiation response on a tissue level [223] are still in an early stage. However, complete multiscale models including AuNP radiosensitization of DNA into a xenograft mouse model highlight already what can be achieved by integration and combination of simulation and modelling techniques on different scales [258].…”

“…However, complete multiscale models including AuNP radiosensitization of DNA into a xenograft mouse model highlight already what can be achieved by integration and combination of simulation and modelling techniques on different scales [258]. Thus, important first steps and proof of concepts were successfully delivered and will be extended and applied to a broader range of conditions during ongoing and future work [222,223].…”

“…Their method allows for quantitative studies of radiation damage in cells, with the long-term goal to study radiation response on the tissue level. Another project which was recently proposed and is currently under development is the MIcrodosimetry and NAnodosimetry to Simulate The Initial Radiation-Induced damage Topologys Heterogeneity (MINAS TIRITH), which is a Geant4-DNA based tool to model radiation damage at the cell population scale which was recently described [223].…”

“…There the two lesion kinetics (TLK) model was implemented and successfully applied together with an optimized parameter set to predict DNA repair kinetics and cell survival. Furthermore, the recently described MINAS TIRITH is planned to be connected with repair models, especially for the case of the kinetic modeling of foci, to approach real world experimental conditions [223].…”

Experimental validation in a neutron exposure frame of the MINAS TIRITH for cell damage simulation

“…Thus, the description of the damage at the cell population scale is necessary for a better comparison between simulated and experimental results (Chatzipapas et al 2020), since the correlation between the population response and the variability of imparted energy has been previously highlighted (Gruel et al 2016). In this context, the MINAS TIRITH tool has been proposed in order to model the distribution of radiation-induced DNA damage at the scale of a cell population (Thibaut et al 2023). This tool is based on databases generated by Monte Carlo simulation with the Geant4-DNA tool (Incerti et al 2010a, 2010b, Bernal et al 2015, Incerti et al 2018 coupled to realistic nucleus geometries (Meylan et al 2016, Tang et al 2019a, Thibaut et al 2022.…”