Bio-2 The Geant4-DNA project Takashi Sasaki – KEK, Japan Sébastien Incerti – IN2P3/CENBG,...
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Transcript of Bio-2 The Geant4-DNA project Takashi Sasaki – KEK, Japan Sébastien Incerti – IN2P3/CENBG,...
Bio-2The Geant4-DNA project
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
http://geant4-dna.org
Outline• Context
– Development of a simulation platform dedicated to the modelling
biological effects of ionising radiation down to the cellular & sub-
cellular scales
– the Geant4-DNA project
• Proposed workplan for 2013
1. Validation of theoretical cross section models in biomolecules
through
dedicated measurements
2. Development of realistic cellular geometries
3. Efforts toward Geant4-DNA computation speedup
4. Application in targeted radiotherapy
• Collaboration matters2
Modelling biological effects of ionising radiation remains a major scientific
challenge
« 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) 3NCC
Mars
Chronic exposure
http://rcwww.kek.jp/norm/index-e.html
Diagnosis
Space exploration
Space missions
Proton & hadrontherapy
ISS
Fukushima
The Monte Carlo approach• Can « reproduce » with accuracy the stochastic nature of particle-matter interactions
• Many Monte Carlo codes are already available today in radiobiology for the
simulation of track structures at the molecular scale in biological medium
– E.g. PARTRAC, TRIOL, PHITS, KURBUC, NOREC…
– Include physics & physico-chemistry processes, detailed geometrical descriptions of biological
targets down to the DNA size, DNA and chromosome damage simulation and even repair
mechanisms (PARTRAC)…
• Usually designed for very specific applications
• Not always easily accessible
– Is it possible to access the source code ?
– Are they adapted to recent OSs ?
– Are they extendable by the user ?
« To expand accessibility and avoid ‘reinventing the wheel’, track structure codes should
be made available to all users via the internet from a central data bank»
H. Nikjoo, IJRB 73, 355 (1998)
5
Earth magnetosphere
ISS
GAIA
GLAST/FERMI
(NASA)
Brachytherapy
PET Scan(GATE)
Hadrontherapy
DICOM dosimetry
Medical linac
ATLAS, CMS, LHCb, ALICE @ CERN
BaBar, ILC…
Physics-Biology
Geant4 ?• Can we try to extend Geant4 to model biological effects of
radiation ?
• Strong limitations 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...
6
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... 7
See Int. J. Model. Simul. Sci. Comput. 1 (2010) 157–178
How can Geant4-DNA model radiation biology ?
8
Physics stagestep-by-step modelling of physical interactions of
incoming & secondary ionising radiation with
biological medium (liquid water)
Physico-chemistry/chemistry stage • Radical species production• Diffusion• Mutual interactions
Geometry stageDNA strands, chromatin fibres, chromosomes, whole cell nucleus, cells…
for the prediction of damages resulting from direct and indirect hits
• Excited water molecules• Ionised water molecules• Solvated electrons
Biology stage DIRECT DNA damages
Biology stageINDIRECT DNA damages (dominant @ low
LET)
t=0 t=10-15s t=10-6s
FJPPL
FJPPL
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
• Purely discrete
– 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 10
Overview of physics models for liquid water
• Electrons
– Elastic scattering
• Screened Rutherford and Brenner-Zaider below
200 eV
• Partial wave framework model,
3 contributions to the interaction potential
– Ionisation
• 5 levels for H2O
• Dielectric formalism & FBA using Heller optical
data up to 1 MeV, and low energy corrections
– Excitation
• 5 levels for H2O
• Dielectric formalism & FBA using Heller optical
data and semi-empirical low energy corrections
– Vibrational excitation
• Michaud et al. xs measurements in amorphous
ice
• Factor 2 to account for phase effect
– Dissociative attachment
• Melton et al. xs measurements
• Protons & H
– Excitation
• Miller & Green speed scaling of e- excitation at
low energies and Born and Bethe theories
above 500 keV
– Ionisation
• Rudd semi-empirical approach by Dingfelder et
al. and Born and Bethe theories & dielectric
formalism above 500 keV (relativistic + Fermi
density)
– Charge change
• Analytical parametrizations by Dingfelder et al.
• He0, He+, He2+
– Excitation and ionisation
• Speed and effective charge scaling from
protons by Dingfelder et al.,
– Charge change
• Semi-empirical models from Dingfelder et al.
• C, N, O, Fe
– Ionisation
• Speed scaling and global effective charge by
Booth and Grant
• Photons
– from EM « standard » and « low energy »
11See Med. Phys. 37 (2010) 4692-4708
and Appl. Radiat. Isot. 69 (2011) 220-226
Electron process cross sections in liquid water
• Electron process cross sections cover energy range up to 1 MeV down to
either – 7.4 eV for the partial wave elastic scattering model (default)
– or 9 eV for the Screened Rutherford elastic scattering model 12
Vib. excitations
Dissociative attachment
Ionization = excitation
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
13
Examples of integral cross sections
• 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)
14
Liquid water Adenine
Is DNA equivalent to water ?• A commonly used
approximation
• Not necessarily true when
studying elementary
energy deposition events
in nanometer size
biological targets ...
15
Chromatine
DNA segment (10 bp)
Nucleosome
Incident protons
Nucl. Instrum. Methods B, in press (2013)
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 theoretical models
16
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.
17
Nucl. Instrum. Methods B, in press (2013)
Experimental setup• A beam of 1 MeV H+ is extracted from a Van de Graff accelerator at Kyoto
University
• Beam was well collimated to 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%. 18
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) 20
Frequency of energy deposition in DNA backbone
21
• 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
Estimating DNA damages
22
• 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)
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
23
5.4x104 voxels46 chromosomes
KEK/CENBG
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
24
KEK/CENBG
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
26
Radionuclide therapy with 125I labeled antibodies to HERUse Geant4-DNA physical processes: ionization, excitation, vibration excitation, electron attachment in water
Electron trajectory (50keV)
Distribution of energy deposit
to simulate energy deposition (or dose) in cell nucleus or membrane by Auger electrons (I-125)
Energy deposit (dose)/ decay of I-125
I-125 located at cell nucleus
I-125 located at cell membrane
Energy depositin nucleus (dose)
9.3keV (3.7mGy) 0.4keV (0.18mGy)
Energy depositin cytoplasm (dose)
4.4keV (0.26mGy) 6.6keV (0.38mGy)
Energy depositin membrane (dose)
0.001keV (0.09mGy) 0.15keV (10mGy)
The simulation results will be useful for the optimization of injected dose and configuration of RI
Diameter of cell nucleus: 10μm Size of cell: 20 μmThickness membrane: 5 nm
Simple cell phantom
100μm 100μm
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
29
accuracy
Participants
France Japan
C. Champion CENBG K. Amako KEK
S. Incerti CENBG S. Hasegawa NIRS
(M. Karamitros) CENBG Y. Hirano NIRS
A. Itoh Kyoto U.
A. Kimura Ashikaga IT
K. Murakami KEK
C. Omachi Nagoya city hosp.
T. Sasaki KEK
31
Budget request for 2013• Request from France
– 2 french visitors to KEK & Kyoto U.
• Participation to experimental program
• (possibly participate to a Geant4 Japanese tutorial)
• Request from Japan
– 3 japanese visitors to CENBG for a week
• Note: we do not befenit from any other funding for Japan-
France collaboration around Geant4-DNA & Geant4
32
Geant4-DNA from the InternetA unique web site for Geant4-DNA: http://geant4-dna.org
33
Fully included in Geant4