Radiobiological models implementation in Geant4 DNA 4 th Geant4 Space Users’ Workshop and 3 rd...
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Transcript of Radiobiological models implementation in Geant4 DNA 4 th Geant4 Space Users’ Workshop and 3 rd...
Radiobiological models Radiobiological models implementation in Geant4implementation in Geant4
DNA
4th Geant4 Space Users’ Workshop and 3rd Spenvis Users’ Workshop Pasadena, 6 November – 9 November 2006
S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino, Ph. Moretto, G. Montarou, P. Nieminen, M.G. Pia
for radiation biologyfor radiation biology• Several specialized Monte Carlo codes have been developed for
radiobiology/microdosimetry – Typically each one implementing models developed by its authors
– Limited application scope
– Not publicly distributed
– Legacy software technology (FORTRAN, procedural programming)
• Geant4-DNAGeant4-DNA– Full power of a general-purpose Monte Carlo system
– Toolkit: multiple modeling options, no overhead (use what you need)
– Versatility: from controlled radiobiology setup to real-life ones
– Open source, publicly released
– Modern software technology
– Rigorous software process
• Simulation of Interactions of Radiation with Biological Systems at Simulation of Interactions of Radiation with Biological Systems at the Cellular and DNA levelthe Cellular and DNA level– Various scientific domains involved
medical, biology, genetics, physics, software engineering
– Multiple approaches can be addressed with Geant4
RBE parameterisation, detailed biochemical processes, etc.
DNA “Sister” activity to Geant4 Low-Energy Electromagnetic PhysicsFollows the same rigorous software standards
International (open) collaborationESAESA INFNINFN (Genova, Torino) -
IN2P3IN2P3 (CENBG, Univ. Clermont-Ferrand) - …
For the first time a general-purpose Monte Carlo system is For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of equipped with functionality specific to the simulation of
biological effects of radiationbiological effects of radiation
http://www.ge.infn.it/geant4/dnahttp://www.ge.infn.it/geant4/dna
ToolkitToolkitA set of compatible componentsA set of compatible components• each component is specialisedspecialised for a specific functionality• each component can be refinedrefined independently to a great detail• components can be integratedintegrated at any degree of complexity• it is easy to provide (and use) alternativealternative components• the user application can be customisedcustomised as needed
Openness to extensionextension and evolution evolution new implementations can be added w/o changing the existing code
Robustness and ease of maintenancemaintenance
protocolsprotocols and well defined dependenciesdependencies minimize coupling
OO OO technologytechnology
Strategic Strategic visionvision
MULTIDISCIPLINARYMULTIDISCIPLINARYSTUDY STUDY
Multiple domains in the Multiple domains in the same software same software environmentenvironment• Macroscopic levelMacroscopic level
– calculation of dose– already feasible with Geant4– develop useful associated tools
• Cellular levelCellular level– cell modelling– processes for cell survival, damage etc.
• DNA levelDNA level– DNA modelling– physics processes at the eV scale– bio-chemical processes– processes for DNA damage, repair etc.
Complexity of
SOFTWARESOFTWARE
PHYSICS PHYSICS
BIOLOGYBIOLOGY
addressed with an iterative and incremental software
process
Parallel development at all the three levels
(domain decompositiondomain decomposition)
Damage tochromosome
Before irradiation: Normal CellBefore irradiation: Normal Cell
After irradiation: Abnormal CellAfter irradiation: Abnormal Cell
Radiation
Broken or changedchromosome(mutation)
CELL DEATH
REPAIR
VIABLE CELL (BUT MODIFIED)
Cellular level Cellular level Cellular level Cellular level
SOME OF THE MOST STUDIED CELL LINES HeLa cellsHeLa cells, derived from human cervical cancerV79 cellsV79 cells, derived from hamster lungCHO cellsCHO cells, derived from ovary9L cells9L cells, derived from rat gliosarcomaT1 cellsT1 cells, derived from human kidney
The biological effects of radiation can be manifold, from cell killing, to The biological effects of radiation can be manifold, from cell killing, to
mutation in germ cells, up to carcinogenesis or leukemogenesismutation in germ cells, up to carcinogenesis or leukemogenesis
Biological outcome: cell survivalBiological outcome: cell survival
• A cell survival curvecell survival curve describes the relationship between the radiation doseradiation dose and the proportion of cells that surviveproportion of cells that survive.
• What do we mean with “cell death”?– loss of the capacity for sustained
proliferation or loss of reproductive integrity.
– A cell still may be physically present and apparently intact, but if it has lost the capacity to divide indefinitely and produce a large number of progeny, it is by definition dead.
Human cell lines irradiated with X-raysHuman cell lines irradiated with X-rays
Courtesy E. Hall
DOSE-RESPONSE RELATIONSHIPDOSE-RESPONSE RELATIONSHIP
RequirementsProblem domain analysis
Theories and models for cell survivalTheories and models for cell survival
Analysis & DesignImplementation
Test
Experimental validation of Geant4 simulation models
in progress
Incremental-iterative
software process
approach: variety of models all
handled through the same abstract interface
TARGET 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
PrototypePrototype design designSTRATEGY PATTERNSTRATEGY PATTERN
Biological models are encapsulatedencapsulated and made interchangeableinterchangeable.
The flexible design adopted makes the system open to further The flexible design adopted makes the system open to further extension to other radiobiological models available in literature. extension to other radiobiological models available in literature.
Concrete radiobiological models derive from the abstract interface
LINEAR-QUADRATIC MODELLINEAR-QUADRATIC MODEL
LETHAL-POTENTIALLY LETHALLETHAL-POTENTIALLY LETHAL
SINGLE-HIT MULTI-TARGETSINGLE-HIT MULTI-TARGET
Low doses:DSBs are generatedby the same particle
High doses:DSBs are generated by
different electrons
Undamaged state
A
Lethal lesions
C
Potentiallyletal lesions
BηAC
ηAB
εBC
εAB
Based on: - radiation induced lethal and potentially lethal lesions- the capacity of the cell to repair them
B and C lesions are linearly related to dose
SURVIVALSURVIVALOF A OF A
POPULATION OF POPULATION OF RADIATED CELLSRADIATED CELLS
DOSE OF RADIATIONDOSE OF RADIATIONTO WHICH THE CELLSTO WHICH THE CELLS
WERE EXPOSEDWERE EXPOSED
Courtesy E. Hall
- n targets- n targets in the cell, all with the same volume- one or more of these targets must be inactivated- each target has the same probability same probability of being hit- one hit- one hit is sufficient to inactivate each targeteach target (but
not the cell)
- TwoTwo component of cell component of cell killing by radiation, one killing by radiation, one dependent by the dependent by the dosedose and the other one and the other one proportional to the proportional to the square of the dose square of the dose
- cell survival curve is - cell survival curve is continuously bending
Cell survival models verification
Dose (Gy)
Su
rviv
al
Continuous line:LQ theoretical model
with Folkard parameters
Data points:Geant4 simulation results
Monolayer
V79-379A cells
Proton beam E= 3.66 MeV/n
Folkard et al, Int. J. Rad. Biol., 1996
α = 0.32β = -0.039
LQ modelLQ model
Wide and complex Wide and complex problem domainproblem domain
Biological systems responses to irradiation exposure are of critical
concern both to radiotherapy and to risk
assessment
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
WIDE DOMAIN OFWIDE DOMAIN OF NOVEL NOVEL
APPLICATIONS IN APPLICATIONS IN RADIOBIOLOGY RADIOBIOLOGY
AND OTHER AND OTHER FIELDSFIELDS
Dose in sensitive volumes
+ ADVANCED FUNCTIONALITIES OFFEREND BY GEANT4 IN OTHER
SIMULATION DOMAINS (GEOMETRY, PHYSICS, INTERACTIVE TOOLS)
RigorousRigorous software engineering software engineering AdvancedAdvanced object oriented technology object oriented technology
in support ofin support of Geant4 modellingGeant4 modelling versatilityversatility
ConclusionsConclusions• The Geant4-DNAGeant4-DNA project is in progress to extend the Geant4 simulation toolkit to
model the effects of radiation with biological systems at cellularcellular and DNADNA level
• According to the rigorous software processrigorous software process adopted, a variety of radiobiological models has been designed, implemented and tested in Geant4
• The flexible design adopted makes the system open to further extensionextension to other radiobiological models available in literature
• For the first time a general-purpose Monte Carlo system is equipped For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of with functionality specific to the simulation of biological effects of radiationradiation