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Maria Grazia Pia, INFN Genova - DNA Slide 2 Maria Grazia Pia, INFN Genova Based on Partly funded by Geant4-DNA Simulation 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.) Slide 3 Maria Grazia Pia, INFN Genova Medical applications Courtesy of R. Taschereau, UCSF Radiotherapy with external beams, IMRT Brachytherapy PET, SPECT Hadrontherapy Slide 4 Maria Grazia Pia, INFN Genova Relevance for space: astronaut and aircrew radiation hazards Slide 5 Maria Grazia Pia, INFN Genova 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,... Slide 6 Maria Grazia Pia, INFN Genova -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 Programme Slide 7 Maria Grazia Pia, INFN Genova Solar flare electrons, protons, and heavy ions Jovian electrons Solar flare neutrons and -rays Solar X-rays Galactic and extra-galactic cosmic rays Induced emission (Neutrinos) Trapped particles Anomalous cosmic rays Slide 8 Maria Grazia Pia, INFN Genova Courtesy A. Brahme (KI) Courtesy A. Brahme (Karolinska Institute) Biological processes Complexity Multiple disciplines involved physics chemistry biology Still object of active research not fully known no general models, only partial/empirical ones Slide 9 Maria Grazia Pia, INFN Genova 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 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 Slide 10 Maria Grazia Pia, INFN Genova Physical processes Biological processes Chemical processes Process user requirement s Courtesy Nature Known, available Unknown, not available E.g. generation of free radicals in the cell User requirements on geometry and visualisation Collection of User Requirements Slide 11 Maria Grazia Pia, INFN Genova 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 Slide 12 Maria Grazia Pia, INFN Genova 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) Slide 13 Maria Grazia Pia, INFN Genova 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 Macroscopic level Slide 14 Maria Grazia Pia, INFN Genova Requirements Problem domain analysis 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 Analysis & Design Implementation Test Experimental validation of Geant4 simulation models Critical evaluation of the models done in progress future Cellular level Slide 15 Maria Grazia Pia, INFN Genova Target theory models Single-hit model Multi-target single-hit model Single-target multi-hit model Joiner & Johns model No hits: cell survives One or more hits:cell dies S(, ) = P SURV ( 0, h=0, ) = (1- 0 ) = exp[ ln (1- 0 )] P SURV (q,b,n,D) = B(b) (e -q D ) (n-b) (1- e -q D ) b n! b! (n -b)! Extension of single-hit model S = e - R [1 + ( S / R -1) e ] D D - D/D C Cell survival equations Cell survival equations based on model-dependent assumptions S= e -D 2 two hits No assumption onTime Enzymatic repair of DNA Slide 16 Maria Grazia Pia, INFN Genova Molecular theory of radiation action (linear-quadratic model) Theory of dual radiation action Repair or misrepair of cell survival Lethal-potentially lethal model Chadwick and Leenhouts (1981) Tobias et al. (1980) Kellerer and Rossi (1971) Curtis (1986) Molecular models for cell death More sophisticated models Slide 17 Maria Grazia Pia, INFN Genova 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 DNA level Slide 18 Maria Grazia Pia, INFN Genova http://www.ge.infn.it/geant4/dna Slide 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