Geant4-DNA: Simulation of Radiation Interactions at Cellular and DNA Level

1. - DNA

2. Based on Geant4-DNASimulation of Interactions of Radiation with Biological Systems at the Cellular and DNA Level R. Capra, S. Chauvie, R. Cherubini, Z. Francis, S. Gerardi, S. Guatelli, G. Guerrieri, S. Incerti, B. Mascialino, G. Montarou, Ph. Moretto, P. Nieminen, M.G. Pia, M. Piergentili, C. Zacharatou + biology experts (E. Abbondandolo, G. Frosina, E. Giulotto et al.) Partly funded by

3. Courtesy of R. Taschereau, UCSF Medicalapplications PET, SPECT Hadrontherapy Radiotherapy with external beams, IMRT Brachytherapy

4. Relevance for space: astronaut and aircrew radiation hazards

5. Relevance • The concept of “dose” fails at cellular and DNA scales • It is desirable to gain an understanding to the processes at all levels (macroscopic vs. microscopic+cybernetic) • Quantitative knowledge and strict user requirements scientifically satisfying; may be used as feedback to experimentalists • Potential later connection to other than radiation-induced effects at the cellular and DNA level • Relevance for space: astronaut and airline pilot radiation hazards, biological experiments • Applications in radiotherapy, radiobiology, ...

6. Programme • -based “sister” activity to the Geant4 Low-Energy Electromagnetic Working Group • Follows the same rigorous software standards • International (open) collaboration • ESA, INFN (Genova, LNL, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund • Simulation of nano-scale effects of radiation at the DNA level • Various scientific domains involved: medical, biology, genetics, software engineering, high and low energy physics, space physics • Multiple approaches (RBE parameterisation, detailed biochemical processes, etc.) can be implemented with Geant4 • First phase: 2000-2001 • Collection of user requirements & first prototypes • Second phase: 2004-2008 • Software development & release

7. Anomalous cosmic rays Galactic and extra-galactic cosmic rays Jovian electrons (Neutrinos) Solar X-rays Trapped particles Induced emission Solar flare neutrons and g-rays Solar flare electrons, protons, and heavy ions

8. Biological processes • Complexity • Multiple disciplines involved • physics • chemistry • biology • Still object of active research • not fully known • no general models, only partial/empirical ones Courtesy A. Brahme (KI) Courtesy A. Brahme (Karolinska Institute)

9. First phase • Collection of user requirements • from various sources: physics, space science, radiobiology, genetics, radiotherapy etc. • analysis of existing models and software codes • …not an easy task (as usual in requirements engineering!) • User Requirements Document available from http://www.ge.infn.it/geant4/dna • Development of a toy prototype • to investigate Geant4 capabilities • to elaborate ideas for future software design and physics/biological models 5.3 MeV  particle in a cylindrical volume inside cell nucleus.The inner cylinder has a radius of 50 nm

10. Collection of User Requirements Biologicalprocesses Physicalprocesses Known, available Process userrequirements Unknown, not available E.g. generation of free radicals in the cell User requirements on geometry and visualisation Chemicalprocesses Courtesy Nature

11. Second phase • Scope revisited • based on the experience of the fist phase • Team largely re-organized w.r.t. the first phase • focus on software development • physicists: Geant4 Collaboration members + experimental teams • biologists, physicians as supporting experts • Iterative and incremental software process • mandatory in such a complex, evolving research field • Realistic, concrete objectives • code releases with usable functionality

12. Scope • Re-focused w.r.t. the first phase • goal: provide capabilities to study the biological effects of radiation at multiple levels • Macroscopic • calculation of dose • already feasible with Geant4 • develop useful tools • Cellular level • cell modeling • processes for cell survival, damage etc. • DNA level • DNA modeling • physics processes at the eV scale • processes for DNA strand breaking, repair etc. Complexity of software, physics and biology addressed with an iterative and incremental software process Parallel development at all the three levels (domain decomposition)

13. Macroscopic level Anthropomorphic phantoms • Development of anthropomorphic phantoms models for Geant4 • evaluate dose deposited in critical organs • radiation protection studies in the space environment • other applications, not only in space science • Original approach facilitated by the OO technology • analytical and voxel phantoms in the same simulation environment • mix & match • see dedicated presentation in this workshop • Status: first release December 2005

14. Cellular level 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 Critical evaluation of the models future done Experimental validation of Geant4 simulation models Requirements Problem domain analysis

15. - D/DC n! PSURV(q,b,n,D) = B(b) (e-qD)(n-b) (1- e-qD)b b! (n -b)! S = e-αR [1 + ( αS / αR -1)e ] D – ß D 2 S= e-ßD Target theory models Extension of single-hit model No hits: cell survives One or more hits:cell dies Multi-target single-hit model Cell survival equations based on model-dependent assumptions Single-hit model S(ρ,Δ) = PSURV(ρ0, h=0, Δ) = (1- ρ0)Δ= exp[Δ ln (1- ρ0)] Single-target multi-hit model No assumption on Time Enzymatic repair of DNA Joiner & Johns model two hits

16. Molecular models for cell death More sophisticated models Theory of dual radiation action Molecular theory of radiation action (linear-quadratic model) Kellerer and Rossi (1971) Chadwick and Leenhouts (1981) Lethal-potentially lethal model Repair or misrepair of cell survival Tobias et al. (1980) Curtis (1986)

17. DNA level Low Energy Physics extensions • Current Geant4 low energy electromagnetic processes: down to 250/100 eV (electrons and photons) • not adequate for applications at the DNA level • Specialised processes down to the eV scale • at this scale depend on material, phase etc. • some models exist in literature (Dingfelder et al., Emfietzoglou et al. etc.) • In progress: Geant4 processes in water at the eV scale • see talk by Riccardo Capra in this workshop • Status: first release in December 2005

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

19. Summary • Geant4 is being extended to a novel field of simulation capability and applications • biological effects of radiation at the cellular and DNA level • made possible by Geant4 architecture • facilitated by the OO technology • Three levels • macroscopic • cell • DNA • On-going activity at all levels • anthropomorphic phantoms, cell survival models, low energy physics extensions down to the eV scale etc. • Key elements • Rigorous software process • Collaboration with domain experts (biologists, physicians) • Team including groups with cellular irradiation facilities