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DNA. Based on. Geant4-DNA Simulation of Interactions of Radiation with Biological Systems at the Cellular and DNA Level.

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slide2

Based on

Geant4-DNASimulation of Interactions of Radiation with Biological Systems at 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.)

Partly funded by

University of Lund

medical applications

Courtesy of R. Taschereau, UCSF

Medicalapplications

PET, SPECT

Hadrontherapy

Radiotherapy with external beams, IMRT

Brachytherapy

relevance
Relevance
  • 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, ...
programme
Programme
  • 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
biological processes
Biological processes
  • Complexity
  • Multiple disciplines involved
    • physics
    • chemistry
    • biology
  • Still object of active research
    • not fully known
    • no general models, only partial/empirical ones

Courtesy A. Brahme (KI)

Courtesy A. Brahme (Karolinska Institute)

first phase
First phase
  • Collection 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

collection of user requirements
Collection of User Requirements

Biologicalprocesses

Physicalprocesses

Known,

available

Process requirements

Unknown,

not available

E.g. generation of free rad icals in the cell

Chemicalprocesses

Courtesy Nature

User requirements on geometry and visualisation

second phase
Second 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
scope
Scope
  • Re-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 biology

addressed with an iterative and incremental software process

Parallel development at all the three levels

(domain decomposition)

anthropomorphic phantoms

Macroscopic level

Anthropomorphic phantoms
  • Development 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)
theories and models for cell survival

Cellular level

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

Critical evaluation of the models

future

done

Experimental validation of Geant4 simulation models

Requirements

Problem domain analysis

target theory models

- D/DC

n!

PSURV(q,b,n,D) = B(b) (e-qD)(n-b) (1- e-qD)b

b! (n -b)!

S = e-αR [1 + ( αS / αR -1)e ] D – ß D

2

S= e-ßD

Target theory models

Extension of single-hit model

No hits: cell survives

One or more hits: cell dies

Multi-target

single-hit

model

Cell survival equations based on

model-dependent assumptions

Single-hit

model

S(ρ,Δ) = PSURV(ρ0, h=0, Δ) = (1- ρ0)Δ= exp[Δ ln (1- ρ0)]

Single-target

multi-hit

model

  • No assumption on:
  • Time
  • Enzymatic repair of DNA

Joiner & Johns

model

two hits

molecular models for cell death
Molecular models for cell death

More sophisticated models

Theory of dual

radiation action

Molecular theory

of radiation action

(linear-quadratic model)

Kellerer and Rossi (1971)

Chadwick and Leenhouts (1981)

Lethal-potentially

lethal model

Repair or misrepair

of cell survival

Tobias et al. (1980)

Curtis (1986)

current status
Current 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!
slide17

S = e –p ( αD + ßD )

2

2

S = S0 e - k (ξD + D )

NPL

S = exp[ - NTOT[1 + ]ε]

ε (1 – e- εBAtr)

S = e-q1D [ 1- (1- e-qnD)n ]

S = e-αD[1 + (αDT / ε)]ε

S= e-D / D0

REVISED MODEL

S = 1- (1- e-qD)n

In progress: calculation of model parameters from clinical data

S = e-αD[1 + (αD / ε)]εΦ

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]

low energy physics extensions

DNA level

Low 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
summary
Summary
  • 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
scenario for aurora

Geant4 simulation

space environment

+

spacecraft, shielding etc.

+

anthropomorphic phantom

Scenario for Aurora

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

Dose in organs at risk

Oncological risk to astronauts

Risk of nervous system damage

Phase space input to nano-simulation

Geant4 simulation with

physics at eV scale

+

DNA processes

by products
By-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 Pests:

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