DNA. for Microdosimetry. Maria Grazia Pia INFN Genova. CECAM Workshop. S. Chauvie (Cuneo Hospital and INFN), S. Incerti and Ph.

Size: px

Start display at page:

Download "DNA. for Microdosimetry. Maria Grazia Pia INFN Genova. CECAM Workshop. S. Chauvie (Cuneo Hospital and INFN), S. Incerti and Ph."

Roderick Marsh
5 years ago
Views:

1 Partly funded by for Microdosimetry Maria Grazia Pia INFN Genova DNA S. Chauvie (Cuneo Hospital and INFN), S. Incerti and Ph. Moretto (CENBG) CECAM Workshop Lyon, 3-6 December 2007

2 Courtesy Borexino Courtesy CMS Collaboration Courtesy ATLAS Collaboration Born from the requirements of large scale HEP experiments S. Agostinelli et al. GEANT4 - a simulation toolkit NIM A 506 (2003) Most cited Nuclear Science and Technology publication! Courtesy H. Araujo and A. Howard, IC London ZEPLIN III Widely used also in Space science and astrophysics Medical physics, nuclear medicine Radiation protection Accelerator physics Humanitarian projects, security etc. Technology transfer to industry, hospitals Courtesy K. Amako et al., KEK Courtesy GATE Collaboration Courtesy R. Nartallo et al.,esa

3 Complex physics Complex detectors 20 years software life-span LHCb LHC ATLAS

4 Multi-disciplinary application environment Dosimetry Courtesy of ESA Space science Radiotherapy Courtesy of CERN RADMON team Effects on components Wide spectrum of physics coverage, variety of physics models Precise, quantitatively validated physics Accurate description of geometry and materials

5 Dosimetry in Medical Applications Hadrontherapy Radiotherapy with external beams, IMRT Courtesy of F. Foppiano et al., IST and INFN Genova Courtesy of P. Cirrone et al., INFN LNS Courtesy of F. Foppiano et al,. IST and INFN Genova Radiation Protection Brachytherapy Courtesy of J. Perl, SLAC Courtesy of L. Beaulieu et al., Laval

6 Exotic Geant4 applications 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

7 Precise dose calculation Geant4 Low Energy Electromagnetic Physics package Electrons and photons (250/100 ev < E < 100 GeV) Models based on the Livermore libraries (EEDL, EPDL, EADL) Models à la Penelope Hadrons and ions Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch Nuclear stopping power, Barkas effect, chemical formula, effective charge etc. Atomic relaxation Fluorescence, Auger electron emission, PIXE shell effects ions Atomic relaxation Fluorescence Auger effect Fe lines GaAs lines

8 Fundamental concepts Functionality: physics, geometry etc. Software technology Toolkit Transparency Open source distribution International Collaboration

9 Physics From the Minutes of LCB (LHCC Computing Board) meeting on 21 October, 1997: It was noted that experiments have requirements for independent, alternative physics models. In Geant4 these models, differently from the concept of packages, allow the user to understand how the results are produced, and hence improve the physics validation. Geant4 is developed with a modular architecture and is the ideal framework where existing components are integrated and new models continue to be developed.

10 Geant4 architecture Software Engineering plays a fundamental role in Geant4 Interface to external products w/o dependencies Domain decomposition hierarchical structure of subdomains Uni-directional flow of dependencies User Requirements formally collected systematically updated PSS-05 standard spiral iterative approach Software Process regular assessments and improvements (SPI process) monitored following the ISO model Object Oriented methods OOAD use of CASE tools openness to extension and evolution contribute to the transparency of physics interface to external software without dependencies commercial tools Quality Assurance code inspections automatic checks of coding guidelines testing procedures at unit and integration level dedicated testing team Use of Standards de jure and de facto

11 OO technology Openness to extension and evolution new implementations can be added w/o changing the existing code Robustness and ease of maintenance protocols and well defined dependencies minimize coupling Strategic vision components Toolkit A set of compatible components each component is specialised for a specific functionality each component can be refined independently to a great detail components can be integrated at any degree of complexity it is easy to provide (and use) alternative components the user application can be customised as needed

13 Biological models in Geant4 Relevance for space: astronaut and aircrew radiation hazards Project originally motivated and partly funded by

14 INFN (Genova) - IN2P3 (CENBG) Partly sponsored by ESA New collaborators welcome! DNA Sister activity to Geant4 Low-Energy Electromagnetic Physics Follows the same rigorous software standards Simulation of nano-scale effects of radiation at the DNA level Various scientific domains involved medical, biology, genetics, physics, software engineering Multiple approaches can be implemented with Geant4 RBE parameterisation, detailed biochemical processes, etc. First phase: Collection of user requirements & first prototypes Second phase: started in 2004 Software development & open source release

15 Macroscopic level calculation of dose already feasible with Geant4 develop useful associated tools Cellular level cell modelling processes for cell survival, damage etc. Multiple domains in the same software environment Complexity of software, physics and biology addressed with an iterative and incremental software process DNA level DNA modelling physics processes at the ev scale bio-chemical processes processes for DNA damage, repair etc. Parallel development at all the three levels (domain decomposition)

16 What s s new? Many track structure Monte Carlo codes previously developed A lot of modelling expertise embedded in these codes Each code implements one modelling approach (developed by its authors) Stand-alone codes, with limited application scope Legacy software technology (FORTRAN, procedural programming) Not publicly distributed Geant4-DNA Track structure simulation in a general-purpose Monte Carlo system Toolkit approach: many interchangeable models Advanced software technology Rigorous software process Open source, freely available, supported by an international organization Foster a collaborative spirit in the scientific community Benefit of the feedback of a wider user community

17 1 st development cycle: Geant4 physics extensions Complex domain Physics down to the ev scale Physics: collaboration with theorists Technology: innovative design technique introduced in Geant4 (1 st time in Monte Carlo) Experimental complexity as well Scarce experimental data Collaboration with experimentalists for model validation Geant4 physics validation at low energies is difficult!

18 Geant4-DNA physics processes Specialised processes for low energy interactions with water Models in liquid water More realistic than water vapour Theoretically more challenging Hardly any experimental data New measurements needed Status 1st β-release Geant4 8.1 Full release on 14 December 2007 Further extensions in progress Models for water vapour Models for other materials than water Particle Processes e - p H He++ He+ He Elastic scattering Excitation Ionisation Charge decrease Excitation Ionisation Charge increase Ionisation Charge decrease Excitation Ionisation Charge decrease Charge increase Excitation Ionisation Charge increase Excitation Ionisation

19 (Current) Physics Models e p H α He+ He Elastic > 7.5 ev Screened Rutherford + empirical Brenner-Zaider Excitation Charge Change Ionisation 7.5 ev 10 kev A 1 B 1, B 1 A 1, Ryd A+B, Ryd C+D, diffuse bands 7 ev 10 kev Emfietzoglou 1b 1, 3a 1, 1b 2, 2a 1 + 1a 1 10 ev 500 kev Dingfelder 500 kev 10 MeV Emfietzoglou 100 ev 10 MeV Dingfelder 100 ev 500 kev Rudd 500 kev 10 MeV Dingfelder (Born) 100 ev 10 MeV Dingfelder 100 ev 10 MeV Dingfelder 100 ev 10 MeV Dingfelder Effective charge scaling from same models as for proton Dingfelder

20 Why these models? No emotional attachment to any of the models Toolkit: offer a wide choice among many available alternatives Complementary/alternative models No one size fits all Powerful design Abstract interfaces: the kernel is blind to any specific modelling The system is intrinsically open to multiple implementations Improvements, extensions, options Open system Collaboration is welcome (experimental/modelling/software)

21 What is behind A policy defines a class or class template interface Policy host classes are parameterised classes classes that use other classes as a parameter Advantage w.r.t. a conventional strategy pattern Policies are not required to inherit from a base class The code is bound at compilation time No need of virtual methods, resulting in faster execution Policy-based class design New technique 1 st time introduced in Monte Carlo Weak dependency of the policy and the policy based class on the policy interface Syntax-oriented rather than signature-oriented Highly customizable design Open to extension Policies can proliferate w/o any limitation

22 Geant4-DNA physics process Handled transparently by Geant4 kernel Deprived of any intrinsic physics functionality Configured by template specialization to acquire physics properties

23 Development metrics Open to extension: what does it mean in practice? Implementation + unit test of a new physics model ~ 5 to 7 hours (average computing experience) No integration effort at all Other software processes Peer review of the code Integration testing System testing Porting to other supported platforms User documentation Experimental validation Investment in software technology!

24 More details on both software and physics in IEEE Trans. Nucl. Sci., Vol. 54, no. 6, Dec. 2007

= 20 kev Shower of particles at the nm / ev scale

25 Example of simulation Liquid water sphere 0.2 µm diameter 1000 electrons shot from central source E = 20 kev Shower of particles at the nm / ev scale Geant4 physics processes: Elastic scattering Excitation Ionisation 0.2 µm

26 How accurate are Geant4-DNA physics models? Both theoretical and experimental complexity in the very low energy régime Theoretical calculations must take into account the detailed dielectric structure of the interacting material Approximations, assumptions, semi-empirical models Experimental measurements are difficult Control of systematics Practical constraints depending on the phase

27 Verification & Validation Verification Conformity with theoretical models Performed on all physics models Validation Against experimental data Lack of experimental data in liquid water in the very low energy range New measurements needed Evaluation of plausibility Only practical option at the present stage Comparison against experimental data in water vapour/ice Interesting also to study phase-related effects

28 A selection of results Systematic comparison in progress Survey of literature: extensive collection of experimental data (goal: all!) No time to show all of them ( paper) Selection of a few interesting cases Highlight the complexity of the experimental domain Discuss physics modelling features S. Chauvie, S. Incerti, P. Moretto, M. G. Pia, Evaluation of Phase Effects in Geant4 Microdosimetry Models for Particle Interactions in Water, Proc. IEEE NSS 2007

29 Electron elastic scattering Theoretical challenge to model accurately at very low energy Various theoretical approaches at different degrees of complexity From simple screened Rutherford cross section to sophisticated phase shift calculations No experimental data in liquid water Geant4-DNA Simple screened Rutherford cross section + semi-empirical model based on vapour data (Why so unsophisticated? Look at the experimental data ) Open to evolution along with the availability of new data

30 Electron elastic scattering: total cross section Cross section(cm 2 ) Not all available experimental data reported the picture would be too crowded! Recommended total cross section smaller than elastic only one! Geant4-DNA elastic Itikawa & Mason elastic (recommended) Itikawa & Mason total (recommended) Danjo & Nishimura Seng et al. Sueoka et al. Saglam et al. Evident discrepancy of the experimental data Puzzle: inconsistency in recommended evaluated data from Itikawa & Mason, J. Phys. Chem. Ref. Data, 34-1, pp. 1-22, Geant4-DNA Better agreement with some of the data sets Hardly conclusive comparison, given the experimental status Energy (ev)

31 Electron ionisation Semi-empirical model D. Emfietzoglou and M. Moscovitch, Inelastic collision characteristics of electrons in liquid water, NIM B, vol. 193, pp , 2002 Based on dielectric formalism for the valence shells (1b1, 3a1, 1b2 and 2a1) responsible for condensedphase effects Based on the binary encounter approximation for the K-shell (1a1)

32 Electron ionisation: total cross section Different phases Geant4-DNA model: liquid water Experimental data: vapour Plausible behaviour of Geant4 implementation Geant4-DNA Born ionisation Itikawa & Mason ionisation (recommended) Phase differences appear more significant at lower energies

33 Proton ionisation Cross section based on two complementary models a semi-empirical analytical approach with parameters specifically calculated for liquid water for 100 ev < E < 500 kev a model based on the Born theory for 500 kev < E < 10 MeV M. Dingfelder et al., Inelastic-collision cross sections of liquid water for interactions of energetic protons, Radiat. Phys. Chem., vol. 59, pp , M. E. Rudd et al., Cross sections for ionisation of water vapor by kev protons, Phys. Rev. A, vol. 31, pp , M. E. Rudd et al., Electron production in proton collisions: total cross sections, Rev. Mod. Phys., vol. 57, no. 4, pp , 1985.

34 Proton ionisation: total cross section Different phases Geant4-DNA model: liquid water Experimental data: vapour M. E. Rudd, T. V. Goffe, R. D. DuBois, L. H. Toburen, Cross sections for ionisation of water vapor by kev protons, Phys. Rev. A, vol. 31, pp , Geant4-DNA All measurements performed by the same team at different accelerators and time Even data taken by the same group exhibit inconsistencies! systematic is difficult to control in delicate experimental conditions Geant4-DNA models look plausible PNL data early Van de Graaff data late Van de Graaff data early Univ. Nebraska-Lincoln data late Univ. Nebraska-Lincoln data tandem Van de Graaff data Fit to experimental data Hard to discuss phase effects in these experimental conditions! Goodness-of-fit test Geant4 DNA model incompatible with experimental data (p-value < 0.001) Compatibility w.r.t. data fit? Cramer-von Mises test: p-value = 0.1 Anderson-Darling test: p-value <0.001

35 Proton and hydrogen charge change Cross section based on a semi-empirical approach Described by an analytical formula With parameters optimised from experimental data in vapour M. Dingfelder et al., Inelastic-collision cross sections of liquid water for interactions of energetic protons, Radiat. Phys. Chem., vol. 59, pp , B. G. Lindsay et al., Charge transfer of 0.5-, 1.5-, and 5-keV protons with H2O: absolute differential and integral cross sections, Phys. Rev. A, vol. 55, no. 5, pp , R. Dagnac et al., A study on the collision of hydrogen ions H + 1, H+ 2 and H+ 3 with a water-vapour target, J. Phys. B, vol. 3, pp , L. H. Toburen et al., Measurement of highenergy charge transfer cross sections for incident protons and atomic hydrogen in various gases, Phys. Rev., vol. 171, no. 1, pp , 1968

36 Charge change cross section: proton and hydrogen Large discrepancies among the data! Different phases Geant4-DNA model: liquid Experimental data: vapour Lindsay et al. Dagnac et al. Toburenetal. Berkner et al. Cable Koopman Chambers et al. Goodness-of-fit test Geant4-DNA model experimental data (white symbols only) Anderson-Darling test Cramer-von Mises test Kolmogorov-Smirnov test Kuiper test Watson test p-value > 0.1 from all tests but some data were used to optimise the semi-empirical empirical model!

37 Conclusion from comparisons Geant4-DNA models (liquid) look plausible when compared to available experimental data (vapour) More experimental data are needed In liquid water for simulation model validation In vapour and ice to study the importance of phase effects in modelling particle interactions with the medium With good control of systematic and reproducibility of experimental conditions! Hard to draw firm conclusions about phase effects Available experimental data exhibit significant discrepancies in many cases Some of these data have been already used to constrain or optimize semiempirical models

38 Exploiting the toolkit For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of radiation Geant4-DNA physics processes Kernel User Interface Geometry Visualisation

39 Microdosimetry in high resolution cellular phantoms with Geant4-DNA IPB/CENBG

40 Context Understanding the health effects of low doses of ionizing radiation is the challenge of today s radiobiology research At the cell scale, recent results include the observation of bystander effects adaptive response gene expression changes genomic instability genetic susceptibility May question the validity of health risk estimation at low doses of radiation Consequences for radiotherapy, environment exposure, space exploration Dedicated worldwide experimental facilities to investigate the interaction of ionizing radiation with living cells radioactive sources classical beams microbeams: allow a perfect control of the deposited dose in the targeted cell (e.g. the CENBG irradiation facility in France)

single cell & single ion mode Targeting accuracy on living cells in

41 CENBG AIFIRA irradiation facility in Bordeaux, France AIFIRA equipped with a cellular irradiation microbeam line 3 MeV proton or α beam single cell & single ion mode Targeting accuracy on living cells in air: a few µm Able to quantify DNA damages like double strand breaks IPB/CENBG

Realistic cellular geometries from confocal microscopy Confocal microscopy offers several advantages over conventional widefield optical microscopy ability to control

42 Realistic cellular geometries from confocal microscopy Confocal microscopy offers several advantages over conventional widefield optical microscopy ability to control depth of field elimination of background information away from the focal plane (that leads to image degradation) Olympus collect serial optical sections from thick specimens

43 Confocal microscopy IPB/CENBG IPB/CENBG Images of human keratinocyte cells HaCaT/(GFP-H2B)Tg acquired at CENBG cell line used in single cell irradiation at CENBG Cells fixed after 4 hours or 24 hours of incubation (cell irradiation conditions) Staining Nucleus: Hoechst dye (DNA marker) Cytoplasm: propidium iodide, (RNA and DNA marker). Nucleoli (high chromatine and protein concentration regions): idem Acquisition 2D images acquired every 163 nm with a Leica DMR TCS SP2 confocal microscope several 2D resolutions, up to pixels Image reconstruction 3D stacking using the Leica Confocal Software filtering and phantom geometry reconstruction with Mercury Computer Systems, Inc. Amira suite

44 Building cellular models a b Selection of four phantoms reconstructed from D confocal images. c d Incubation : 4 hours for cells a and b 24 hours for cells c and d IPB/CENBG The cytoplasm and nucleoli appear in red while the nucleus is shown in blue

45 Geometry modelling Exploit the advantage of a general purpose Monte Carlo system Powerful Geant4 geometry package Use of functionality already existing in Geant4 Voxel geometries + Navigation optimisation techniques Not available in ad-hoc Monte Carlo codes Parameterised volumes Nested parameterisation Direct benefit from investment in the Geant4 toolkit Realistic rendering of the biological systems Important for overall realistic simulation results

46 Cellular phantoms in Geant4 Implemented either as parameterised volumes or nested geometries (faster navigation above 64x64 resolution) Composition: liquid water (compatible with Geant4 DNA models) These cellular models are publicly available in the Geant4 microbeam Advanced Example geant4/examples/advanced/microbeam

47 Cellular phantom model 24h incubated cell Irradiated with a 2.37 MeV α + beam 64 x 64 x 60 resolution 0.36 x 0.36 x 0.16 µm 3 voxel size 2.37 MeV α + hitting the cell cytoplasm ~10 µm nucleus

48 Shower in cellular phantom 2.37 MeV α+ delivered on targeted cell by the CENBG microbeam irradiation facility ZOOM Elastic scattering Ionisation G4 DNA processes CPU ~45 min (preliminary timing) Charge decrease Charge increase Excitation (unit: µm)

49 Geant4 DNA capabilities With this Geant4 extension, it is now possible to study the energy deposit distribution produced by a primary particle and its secondaries inside a cell Access distributions in nucleus, cytoplasm, mitochondria What you get in return is more than your own investment!

50 Changing scale Courtesy E. Hall Large effort for microscopic modelling of interactions and biological systems in Geant4 Parallel approach: macroscopic modelling in Geant4 Concept of dose in a cell population Statistical evaluation of radiation effects from empirical data All this is possible in the same simulation environment (toolkit) Human cell lines irradiated with X-rays Example: modelling cell survival fraction in a population of irradiated cells

$parameters Computation of dose in a cell population and estimation of survival fraction Monolayer V79-379A$ cells Proton beam E= 3.66 MeV/n Linear-Quadratic model Dose (Gy) α = 0.32 β = -0.039 Folkard et al., Int. J.

cells Proton beam E= 3.66 MeV/n Linear-Quadratic model Dose (Gy) α = 0.32 β = -0.039 Folkard et al., Int. J.

51 Survival Example Data points: Geant4 simulation results Continuous line: LQ theoretical model with Folkard parameters Computation of dose in a cell population and estimation of survival fraction Monolayer V79-379A cells Proton beam E= 3.66 MeV/n Linear-Quadratic model Dose (Gy) α = 0.32 β = Folkard et al., Int. J. Rad. Biol., 1996 Macroscopic cell survival models to be distributed in Geant4 (advanced example in preparation)

52 Conclusion The Geant4 DNA processes are publicly available Can be applied to realistic cell geometries Full comparison against vapour/ice will be published evaluation of phase effects Thanks to the flexibility of policy-based code design of Geant4 DNA, any interaction model can be easily implemented in a few hours and automatically integrated in Geant4! Not limited to radiation biology

53 Short term Geant4 DNA processes Perspectives will be publicly available in Geant4 9.1 on 14 December 2007 Microdosimetry advanced example will be available in the next Geant4 releases (presumably end of June 2008) illustrates how to use the Geant4 DNA physics processes Cellular survival advanced example in preparation Other physics models thanks to the novel software design Longer term Chemical phase: production of radical species Geometry-dedicated development cycle: DNA geometry modelling Biological phase: prediction of DNA damages (double strand breaks fatal lesions, DNA fragments ) after irrradiation Other materials than liquid water: DNA bases, silicon etc.

54 For discussion Geant4-DNA proposes a paradigm shift Open source, freely available software Microdosimetry/radiobiology functionality in a general-purpose Monte Carlo code Availability of multiple models in the same environment Equal importance to functionality and software technology Foster collaboration within the scientific community Theoretical modelling, experimental measurements, software technology Promote feedback from users of the software Comments and suggestions are welcome...

55 Acknowledgment Thanks to M. Dingfelder and D. Emfietzoglou for theoretical support W. Friedland and H. Paretzke for fruitful discussions and suggestions P. Nieminen for motivation and support to the project through ESA funding COST-P9 for supporting short-term visits R. Capra, Z. Francis, G. Montarou for preliminary contributions at an early stage G. Cosmo and I. McLaren for support in the Geant4 system testing process K. Amako for support in releasing the Geant4-DNA code documentation Z. W. Bell (TNS Senior Editor) for his advice in the paper publication process CERN Library for providing many reference papers Thanks to Nigel Mason and CECAM for organizing this workshop and supporting our participation!

Radiobiology, nanotechnology, radiation effects on components. S. Chauvie (Cuneo Hospital and INFN Genova) Maria Grazia Pia (INFN Genova)

for microdosimetry Radiobiology, nanotechnology, radiation effects on components S. Chauvie (Cuneo Hospital and INFN Genova) Maria Grazia Pia (INFN Genova) Workshop: La radiobiologia dell INFN Trieste,