INFN Seminar

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- DNA
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Geant4-DNASimulation of Interactions of
Radiation with Biological Systems at the
Cellular and DNA Level
Partly funded by

• 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.)

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Medical applications
PET, SPECT
Hadrontherapy
Radiotherapy with external beams, IMRT
Brachytherapy
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Relevance for space astronaut and aircrew
radiation hazards
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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.
  microscopiccybernetic)
• 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, ...

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Programme

• -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 (RBE parameterisation,
  detailed biochemical processes, etc.) can be
  implemented with Geant4
• First phase 2000-2001
• Collection of user requirements first
  prototypes
• Second phase 2004-2008
• Software development release

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Anomalous cosmic rays
Galactic and extra-galactic cosmic rays
Jovian electrons
(Neutrinos)
Solar X-rays
Trapped particles
Induced emission
Solar flare neutrons and g-rays
Solar flare electrons, protons, and heavy ions
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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)
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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
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Collection of User Requirements
Biologicalprocesses
Physicalprocesses
Known, available
Process userrequirements
Unknown, not available
E.g. generation of free radicals in the cell
User requirements on geometry and visualisation
Chemicalprocesses
Courtesy Nature
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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 releases with usable functionality

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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 tools
• Cellular level
• cell modeling
• processes for cell survival, damage etc.
• DNA level
• DNA modeling
• 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)
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Anthropomorphic phantoms
Macroscopic level

• Development of anthropomorphic phantoms 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

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Theories and models for cell survival
Cellular level

• 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
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Target theory models
No hits cell survives One or more hitscell dies
Extension of single-hit model
Multi-target single-hit model
Cell survival equations based on model-dependent
assumptions
Single-hit model
S(?,?) PSURV (?0, h0, ?) (1- ?0)? exp? ln
(1- ?0)
Single-target multi-hit model
No assumption on Time Enzymatic repair of DNA
Joiner Johns model
two hits
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Molecular models for cell death
More sophisticated models
Theory of dual radiation action
Molecular theory of radiation action (linear-quad
ratic 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)
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Low Energy Physics extensions
DNA level

• Current Geant4 low energy electromagnetic
  processes down to 250/100 eV (electrons and
  photons)
• not adequate for applications at the DNA level
• Specialised processes down to the eV scale
• at this scale 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

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http//www.ge.infn.it/geant4/dna
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Summary

• Geant4 is being extended to a novel field of
  simulation capability and applications
• biological effects of radiation at the cellular
  and DNA level
• made possible by Geant4 architecture
• facilitated by the OO technology
• Three levels
• macroscopic
• 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