Bio-2
The 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
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 matters
2
Modelling biological effects of ionising
radiation remains a major scientific challenge
Chronic exposure
Fukushima
Diagnosis
Space missions
http://rcwww.kek.jp/norm/index-e.html
« A major challenge lies in
Space exploration
ISS
Proton &
hadrontherapy
providing a sound mechanistic
understanding of low-dose
radiation carcinogenesis »
L. Mullenders et al.
Mars
Assessing cancer risks of lowdose radiation
Nature Reviews Cancer (2009)
NCC
3
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)
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
5
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
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...
7
How can Geant4-DNA model
radiation biology ?
FJPPL
Physics stage
step-by-step modelling of
physical interactions of
incoming & secondary ionising
radiation with biological medium
(liquid water)
• Excited water molecules
• Ionised water molecules
• Solvated electrons
Physico-chemistry/chemistry stage
• Radical species production
• Diffusion
• Mutual interactions
Geometry stage
DNA strands, chromatin fibres, chromosomes, whole cell nucleus, cells…
for the prediction of damages resulting from direct and indirect hits
Biology stage
DIRECT DNA damages
t=0
FJPPL
Biology stage
INDIRECT DNA damages (dominant @ low LET)
t=10-15s
t=10-6s
8
a) Physics stage:
improving Physics
9
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
•
Protons & H
–
•
Excitation
•
Electrons
–
energies and Born and Bethe theories above 500 keV
Elastic scattering
•
Screened Rutherford and Brenner-Zaider below 200 eV
•
Partial wave framework model,
–
Ionisation
•
5 levels for H2O
•
Dielectric formalism & FBA using Heller optical data up to
1 MeV, and low energy corrections
–
keV (relativistic + Fermi density)
Ionisation
•
–
5 levels for H2O
•
Dielectric formalism & FBA using Heller optical data and
•
–
Michaud et al. xs measurements in amorphous ice
•
Factor 2 to account for phase effect
Speed and effective charge scaling from protons by
Dingfelder et al.,
–
Charge change
•
•
Dissociative attachment
•
Excitation and ionisation
•
Vibrational excitation
•
Analytical parametrizations by Dingfelder et al.
He0, He+, He2+
–
semi-empirical low energy corrections
–
Charge change
•
Excitation
•
Rudd semi-empirical approach by Dingfelder et al. and
Born and Bethe theories & dielectric formalism above 500
3 contributions to the interaction potential
–
Miller & Green speed scaling of e- excitation at low
Semi-empirical models from Dingfelder et al.
C, N, O, Fe
–
Ionisation
Melton et al. xs measurements
•
Speed scaling and global effective charge by Booth and
Grant
See Med. Phys. 37 (2010) 4692-4708
and Appl. Radiat. Isot. 69 (2011) 220-226
•
Photons
–
from EM « standard » and « low energy »
11
Electron process cross sections in liquid water
Vib. excitations
Ionization = excitation
Dissociative
attachment
•
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
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
Liquid water
Adenine
•
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
Nucl. Instrum. Methods B, in press (2013)
Is DNA equivalent to water ?
•
A commonly used
Incident protons
approximation
•
Not necessarily true when
studying elementary energy
Chromatine
deposition events in nanometer
size biological targets ...
Nucleosome
DNA segment (10 bp)
15
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
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.
17
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 mumetal 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
b) Geometry stage:
improving geometries
19
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 nonoverlapping fragments of chromatine fibers
–
Based on voxellized nucleus phantom (see
« microbeam » advanced example)
20
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
21
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)
Nucl. Instrum. Methods B, in press (2013)
Reasonnable agreement with experimental data
–
Difficult to clearly distinguish direct from non-direct effects
22
Including chromosomal territories
•
Voxellized appoach
– Voxels cotain a chromatine fiber
element of 6 nucleosomes, each
5.4x104 voxels
46 chromosomes
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
KEK/CENBG
23
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
24
c) Software performance
25
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
d) Application:
targeted radiotherapy
27
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
Energy deposit (dose)
/ decay of I-125
Energy deposit
in nucleus (dose)
I-125 located at
cell nucleus
9.3keV (3.7mGy)
I-125 located at
cell membrane
0.4keV (0.18mGy)
Energy deposit
in cytoplasm (dose)
4.4keV (0.26mGy)
6.6keV (0.38mGy)
Energy deposit
in 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
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
29
Bio-2 collaboration matters
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 Internet
A unique web site for Geant4-DNA: http://geant4-dna.org
Fully included in Geant4
33
Thank you very much