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Bio-2 The Geant4-DNA project

Bio-2 The Geant4-DNA project. http://geant4-dna.org. Takashi Sasaki – KEK, Japan Sébastien Incerti – IN2P3/CENBG, France o n behalf of the Bio-2 team. TYL-FKPPL Joint Workshop, Seoul, June 4-6, 2013. Outline. Context

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Bio-2 The Geant4-DNA project

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  1. Bio-2The Geant4-DNA project http://geant4-dna.org Takashi Sasaki – KEK, Japan Sébastien Incerti – IN2P3/CENBG, France on behalf of the Bio-2 team TYL-FKPPL Joint Workshop, Seoul, June 4-6, 2013

  2. Outline • Context • Development of a simulation platformdedicated to the modellingbiologicaleffects of ionising radiation down to the cellular & sub-cellular scales • the Geant4-DNA project • Proposedworkplan for 2013 • Validation of theoretical cross section models in biomoleculesthroughdedicatedmeasurements • Development of realistic cellular geometries • Efforts toward Geant4-DNA computation speedup • Application in targetedradiotherapy • Collaboration matters

  3. Modelling biological effects of ionising radiation remains a major scientific challenge Chronic exposure «  A major challenge lies in providing a sound mechanistic understanding of low-dose radiation carcinogenesis » L. Mullenders et al. Assessing cancer risks of low-dose radiation Nature Reviews Cancer (2009) Fukushima Diagnosis Space missions http://rcwww.kek.jp/norm/index-e.html ISS Space exploration Proton & hadrontherapy Mars NCC

  4. The Monte Carlo approach • Can « reproduce » with accuracy the stochastic nature of particle-matter interactions • Many Monte Carlo codes are alreadyavailabletoday in radiobiology for the simulation of track structures at the molecularscale in biological medium • E.g. PARTRAC, TRIOL, PHITS, KURBUC, NOREC… • Includephysics & physico-chemistryprocesses, detailedgeometrical descriptions of biologicaltargets down to the DNA size, DNA and chromosome damage simulation and evenrepairmechanisms (PARTRAC)… • Usuallydesigned for veryspecific applications • Not alwayseasilyaccessible • Is it possible to access the source code ? • Are theyadapted to recentOSs ? • Are theyextendable by the user ? « To expandaccessibility and avoid ‘reinventing the wheel’, track structure codes shouldbe made available to all users via the internet from a central data bank» H. Nikjoo, IJRB 73, 355 (1998)

  5. ATLAS, CMS, LHCb, ALICE @ CERN PET Scan(GATE) BaBar, ILC… Brachytherapy Medical linac Earth magnetosphere GLAST/FERMI(NASA) GAIA Physics-Biology DICOM dosimetry ISS Hadrontherapy

  6. Geant4 ? • Can we try to extend Geant4 to model biological effects of radiation ? • Stronglimitations prevent its usage for the modelling of biological effects of ionising radiation at the sub-cellular & DNA scale • Condensed-history approach • No step-by-step transport on small distances, a key requirement for micro/nano-dosimetry • Low-energy limit applicability of EM physics models is limited • ~250 eV for Livermore Low Energy EM models • ~100 eV for Penelope Low Energy EM models • No description of target molecular properties • Liquid water, DNA nucleotides • Only physical particle-matter interactions • Physical interactions are NOT the dominant processes for DNA damage at low LET...

  7. See Int. J. Model. Simul. Sci. Comput. 1 (2010) 157–178 The Geant4-DNA project • Initiated in 2001 by Dr Petteri Nieminen at the European Space Agency/ESTEC • Main objective: extension of the general purpose Geant4 Monte Carlo toolkit for the simulation of interactions of radiation with biological systems at the cellular and DNA level in order to predict early DNA damages in the context of manned space exploration missions (« bottom-up » approach) • Providing an open source access to the scientific community that can be easily upgraded & improved • First prototypes of physics models were added to Geant4 in 2007 • It is now a full independent sub-category of the electromagnetic category of Geant4 • $G4INSTALL/source/processes/electromagnetic/dna • Usable from external codes such as GATE since 2012 • Currently an on-going interdisciplinary activity of the Geant4 collaboration « low energy electromagnetic physics » working group • Coordinated by CNRS/IN2P3 since 2008 • Supported by several funding agencies : ESA (AO6041, AO 7146), ANR, INSERM...

  8. How can Geant4-DNA model radiation biology ? FJPPL Physics stage step-by-stepmodelling of physical interactions of incoming & secondaryionising radiation withbiological medium (liquid water) • Excited water molecules • Ionised water molecules • Solvatedelectrons • Physico-chemistry/chemistry stage • Radicalspecies production • Diffusion • Mutual interactions FJPPL Geometry stage DNA strands, chromatin fibres, chromosomes, wholecell nucleus, cells… for the prediction of damages resultingfrom direct and indirect hits Biology stage DIRECT DNA damages Biology stageINDIRECT DNA damages (dominant @ low LET) t=0 t=10-15s t=10-6s

  9. a) Physics stage:improving Physics

  10. Physics models available in Geant4 9.6+P01 (Spring 2013) • Geant4-DNA physics models are applicable to liquid water, the main component of biological matter • They can reach the very low energy domain down to electron thermalization • Compatible with molecular description of interactions (5 excitation & ionisation levels of the water molecule) • Sub-excitation electrons (below ~9 eV ) can undergo vibrational excitation, attachment and elastic scattering • Purelydiscrete • Simulate all elementary interactions on an event-by-event basis • No condensed history approximation • Models can be purely analytical and/or use interpolated data tables • For eg. computation of integral cross sections • They use the same software design as all electromagnetic models available in Geant4 (« standard » and « low energy » EM models and processes) • Allows the combination of models and processes

  11. Overview of physicsmodels for liquid water • Electrons • Elasticscattering • Screened Rutherford and Brenner-Zaiderbelow 200 eV • Partial waveframework model, 3 contributions to the interaction potential • Ionisation • 5 levels for H2O • Dielectricformalism & FBA using Heller optical data up to 1 MeV, and lowenergy corrections • Excitation • 5 levels for H2O • Dielectricformalism & FBA using Heller optical data and semi-empiricallowenergy corrections • Vibrational excitation • Michaud et al. xsmeasurements in amorphousice • Factor 2 to account for phase effect • Dissociative attachment • Melton et al. xsmeasurements • Protons & H • Excitation • Miller & Green speed scaling of e- excitation atlowenergies and Born and Bethe theoriesabove 500 keV • Ionisation • Rudd semi-empiricalapproach by Dingfelderet al. and Born and Bethe theories & dielectricformalismabove 500 keV (relativistic + Fermi density) • Charge change • Analyticalparametrizations by Dingfelderet al. • He0, He+, He2+ • Excitation and ionisation • Speed and effective charge scalingfrom protons by Dingfelderet al., • Charge change • Semi-empiricalmodelsfromDingfelderet al. • C, N, O, Fe • Ionisation • Speed scaling and global effective charge by Booth and Grant • Photons • from EM « standard » and « low energy » SeeMed. Phys. 37 (2010) 4692-4708 and Appl. Radiat. Isot. 69 (2011) 220-226

  12. Electron process cross sections in liquid water • Electron process cross sections coverenergy range up to 1 MeV down to either • 7.4 eV for the partial waveelasticscattering model (default) • or 9 eV for the Screened Rutherfordelasticscattering model Vib. excitations Ionization = excitation Dissociative attachment

  13. Extension to DNA material • We have implemented physics processes and models for the modeling of proton and neutral hydrogen atom interactions with • liquid water • the four DNA nucleobases : Adenine (A), Thymine (T), Guanine (G) and Cytosine (C) • within a Classical Trajectory Monte Carlo approach and taking into account specific energetic criteria • Mean energy transfers (potential and kinematical) during interactions were computed from quantum mechanics and are tabulated • First time that a general purpose Monte Carlo toolkit is equipped with such functionnalities • Dedicated Physics constructor:G4EmDNACTMCPhysics • Expected to be released in Geant4 X

  14. Examples of integral cross sections Adenine Liquid water • Protons : single capture, single ionization, transfer ionization (new process), double ionization (new process) • Neutral hydrogen : single ionization, stripping • Adenine cross sections are of about one order of magnitude greater than their homologous in liquid water for all the ionizing processes (double ionization shows a 2 orders of magnitude ratio)

  15. Nucl. Instrum. Methods B, in press (2013) Is DNA equivalent to water ? Incident protons • A commonly used approximation • Not necessarily true when studying elementary energy deposition events in nanometer size biological targets ... Chromatine Nucleosome DNA segment (10 bp)

  16. Need for experimental validation of theoretical cross section models • Experimental measurement of cross section in biomolecules remain very scarce today • Pr A. Itoh, Kyoto University, joined this proposal in order to propose an experimental workplan dedicated to the measurement of cross sections in biomolecules • Ion induced collisions on DNA & RNA components • Ionisation and electronic capture processes • Measurement of multi-differential and total cross sections • Will allow the validation Geant4-DNA theoreticalmodels

  17. Nucl. Instrum. Methods B, in press (2013) Eg.: ionisation of Uracil Comparison between experimental and theoretical doubly differential cross sections (CDW-EIS and CB1: solid and dashed line, respectively) for 1 MeV-protons colliding with uracil at different electron emission angles.

  18. Experimental setup • A beam of 1 MeV H+is extracted from a Van de Graff accelerator at Kyoto University • Beam was well collimatedto about 1x3 mm2 in size and was introduced into a double mu-metal shielded collision chamber. • A typical beam current of about 50 nA measured by a Faraday cup was used in this work. • An effusive molecular beam target of uracil was produced by heating crystalline uracil powder (99 % purity) in a stainless steel oven at a temperature of 473 K. • The energy and angular distributions of secondary electrons ejected from uracil molecules were measured by a 45° parallel plate electrostatic spectrometer. • The measurements were carried out for electron energies from 1 eV to 1 keV and emission angles from 15° to 165°. • Experimental errors on the obtained single and doubly differential cross sections are 8-13%.

  19. b) Geometry stage:improving geometries

  20. Towards DNA and cell geometries • Dose Point Kernel simulations and the CENBG« nanobeam » simulations (see Geant4 « nanobeam » advanced example) have shown that the Geant4/Geant4-DNA transport is accurate at nanometer scale • Being included in Geant4, Geant4-DNA can use Geant4 geometry modelling capabilities • We have built a cell nucleus (15 μm diameter) containing 6×109 base pairs of DNA in the B-DNA conformation • Containing randomly oriented and non-overlapping fragments of chromatine fibers • Based on voxellized nucleus phantom (see « microbeam » advanced example)

  21. Frequency of energy deposition in DNA backbone • It is possible to simulate the frequency of energy deposition events in the sugar-phosphate volumes (backbone) of the DNA segments contained in the whole nucleus • This allows for the quantification of DNA direct strand breaks

  22. Estimating DNA damages • Possibility to investigate direct single and double strand breaks • Results depend mainly on • Energy threshold value for induction of a single strand break • Fixed threshold (8.22 eV) • Linear probability (à la PARTRAC) • Geometrical volumes of sugar-phosphate groups (backbone) • Reasonnable agreement with experimental data • Difficult to clearly distinguish direct from non-direct effects Nucl. Instrum. Methods B, in press (2013)

  23. Including chromosomal territories • Voxellized appoach • Voxels cotain a chromatine fiber element of 6 nucleosomes, each including 2 x 100 base pair B-DNA loops • The B-DNA sequence follows the ratio 6:4 (A-T VS G-C) • 46 chromosomes are built from a random walk approach • Each chromosome has a selectable overall shape • Sphere, cylinder, box 5.4x104voxels 46 chromosomes KEK/CENBG

  24. Toward skin tissue • The geometrical model was extended to a skin-like tissue • Top view of three layers of skin-like tissue. • One layer consists 100 voxels with 100 x 100 x 10 micrometer µm3 volume each. • Each voxel contains one nucleus shown as a green sphere that includes the 46 choromosomes. • Deliver a Geant4-DNA example KEK/CENBG

  25. c) Software performance

  26. Improving the computation speed of Geant4-DNA • Hot spots requiring heavy CPU usage will be identified through profiling • Improvement of existing models is proposed, focusing first on two major processes • Simulation of electron elastic scattering – dominant process at low energy • Electron & proton ionization speed-up (Born) • Main energy loss mecanism • Speed improvement on-going through switching to cumulated single differential cross sections

  27. d) Application:targetedradiotherapy

  28. Radionuclide therapy with 125I labeled antibodies to HER Use Geant4-DNA physical processes: ionization, excitation, vibration excitation, electron attachment in water Distribution of energy deposit Electron trajectory (50keV) 100μm 100μm to simulate energy deposition (or dose) in cell nucleus or membrane by Auger electrons (I-125) Simple cell phantom Diameter of cell nucleus: 10μm Size of cell: 20 μm Thickness membrane: 5 nm The simulation results will be useful for the optimization of injected dose and configuration of RI

  29. TRI with Geant4-DNA • More accurate cellular geometries • Cellular phantoms (eg. Rad Prot. Dos. 133 (2009) 2-11 ) • Include new cross section models for biological targets • Theory (including quantum chemistry : GAUSSIAN) • Experiments at Kyoto U. • Simulate oxydative radical generation, interaction and transportation in cells • Other radioemitters • At-211 alpha emitter accuracy

  30. Bio-2 collaboration matters

  31. Participants

  32. Budget request for 2013 • Requestfrom France • 2 french visitorsto KEK & Kyoto U. • Participation to experimental program • (possiblyparticipate to a Geant4 Japanese tutorial) • RequestfromJapan • 3 japanesevisitorsto CENBG for a week • Note: we do not befenitfromanyotherfunding for Japan-France collaboration around Geant4-DNA & Geant4

  33. Geant4-DNA from the Internet A unique web site for Geant4-DNA: http://geant4-dna.org Fullyincluded in Geant4

  34. Thank you very much

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