1. Maria Grazia Pia, INFN Genova DNA

2. 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.) University of Lund

3. Maria Grazia Pia, INFN Genova Medical applications Courtesy of R. Taschereau, UCSF Radiotherapy with external beams, IMRT Brachytherapy PET, SPECT Hadrontherapy

4. Maria Grazia Pia, INFN Genova Biological models in Geant4 Relevance for space: astronaut and aircrew radiation hazards

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,...

6. Maria Grazia Pia, INFN Genova 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 Programme

7. 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

8. 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

9. Maria Grazia Pia, INFN Genova Physical processes Biological processes Chemical processes Process requirements Courtesy Nature Known, available Unknown, not available E.g. generation of free rad icals in the cell User requirements on geometry and visualisation Collection of User Requirements

10. 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 release with usable functionality

11. 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 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. Maria Grazia Pia, INFN Genova 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) Macroscopic level

13. 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

14. 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(ρ, Δ ) = P SURV (ρ 0, h=0, Δ ) = (1- ρ 0 ) Δ = exp[Δ ln (1- ρ 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 -α R [1 + ( α S / α R -1) e ] D – ß D - D/D C Cell survival equations Cell survival equations based on model-dependent assumptions S= e -ßD 2 two hits No assumption on: Time Time Enzymatic repair of DNA Enzymatic repair of DNA

15. 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

16. Maria Grazia Pia, INFN Genova 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. Maria Grazia Pia, INFN Genova TARGET THEORY SINGLE-HIT TARGET THEORY MULTI-TARGET SINGLE-HIT MOLECULAR THEORY RADIATION ACTION MOLECULAR THEORY DUAL RADIATION ACTION MOLECULAR THEORY REPAIR-MISREPAIR LIN REP / QUADMIS MOLECULAR THEORY REPAIR-MISREPAIR LIN REP / MIS MOLECULAR THEORY LETHAL-POTENTIALLY LETHAL MOLECULAR THEORY LETHAL-POTENTIALLY LETHAL – LOW DOSE MOLECULAR THEORY LETHAL-POTENTIALLY LETHAL – HIGH DOSE MOLECULAR THEORY LETHAL-POTENTIALLY LETHAL – LQ APPROX S= e -D / D 0 S = 1- (1- e -q D ) n S = e –p ( αD + ßD ) 2 S = S 0 e - k (ξ D + D ) 2 S = e -αD [1 + (αD / ε) ] εΦ S = e -αD [1 + (αDT / ε) ] ε S = exp[ - N TOT [1 + ] ε ] ε (1 – e - εBAtr ) N PL S = e -η AC D - ln[ S(t)] = (η AC + η AB ) D – ε ln[1 + ( η AB D/ ε)(1 – e -εBA tr )] - ln[ S(t)] = (η AC + η AB e -εBAtr ) D + ( η 2 AB /2 ε)(1 – e -εBA tr ) 2 D 2 ] S = e -q 1 D [ 1- (1- e -q n D ) n ] REVISED MODEL In progress: calculation of model parameters from clinical data

18. 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 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 DNA level

19. Maria Grazia Pia, INFN Genova 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. Maria Grazia Pia, INFN Genova Scenario for Aurora Geant4 simulation space environment + spacecraft, shielding etc. + anthropomorphic phantom Dose in organs at risk 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 Oncological risk to astronauts Risk of nervous system damage

22. Maria Grazia Pia, INFN Genova 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 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