1. 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

2. for radiation biology Geant4-DNA
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

3. DNA International (open) collaboration ESA INFN (Genova, Torino) -
IN2P3 (CENBG, Univ. Clermont-Ferrand) - …
DNA
“Sister” activity to
Geant4 Low-Energy Electromagnetic Physics
Follows the same rigorous software standards
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.
For the first time a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of radiation

5. Strategic vision Toolkit OO technology
MULTIDISCIPLINARY
STUDY
OO technology
Openness to extension and evolution
new implementations can be added w/o changing the existing code
Robustness and ease of maintenance
protocols and well defined dependencies minimize coupling
Strategic vision
Toolkit
A set of compatible components
each component is specialised for a specific functionality
each component can be refined independently to a great detail
components can be integrated at any degree of complexity
it is easy to provide (and use) alternative components
the user application can be customised as needed

6. 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)

7. VIABLE CELL (BUT MODIFIED)
Cellular level
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)
The biological effects of radiation can be manifold, from cell killing, to mutation in germ cells, up to carcinogenesis or leukemogenesis

8. Biological outcome: cell survival
DOSE-RESPONSE RELATIONSHIP
Human cell lines irradiated with X-rays
Courtesy E. Hall
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.

9. 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
approach:
variety of models all handled through the same abstract interface
in progress
Analysis & Design
Implementation
Test
Requirements
Problem domain analysis
Experimental validation of Geant4 simulation models
Incremental-iterative software process

10. Prototype design STRATEGY PATTERN
Biological models are encapsulated and made interchangeable.
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.

11. LINEAR-QUADRATIC MODEL
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
Undamaged
state A
Lethal
lesions C
Potentially
letal lesions B
εAB
ηAC
ηAB
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

12. Cell survival models verification
Dose (Gy)
Survival
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 =
Folkard et al, Int. J. Rad. Biol., 1996

13. 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)

14. Conclusions Rigorous software engineering
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 of Geant4 modelling versatility