Radiobiological models implementation in Geant4

1. 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

2. 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-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 Various scientific domains involved medical, biology, genetics, physics, software engineering Multiple approaches can be addressed with Geant4 RBE parameterisation, detailed biochemical processes, etc. DNA International (open) collaboration ESA INFN(Genova, Torino) - IN2P3(CENBG, Univ. Clermont-Ferrand) - … “Sister” activity to Geant4 Low-Energy Electromagnetic Physics Follows the same rigorous software standards 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. Openness to extensionandevolution new implementations can be added w/o changing the existing code Robustness and ease of maintenance protocols and well defined dependenciesminimizecoupling MULTIDISCIPLINARY STUDY Toolkit OO technology A set of compatible components • each component is specialised for a specific functionality • each component can be refinedindependently to a great detail • components can be integrated at any degree of complexity • it is easy to provide (and use) alternativecomponents • the user application can be customisedas needed Strategic vision

6. 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)

7. Cellular level The biological effects of radiation can be manifold, from cell killing, to mutation in germ cells, up to carcinogenesis or leukemogenesis 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)

8. Courtesy E. Hall Human cell lines irradiated with X-rays Biological outcome: cell survival DOSE-RESPONSE RELATIONSHIP • 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.

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

10. Prototype design STRATEGY PATTERN Biological models areencapsulatedand madeinterchangeable. 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.

11. Undamaged state A Potentially letal lesions B Lethal lesions C 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 εAB ηAB ηAC • 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

12. Survival Dose (Gy) Cell survival models verification 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

13. 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)

14. Conclusions • 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 ofGeant4 modellingversatility