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)

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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...

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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 ?

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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

a) Physics stage:improving Physics

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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

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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)

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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 ...

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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

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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.

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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

b) Geometry stage:improving geometries

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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

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• 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

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• 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

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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

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KEK/CENBG

c) Software performance

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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

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d) Application: targeted radiotherapy

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

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accuracy

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

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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

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Geant4-DNA from the InternetA unique web site for Geant4-DNA: http://geant4-dna.org

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Fully included in Geant4

Thank you very much