Radiobiological models implementation in Geant4 DNA Radiobiological models implementation in Geant4 S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino, Ph. Moretto, G. Montarou, P. Nieminen, M.G. Pia 4th Geant4 Space Users’ Workshop and 3rd Spenvis Users’ Workshop Pasadena, 6 November – 9 November 2006

for radiation biology Geant4-DNA Several specialized Monte Carlo codes have been developed for radiobiology/microdosimetry Typically each one implementing models developed by its authors Limited application scope Not publicly distributed Legacy software technology (FORTRAN, procedural programming) Geant4-DNA Full power of a general-purpose Monte Carlo system Toolkit: multiple modeling options, no overhead (use what you need) Versatility: from controlled radiobiology setup to real-life ones Open source, publicly released Modern software technology Rigorous software process

DNA International (open) collaboration ESA INFN (Genova, Torino) - IN2P3 (CENBG, Univ. Clermont-Ferrand) - … DNA “Sister” activity to Geant4 Low-Energy Electromagnetic Physics Follows the same rigorous software standards Simulation of Interactions of Radiation with Biological Systems at the Cellular and DNA level Various scientific domains involved medical, biology, genetics, physics, software engineering Multiple approaches can be addressed with Geant4 RBE parameterisation, detailed biochemical processes, etc. For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of radiation

http://www.ge.infn.it/geant4/dna

Strategic vision Toolkit OO technology MULTIDISCIPLINARY STUDY OO technology Openness to extension and evolution new implementations can be added w/o changing the existing code Robustness and ease of maintenance protocols and well defined dependencies minimize coupling Strategic vision Toolkit A set of compatible components each component is specialised for a specific functionality each component can be refined independently to a great detail components can be integrated at any degree of complexity it is easy to provide (and use) alternative components the user application can be customised as needed

Multiple domains in the same software environment Macroscopic level calculation of dose already feasible with Geant4 develop useful associated tools Cellular level cell modelling processes for cell survival, damage etc. DNA level DNA modelling physics processes at the eV scale bio-chemical processes processes for DNA damage, repair etc. Complexity of SOFTWARE PHYSICS BIOLOGY addressed with an iterative and incremental software process Parallel development at all the three levels (domain decomposition)

VIABLE CELL (BUT MODIFIED) Cellular level Before irradiation: Normal Cell SOME OF THE MOST STUDIED CELL LINES HeLa cells, derived from human cervical cancer V79 cells, derived from hamster lung CHO cells, derived from ovary 9L cells, derived from rat gliosarcoma T1 cells, derived from human kidney Radiation Damage to chromosome CELL DEATH Broken or changed chromosome (mutation) REPAIR After irradiation: Abnormal Cell VIABLE CELL (BUT MODIFIED) The biological effects of radiation can be manifold, from cell killing, to mutation in germ cells, up to carcinogenesis or leukemogenesis

Biological outcome: cell survival DOSE-RESPONSE RELATIONSHIP Human cell lines irradiated with X-rays Courtesy E. Hall A cell survival curve describes the relationship between the radiation dose and the proportion of cells that survive. What do we mean with “cell death”? loss of the capacity for sustained proliferation or loss of reproductive integrity. A cell still may be physically present and apparently intact, but if it has lost the capacity to divide indefinitely and produce a large number of progeny, it is by definition dead.

Theories and models for cell survival TARGET THEORY MODELS Single-Hit model Multi-Target Single-Hit model Single-Target Multi-Hit model MOLECULAR THEORY MODELS Theory of Radiation Action Theory of Dual Radiation Action Repair-Misrepair model Lethal-Potentially lethal model approach: variety of models all handled through the same abstract interface in progress Analysis & Design Implementation Test Requirements Problem domain analysis Experimental validation of Geant4 simulation models Incremental-iterative software process

Prototype design STRATEGY PATTERN Biological models are encapsulated and made interchangeable. Concrete radiobiological models derive from the abstract interface The flexible design adopted makes the system open to further extension to other radiobiological models available in literature.

LINEAR-QUADRATIC MODEL SURVIVAL OF A POPULATION OF RADIATED CELLS LINEAR-QUADRATIC MODEL DOSE OF RADIATION TO WHICH THE CELLS WERE EXPOSED Low doses: DSBs are generated by the same particle SINGLE-HIT MULTI-TARGET Two component of cell killing by radiation, one dependent by the dose and the other one proportional to the square of the dose - cell survival curve is continuously bending - n targets in the cell, all with the same volume - one or more of these targets must be inactivated - each target has the same probability of being hit - one hit is sufficient to inactivate each target (but not the cell) High doses: DSBs are generated by different electrons Courtesy E. Hall LETHAL-POTENTIALLY LETHAL Undamaged state A Lethal lesions C Potentially letal lesions B εAB ηAC ηAB Based on: radiation induced lethal and potentially lethal lesions the capacity of the cell to repair them εBC B and C lesions are linearly related to dose

Cell survival models verification Dose (Gy) Survival Monolayer Data points: Geant4 simulation results V79-379A cells Proton beam E= 3.66 MeV/n Continuous line: LQ theoretical model with Folkard parameters LQ model α = 0.32 β = -0.039 Folkard et al, Int. J. Rad. Biol., 1996

Wide and complex problem domain Geant4 simulation with biological processes at cellular level (cell survival, cell damage…) Dose in sensitive volumes Biological systems responses to irradiation exposure are of critical concern both to radiotherapy and to risk assessment WIDE DOMAIN OF NOVEL APPLICATIONS IN RADIOBIOLOGY AND OTHER FIELDS Phase space input to nano-simulation Geant4 simulation with physics at eV scale + DNA processes + ADVANCED FUNCTIONALITIES OFFEREND BY GEANT4 IN OTHER SIMULATION DOMAINS (GEOMETRY, PHYSICS, INTERACTIVE TOOLS)

Conclusions Rigorous software engineering The Geant4-DNA project is in progress to extend the Geant4 simulation toolkit to model the effects of radiation with biological systems at cellular and DNA level According to the rigorous software process adopted, a variety of radiobiological models has been designed, implemented and tested in Geant4 The flexible design adopted makes the system open to further extension to other radiobiological models available in literature For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of radiation Rigorous software engineering Advanced object oriented technology in support of Geant4 modelling versatility