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Subjects:
Physics, Applied
The Geant4-DNA low energy extension of the Geant4 Monte Carlo (MC) toolkit is a continuously evolving MC simulation code permitting mechanistic studies of cellular radiobiological effects. Geant4-DNA considers the physical, chemical, and biological stages of the action of ionizing radiation (in the form of x- and γ-ray photons, electrons and β±-rays, hadrons, α-particles, and a set of heavier ions) in living cells towards a variety of applications ranging from predicting radiotherapy outcomes to radiation protection both on earth and in space.
- Geant4-DNA
- DNA damage
- DNA repair
- mechanistic modeling
- radiobiological modelling
- IRT
1. The Geant4-DNA Extension
Since 2007, Geant4 (release 9.1) is the only open access general-purpose radiation transport MC code offering, through its Geant4-DNA low-energy extension, track-structure capabilities in liquid water down to the eV energy range [22]. Liquid water has been historically the medium of choice in track-structure codes because of its abundance in cells (70–80% by weight) and also because of its role as a source of reactive free radicals [48]. Towards more realistic modelling of direct damage to DNA, several studies have presented interaction cross sections that are specific to DNA bases (or constituents) in the gas phase [49,50,51,52,53,54] some of them being part of the Geant4-DNA ongoing developments. Interaction cross sections that are specific to bulk DNA in the condensed-phase have also been presented based on the dielectric approach [55,56,57].
Geant4-DNA offers the possibility to transport interaction-by-interaction electrons, protons, hydrogen atoms, alphas, and some ions in liquid water medium. Due to the importance of low- and moderate-energy electrons (from few eV to 1 MeV) in track-structure simulations, as well as the large uncertainties that are associated with their transport in biological media, users have the possibility to select among three recommended sets of alternative physics models which correspond to different cross sections for elastic and inelastic scattering. These physics models are the default Geant4-DNA models or Option 2 constructor (available since 2007 in Geant4 version 9.1) [24], the improved models that were developed at the University of Ioannina [58] or Option 4 constructor (available since 2015 in Geant4 version 10.2), and the Option 6 constructor (available since 2017 in Geant4 version 10.4) [14,22,23,24]. The Geant4-DNA models have been tested and validated against reference data (i.e., NIST, ICRU) and wherever available versus experimental data and other MC simulation studies. Comparisons between the condensed history models of Geant4 and the track-structure models of Geant4-DNA have also been undertaken for particular applications [14,23,59,60,61,62,63].
2. Geant4-DNA Extended Examples
As discussed in the previous sections, Geant4-DNA provides functionalities for the simulation of the interactions of ionizing radiation in liquid water as well as the modeling of pre-chemical and chemical stages of water radiolysis that can be combined with simplified models of biological cellular and sub-cellular targets for damage and repair prediction. However, like Geant4, Geant4-DNA provides a set of computing libraries, and their use requires a minimum knowledge of C++ coding. Therefore, to help users understand the functionalities and develop new applications, the Geant4-DNA collaboration has developed a set of examples that are located in the “extended/medical/dna” category of the Geant4 examples that present the usage of processes and models covering from physical interactions to the chemical stage including simplified biological geometric models. A recent publication that was dedicated to track-structure simulations in liquid water medium describes these examples and their main objectives [23]. Interested readers are encouraged to consult the associated references for a detailed description of each particular application. Beyond their pedagogical role, these examples also allow the verification and validation of Geant4-DNA simulations against literature data or international recommendations as well as regular Geant4 regression tests being performed to test each new Geant4 release [23,134,135]. These examples are maintained and updated along with the Geant4 bi-annual releases. They are briefly described in the following subsections and categorized according to the stage of radiation action they serve.
2.1. Physics Examples
These Geant4-DNA examples are directly related to the main transport and energy deposition magnitudes. In each of these examples, the irradiated geometry and physics list can be modified. In many cases, condensed-history physics models can also be enabled.
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The “clustering” example calculates the energy deposition with a dedicated clustering algorithm to assess DNA strand breaks in a simple liquid water geometry [14];
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“dnaphysics” is a general example that enables track-structure simulation of charged particles in a liquid water geometry and allows for the automatic combination between Geant4-DNA physics models and condensed-history models at higher energies (i.e., above 1 MeV) and can be used for benchmarking simulations that are related to track-structure characteristics [23];
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“icsd”, that stands for ionization cluster size distribution, calculates the number of ionizations for each simulated track in a cylinder mimicking a piece of chromatin and uses DNA-like material’s cross sections that were obtained experimentally or by simulations [50];
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“mfp” stands for mean free path and allows the calculation of the aforementioned distance and related distance quantities for a charged particle in a sphere geometry of liquid water [23];
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“microdosimetry” simulates lineal and specific energy distributions and related quantities in liquid water spheres that are randomly placed along the particle track [59];
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“microprox” is another microdosimetric example that calculates proximity functions from energy depositions scored in liquid water spherical shells from randomly selected hits [60];
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“range” example performs a simulation of penetration distances in liquid water [70];
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“slowing” enables simulation of the slowing down spectra of electrons in a cube of liquid water [136];
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“splitting” uses variance reduction techniques to improve the efficiency of the calculation of ionization cluster size distributions. This is done in a nm sized cylinder as in the case of the icsd example and aims to separate secondaries that are generated within the cylinder to avoid the overlapping of tracks [137];
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“spower” allows for stopping power simulations of particles in liquid water with the use of specific physics modules that enable the use of a stationary mode for appropriate computation [23];
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“svalue” calculates the dose to a target volume per unit of cumulated activity in a source volume, called S-value [138,139]. The source and target volumes can be different cell compartments or an entire cell of a simple spherical geometry which can be modified to account for more complex cell geometries, as has been done in many studies i.e. [140,141];
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“wvalue” serves to simulate the mean energy that is expended to form an ion pair known as W-value. It also provides information on the total number of ionizations in a liquid water volume and its penetration details. It is a useful benchmark simulation for the inelastic models given that elastic interactions are indifferent in this simulation scheme [23,58].
2.2. Chemical Examples
The”chemX” examples provide the guide for the chemical module from the activation of the chemical stage to the calculation of radiochemical yields (“G-value”) as a funtion of time. In each example, irradiated geometry is a large water volume and as in the case of physics examples, the physics list can be modified.
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“chem1” aims to show how to activate or deactivate physicochemical and chemical stage after physical stage. Chemical reactions are printed and the step-by-step model is used by default.
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“chem2” provides a user-class “TimeStepAction” which allows users to change Minimum Time Steps. These parameters constrain the minimum time-step that is allowed for each reactant pair using the step-by-step model. The user-class also shows how to print reaction information such as reactants and products as well as their positions.
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“chem3” illustrates how to implement user actions in the chemistry module using the step-by-step model. Users can also visualize the trajectories of the chemical species in time and space using the graphical user interface.
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“chem4” provides scorer classes to compute radiochemical yields (“G”) versus time using the step-by-step model, including a dedicated ROOT graphical interface. The G-value is useful for benchmark simulations in comparing with other MC codes and experimental data [80].
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“chem5” computes radiochemical yields (“G”) versus time using alternative physics and chemical reaction lists using the step-by-step model [142].
2.3. The dnadamage1 Example
Following the “FullSim” simulation chain that is presented above [116], the recent Geant4-DNA example dnadamage1 method has been released since Geant4.10.6. In this example, we placed a cubic volume of 40 × 40 × 40 nm3 at the center of a 2 × 2 × 2 µm3 box made of liquid water (1 g/cm3). Inside the 40 × 40 × 40 nm3 cubic volume, 3640 nucleotide pairs were built to form a piece of 40 nm heterochromatin straight fiber. This geometrical DNA model was generated with the DNAFabric software. More information about the generation of this geometrical model can be found elsewhere [120]. The total number of strand breaks is computed from the combination of direct and indirect damages. Concerning the physical stage leading to direct damage, the default G4EmDNAPhysics is used. Direct damages are scored if the cumulative deposited energy from ionizations and excitations in the individual volumes of a nucleotide backbone (i.e., the volumes that are representing a group of the phosphate, the 2-deoxyribose, and the hydration shell) is greater than 17.5 eV. For the chemical stage, the G4EmDNAChemistry_option2 constructor is then used to simulate the species diffusion and their reactions with each other or with DNA elements (phosphate, the 2-deoxyribose, and base pairs) using the current SBS model [79]. A reaction between OH•radicals and static DNA elements is counted as primary damage. When one reaction happens, the radical is killed and the damaged DNA element is no longer available for further reaction. It has to be noted that simulated damage is primary damage that is transformed into a SSB with a probability of 42% [116]. More details about the C++ classes and their structure can be found through the README file of the example. To improve the computation time of the example, the IRT method is currently implemented in this example as an option [105].
3. Conclusions
MC track-structure codes are capable of providing both the spatial pattern of the energy deposition within a medium as well as the details of the molecular modifications that are taking place after irradiation. As of this moment, this has not been achieved experimentally. The value of such MC codes in elucidating the mechanisms of cellular damage from ionizing radiation is beyond doubt. The spatial distribution of the interaction events dictates the proximity of DNA strand breaks and, at the same time, the alterations that are taking place in the target molecule(s) determine the chemical modifications. It must always be stressed that all the results that are obtained with the MC technique are as accurate as the input information (e.g., the interaction cross sections for the physical stage of radiation action).
The Geant4-DNA low energy extension that was developed for biomedical applications is constantly evolving in terms of the development of physics models towards the accomplishment of a realistic cellular environment subject to irradiation conditions. Currently, it offers different sets of physics models, chemistry modules, and cell geometries. The combination of the above has allowed the realization of mechanistic studies of cellular DNA damage and repair. Extension of the Geant4-DNA Option 4 track-structure model for electrons up to 10 MeV is underway as well as two alternative models for protons up to 300 MeV. Furthermore, material that is specific cross sections for biopolymers [51] and for gold [143,144] that are used in nanodosimetry have already been developed and tested and they are soon going to be made available to the scientific community through Geant4-DNA. Especially, the cross sections for gold can contribute significantly to the gold nanoparticle-aided radiotherapy research [145,146]. The modeling of the chemical stage is currently being improved [133] and extended to longer times and macroscopic volumes [147]. This is a requirement for easier comparison with radiolysis experiments, which also paves the way to the simulation of radiolysis in FLASH radiotherapy conditions, currently a very active research topic. A library of multi-scale geometries from molecules to assemblies of cells that are compatible with Geant4-DNA physical and chemical interfaces, will also be made available to users in the near future, and efforts to improve the computational performance of Geant4-DNA will continue. All these developments will permit a wider range of radiotherapeutic applications of the code under different irradiation scenarios, to be studied in an in silico, bottom-up approach.
The activity on DNA damage and response is intense within the Geant4-DNA framework and important studies have been published that involve mechanistic studies of DNA damage taking into account details of chemistry [11,71,104,128,133]. Such work will continue towards the goal to connect the irradiation of a cell environment to the DNA response to damage and repair. The ultimate goal is to offer the scientific community all the state-of-the-art tools to study the radiation effects in DNA and cells and to illuminate differences in RBE for low and high LET beams which is a matter of importance, not only for radiotherapy purposes, but also for space radiation risk studies and radiation protection low dose issues. It is envisioned that Geant4-DNA will offer a complete open-source platform available in Geant4 that is able to simulate physical, physicochemical, chemical, and biological processes that are occurring after irradiation of human cells. Further work along these lines is ongoing and will be published in future publications.
This entry is adapted from the peer-reviewed paper 10.3390/cancers14010035
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