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Maria Grazia Pia, INFN Genova
DNADNA
Maria Grazia Pia, INFN Genova
Based onBased on
Partly funded byPartly funded by
Geant4-DNAGeant4-DNASimulation of Interactions of Radiation with Biological Simulation of Interactions of Radiation with Biological
Systems Systems at the Cellular and DNA Levelat the Cellular and DNA Level
R. Capra, S. Chauvie, R. Cherubini, Z. Francis, S. Gerardi, S. Guatelli, G. Guerrieri, S. Incerti, B. Mascialino, G. Montarou, Ph. Moretto, P. Nieminen, M.G. Pia, M. Piergentili, C. Zacharatou
+ biology experts (E. Abbondandolo, G. Frosina, E. Giulotto et al.)
University of Lund
Maria Grazia Pia, INFN Genova
MedicalMedical applicationsapplications
Courtesy of R. Taschereau, UCSF
Radiotherapy with external beams, IMRT
Brachytherapy
PET, SPECT
Hadrontherapy
Maria Grazia Pia, INFN Genova
Biological models in Geant4 Biological models in Geant4
Relevance for space: Relevance for space: astronaut and aircrew radiation hazardsastronaut and aircrew radiation hazards
Maria Grazia Pia, INFN Genova
RelevanceRelevance
The concept of “dose” fails at cellular and DNA scales
It is desirable to gain an understanding to the processes at all levels (macroscopic vs. microscopic+cybernetic)
Quantitative knowledge and strict user requirements scientifically satisfying; may be used as feedback to experimentalists
Potential later connection to other than radiation-induced effects at the cellular and DNA level
Relevance for space: astronaut and airline pilot radiation hazards, biological experiments
Applications in radiotherapy, radiobiology, ...
Maria Grazia Pia, INFN Genova
Geant4-based “sister” activity to the Geant4 Low-Energy Electromagnetic Working Group
– Follows the same rigorous software standards
International (open) collaboration– ESA, INFN (Genova, LNL, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand),
Univ. of Lund
Simulation of nano-scale effects of radiation at the DNA level– Various scientific domains involved
medical, biology, genetics, software engineering, high and low energy physics, space physics
– Multiple approaches can be implemented with Geant4 RBE parameterisation, detailed biochemical processes, etc.
First phase: 2000-2001– Collection of user requirements & first prototypes
Second phase: 2004-2008– Software development & release
ProgrammeProgramme
Maria Grazia Pia, INFN Genova
Cou
rtes
y A
. Bra
hme
(KI)
Courtesy A. Brahme (Karolinska Institute)
Biological Biological processesprocesses
Complexity
Multiple disciplines involved– physics– chemistry– biology
Still object of active research– not fully known– no general models, only
partial/empirical ones
Maria Grazia Pia, INFN Genova
First phaseFirst phaseCollection of user requirements
– from various sources: physics, space science, radiobiology, genetics, radiotherapy etc.
– analysis of existing models and software codes– …not an easy task (as usual in requirements engineering!)
User Requirements Document available from http://www.ge.infn.it/geant4/dna
Development of a toy prototype– to investigate Geant4 capabilities– to elaborate ideas for future software design and
physics/biological models
5.3 MeV particle in a cylindrical volume inside cell nucleus.
The inner cylinder has a radius of 50 nm
Maria Grazia Pia, INFN Genova
PhysicalPhysicalprocessesprocesses
BiologicalBiologicalprocessesprocesses
ChemicalChemicalprocessesprocesses
Process Process requirementrequirementss
Cou
rtes
y N
atur
e
Known, available
Unknown, not available
E.g. E.g. generation of generation of free radfree rad icals icals in the cellin the cell
User requirements User requirements on geometry and on geometry and visualisationvisualisation
Collection of User RequirementsCollection of User Requirements
Maria Grazia Pia, INFN Genova
Second phaseSecond phase
Scope revisited– based on the experience of the fist phase
Team largely re-organized w.r.t. the first phase– focus on software development– physicists: Geant4 Collaboration members + experimental teams– biologists, physicians as supporting experts
Iterative and incremental software process– mandatory in such a complex, evolving research field
Realistic, concrete objectives– code release with usable functionality
Maria Grazia Pia, INFN Genova
ScopeScopeRe-focused w.r.t. the first phase
– goal: provide capabilities to study the biological effects of radiation at multiple levels
Macroscopic – calculation of dose– already feasible with Geant4– develop useful associated tools
Cellular level– cell modelling– processes for cell survival, damage etc.
DNA level– DNA modelling– physics processes at the eV scale– processes for DNA strand breaking, repair etc.
Complexity of
software, physics and biologysoftware, physics and biology
addressed with an iterative and incremental software process
Parallel development at all the three levels
(domain decomposition)
Maria Grazia Pia, INFN Genova
Anthropomorphic phantomsAnthropomorphic phantomsDevelopment of anthropomorphic phantom models for Geant4
– evaluate dose deposited in critical organs– radiation protection studies in the space environment– other applications, not only in space science
Original approach facilitated by the OO technology– analytical and voxel phantoms in the same simulation environment– mix & match– see dedicated presentation in this workshop
Status: first release December 2005– G. Guerrieri, Thesis, Univ. Genova, Oct. 2005
Relevant to other fields, not only space– radiation protection– Total Body Irradiation (radiotherapy)
Macroscopic Macroscopic level level
Macroscopic Macroscopic level level
Maria Grazia Pia, INFN Genova
RequirementsProblem domain analysis
Theories and models for cell survivalTheories and models for cell survivalTARGET THEORY MODELSTARGET THEORY MODELS Single-hit model Multi-target single-hit model Single-target multi-hit model
MOLECULAR THEORY MODELSMOLECULAR THEORY MODELS Theory of radiation action Theory of dual radiation action Repair-Misrepair model Lethal-Potentially lethal model
Analysis & DesignImplementationTest
Experimental validation of Geant4 simulation models
Critical evaluation of the models
done
in progress
future
Cellular level Cellular level Cellular level Cellular level
Maria Grazia Pia, INFN Genova
Target theory modelsTarget theory models
Single-hitmodel
Multi-targetsingle-hit
model
Single-targetmulti-hitmodel
Joiner & Johns model
No hits: cell survivesOne or more hits: cell dies
S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]
PSURV(q,b,n,D) = B(b) (e-qD)(n-b) (1- e-qD)b n!
b! (n -b)!
Extension of single-hit model
S = e-αR [1 + ( αS / αR -1) e ] D – ß D - D/DC
Cell survival equationsCell survival equations based on
model-dependent assumptions
S= e-ßD 2
two hits
No assumption on: • TimeTime• Enzymatic repair of DNAEnzymatic repair of DNA
Maria Grazia Pia, INFN Genova
Molecular theory of radiation action
(linear-quadratic model)
Theory of dualradiation action
Repair or misrepair of cell survival
Lethal-potentiallylethal model
Chadwick and Leenhouts (1981)
Tobias et al. (1980)
Kellerer and Rossi (1971)
Curtis (1986)
Molecular models for cell Molecular models for cell deathdeath
More sophisticated modelsMore sophisticated models
Maria Grazia Pia, INFN Genova
Current statusCurrent status
Software– analysis & design in progress– not a trivial problem… extension of Geant4 to a completely new
domain without affecting the current Geant4 kernel– plan to have a first detailed design model by end 2005– implementation expected to be rather quick– software test according to the test process of the Geant4 LowE WG
Work in progress on modelling– models as in biology literature are unusable for concrete software
development!
Maria Grazia Pia, INFN Genova
TARGET
THEORY
SINGLE-HIT
TARGET
THEORY
MULTI-TARGET
SINGLE-HIT
MOLECULAR
THEORY
RADIATION ACTION
MOLECULAR
THEORY
DUAL RADIATION ACTION
MOLECULAR
THEORY
REPAIR-MISREPAIR
LIN REP / QUADMIS
MOLECULAR
THEORY
REPAIR-MISREPAIR
LIN REP / MIS
MOLECULAR
THEORY
LETHAL-POTENTIALLY LETHAL
MOLECULAR
THEORY
LETHAL-POTENTIALLY LETHAL – LOW DOSE
MOLECULAR
THEORY
LETHAL-POTENTIALLY LETHAL – HIGH DOSE
MOLECULAR
THEORY
LETHAL-POTENTIALLY LETHAL – LQ APPROX
S= e-D / D0
S = 1- (1- e-qD)n
S = e –p ( αD + ßD )2
S = S0 e - k (ξ D + D ) 2
S = e-αD[1 + (αD / ε)]εΦ
S = e-αD[1 + (αDT / ε)]ε
S = exp[ - NTOT[1 + ]ε ] ε (1 – e- εBAtr)NPL
S = e-ηAC D
- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]
- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]
S = e-q1D [ 1- (1- e-qn D)n ]
REVISED MODEL
In progress: calculation of
model parameters from clinical
data
Maria Grazia Pia, INFN Genova
Low Energy Physics extensionsLow Energy Physics extensions
Current Geant4 low energy electromagnetic processes: down to 250/100 eV (electrons and photons)
– not adequate for application at the DNA level
Specialised processes down to the eV scale– at this scale physics processes depend on material, phase etc.– some models exist in literature (Dingfelder et al., Emfietzoglou et al. etc.)
In progress: Geant4 processes in water at the eV scale– see talk by Riccardo Capra in this workshop
Status: first release in December 2005
DNA levelDNA levelDNA levelDNA level
Maria Grazia Pia, INFN Genova
http://www.ge.infn.it/geant4/dnahttp://www.ge.infn.it/geant4/dna
Maria Grazia Pia, INFN Genova
SummarySummary
Geant4 is being extended to a novel field of simulation capability and applications
– biological effects of radiation at the cellular and DNA level– extension facilitated by Geant4 architecture and sound OO technology
Three levels– macroscopic/dose– cell– DNA
On-going activity at all levels– anthropomorphic phantoms, cell survival models, low energy physics
extensions down to the eV scale etc.
Key elements– Rigorous software process– Collaboration with domain experts (biologists, physicians)– Team including groups with cellular irradiation facilities
Maria Grazia Pia, INFN Genova
Scenario for AuroraScenario for Aurora
Geant4 simulationspace environment
+spacecraft, shielding etc.
+anthropomorphic phantom
Dose in organs at risk
Geant4 simulation with biological
processes at cellular level (cell survival,
cell damage…)
Phase space input to nano-simulation
Geant4 simulation with physics at eV scale
+DNA processes
Oncological risk to Oncological risk to astronautsastronauts
Risk of nervous Risk of nervous system damagesystem damage
Maria Grazia Pia, INFN Genova
By-productsBy-products
Technology transfer from space science to civil society– Geant4 biological models also relevant to radiotherapy, food irradiation etc.
FAO/IAEA International Conference on
Area-Wide Control of Insect Area-Wide Control of Insect PestsPests:
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
Micro-/nano-dosimetry also relevant to other domains– radiation effects on components