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DNA. Radiobiological models implementation in Geant4. S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino, Ph. Moretto, G. Montarou, P. Nieminen, M.G. Pia. 4 th Geant4 Space Users’ Workshop and 3 rd Spenvis Users’ Workshop Pasadena, 6 November – 9 November 2006.

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radiobiological models implementation in geant4

DNA

Radiobiological models implementation in Geant4

S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,

Ph. Moretto, G. Montarou, P. Nieminen, M.G. Pia

4th Geant4 Space Users’ Workshop and 3rd Spenvis Users’ Workshop

Pasadena, 6 November – 9 November 2006

for radiation biology
for 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-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
slide3
Simulation of Interactions of Radiation with Biological Systems at the 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

International (open) collaboration

ESA

INFN(Genova, Torino) -

IN2P3(CENBG, Univ. Clermont-Ferrand) - …

“Sister” activity to

Geant4 Low-Energy Electromagnetic Physics

Follows the same rigorous software standards

For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of radiation

toolkit

Openness to extensionandevolution

new implementations can be added w/o changing the existing code

Robustness and ease of maintenance

protocols and well defined dependenciesminimizecoupling

MULTIDISCIPLINARY

STUDY

Toolkit

OO technology

A set of compatible components

  • each component is specialised for a specific functionality
  • each component can be refinedindependently to a great detail
  • components can be integrated at any degree of complexity
  • it is easy to provide (and use) alternativecomponents
  • the user application can be customisedas needed

Strategic vision

multiple domains in the same software environment
Multiple domains in the same software environment
  • Macroscopic level
    • 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
    • bio-chemical processes
    • processes for DNA damage, repair etc.

Complexity of

SOFTWARE

PHYSICS

BIOLOGY

addressed with an iterative and incremental software process

Parallel development at all the three levels

(domain decomposition)

slide7

Cellular level

The biological effects of radiation can be manifold, from cell killing, to mutation in germ cells, up to carcinogenesis or leukemogenesis

Before irradiation: Normal Cell

  • SOME OF THE MOST STUDIED CELL LINES
  • HeLa cells, derived from human cervical cancer
  • V79 cells, derived from hamster lung
  • CHO cells, derived from ovary
  • 9L cells, derived from rat gliosarcoma
  • T1 cells, derived from human kidney

Radiation

Damage to

chromosome

CELL DEATH

Broken or changed

chromosome

(mutation)

REPAIR

After irradiation: Abnormal Cell

VIABLE CELL (BUT MODIFIED)

biological outcome cell survival

Courtesy E. Hall

Human cell lines irradiated with X-rays

Biological outcome: cell survival

DOSE-RESPONSE RELATIONSHIP

  • A cell survival curve describes the relationship between the radiation dose and the proportion 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.
theories and models for cell survival

approach:

variety of models all handled through the same abstract interface

Theories and models for cell survival
  • TARGET THEORY MODELS
  • Single-Hit model
  • Multi-Target Single-Hit model
  • Single-Target Multi-Hit model
  • MOLECULAR THEORY MODELS
  • Theory of Radiation Action
  • Theory of Dual Radiation Action
  • Repair-Misrepair model
  • Lethal-Potentially lethal model

in progress

Analysis & Design

Implementation

Test

Requirements

Problem domain analysis

Experimental validation of Geant4 simulation models

Incremental-iterative software process

prototype design
Prototype design

STRATEGY PATTERN

Biological models areencapsulatedand madeinterchangeable.

Concrete radiobiological models derive from the abstract interface

The flexible design adopted makes the system open to further extension to other radiobiological models available in literature.

slide11

Undamaged

state

A

Potentially

letal lesions

B

Lethal

lesions

C

SURVIVAL

OF A POPULATION OF

RADIATED CELLS

LINEAR-QUADRATIC MODEL

DOSE OF RADIATION

TO WHICH THE CELLS

WERE EXPOSED

Low doses:

DSBs are generated

by the same particle

SINGLE-HIT MULTI-TARGET

  • Two component of cell killing by radiation, one dependent by the dose and the other one proportional to the square of the dose
  • - cell survival curve is continuously bending

- 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 of being hit

- one hit is sufficient to inactivate each target (but not the cell)

High doses:

DSBs are generated by

different electrons

Courtesy E. Hall

LETHAL-POTENTIALLY LETHAL

εAB

ηAB

ηAC

  • Based on:
  • radiation induced lethal and potentially lethal lesions
  • the capacity of the cell to repair them

εBC

B and C lesions are linearly related to dose

cell survival models verification

Survival

Dose (Gy)

Cell survival models verification

Monolayer

Data points:

Geant4 simulation results

V79-379A cells

Proton beam

E= 3.66 MeV/n

Continuous line:

LQ theoretical model

with Folkard parameters

LQ model

α = 0.32

β = -0.039

Folkard et al, Int. J. Rad. Biol., 1996

wide and complex problem domain
Wide and complex problem domain

Geant4 simulation with biological processes at cellular level (cell survival, cell damage…)

Dose in sensitive volumes

Biological systems responses to irradiation exposure are of critical concern both to radiotherapy and to risk assessment

WIDE DOMAIN OF

NOVEL APPLICATIONS IN RADIOBIOLOGY AND OTHER FIELDS

Phase space input to nano-simulation

Geant4 simulation with

physics at eV scale

+

DNA processes

+ ADVANCED FUNCTIONALITIES

OFFEREND BY GEANT4 IN OTHER

SIMULATION DOMAINS

(GEOMETRY, PHYSICS, INTERACTIVE TOOLS)

slide14

Conclusions

  • The Geant4-DNA project is in progress to extend the Geant4 simulation toolkit to model the effects of radiation with biological systems at cellular and DNA level
  • According to the rigorous 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 extension to other radiobiological models available in literature
  • For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of radiation

Rigorous software engineering

Advanced object oriented technology

in support ofGeant4 modellingversatility