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DNA

DNA. Based on. Geant4-DNA Simulation of Interactions of Radiation with Biological Systems at the Cellular and DNA Level.

Mercy
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DNA

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  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 University of Lund

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

  4. Biological models in Geant4 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 • Geant4-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 can be implemented with Geant4 • RBE parameterisation, detailed biochemical processes, etc. • First phase: 2000-2001 • Collection of user requirements & first prototypes • Second phase: 2004-2008 • Software development & release

  7. 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)

  8. 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

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

  10. 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 release with usable functionality

  11. 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 associated tools • Cellular level • cell modelling • processes for cell survival, damage etc. • DNA level • DNA modelling • 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)

  12. Macroscopic level Anthropomorphic phantoms • Development of anthropomorphic phantom 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 • G. Guerrieri, Thesis, Univ. Genova, Oct. 2005 • Relevant to other fields, not only space • radiation protection • Total Body Irradiation (radiotherapy)

  13. 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

  14. - 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

  15. 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)

  16. Current status • Software • analysis & design in progress • not a trivial problem… extension of Geant4 to a completely new domain without affecting the current Geant4 kernel • plan to have a first detailed design model by end 2005 • implementation expected to be rather quick • software test according to the test process of the Geant4 LowE WG • Work in progress on modelling • models as in biology literature are unusable for concrete software development!

  17. S = e –p ( αD + ßD ) 2 2 S = S0 e - k (ξD + D ) NPL S = exp[ - NTOT[1 + ]ε] ε (1 – e- εBAtr) S = e-q1D [ 1- (1- e-qnD)n ] S = e-αD[1 + (αDT / ε)]ε S= e-D / D0 REVISED MODEL S = 1- (1- e-qD)n In progress: calculation of model parameters from clinical data S = e-αD[1 + (αD / ε)]εΦ S = e-ηAC D - ln[ S(t)] = (ηAC +ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)] - ln[ S(t)] = (ηAC +ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

  18. DNA level Low Energy Physics extensions • Current Geant4 low energy electromagnetic processes: down to 250/100 eV (electrons and photons) • not adequate for application at the DNA level • Specialised processes down to the eV scale • at this scale physics processes 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

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

  20. Summary • Geant4 is being extended to a novel field of simulation capability and applications • biological effects of radiation at the cellular and DNA level • extension facilitated by Geant4 architecture and sound OO technology • Three levels • macroscopic/dose • 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

  21. Geant4 simulation space environment + spacecraft, shielding etc. + anthropomorphic phantom Scenario for Aurora Geant4 simulation with biological processes at cellular level (cell survival, cell damage…) Dose in organs at risk Oncological risk to astronauts Risk of nervous system damage Phase space input to nano-simulation Geant4 simulation with physics at eV scale + DNA processes

  22. By-products • Technology transfer from space science to civil society • Geant4 biological models also relevant to radiotherapy, food irradiation etc. FAO/IAEA International Conference on Area-Wide Control of Insect Pests: Integrating the Sterile Insect and Related Nuclear and Other Techniques Vienna, May 9-13, 2005 K. Manai, K. Farah, A.Trabelsi, F. Gharbi and O. Kadri (Tunisia) Dose Distribution and Dose Uniformity in Pupae Treated by the Tunisian Gamma Irradiator Using the GEANT4 Toolkit • Micro-/nano-dosimetry also relevant to other domains • radiation effects on components

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