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

2. for radiation biology for radiation biology 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-DNAGeant4-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

3. Simulation of Interactions of Radiation with Biological Systems at the Cellular and DNA level 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. DNA “Sister” activity to Geant4 Low-Energy Electromagnetic Physics Follows the same rigorous software standards International (open) collaborationESA INFN INFN (Genova, Torino) - IN2P3 IN2P3 ( CENBG, Univ. Clermont-Ferrand ) - … For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of radiation

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

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

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

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

8. Biological outcome: cell survival cell survival curve radiation dose proportion of cells that surviveA 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. Human cell lines irradiated with X-rays Courtesy E. Hall DOSE-RESPONSE RELATIONSHIP

9. Requirements Problem domain analysis Theories and models for cell survival Analysis & Design Implementation Test Experimental validation of Geant4 simulation models in progress Incremental-iterative software process approach: variety of models all handled through the same abstract interface 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

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

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

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

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

14. Rigorous software engineering Advanced object oriented technology in support of Geant4 modelling versatility Conclusions Geant4-DNA cellularDNA 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 rigorous software process According to the rigorous software process adopted, a variety of radiobiological models has been designed, implemented and tested in Geant4 extension 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 For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of radiation