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