Title: INFN Seminar
1- DNA
2Geant4-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.)
3Medical applications
PET, SPECT
Hadrontherapy
Radiotherapy with external beams, IMRT
Brachytherapy
4Relevance for space astronaut and aircrew
radiation hazards
5Relevance
- 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, ...
6Programme
- -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
7Anomalous 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
8Biological 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)
9First 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
10Collection 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
11Second 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
12Scope
- 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)
13Anthropomorphic 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
14Theories 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
15Target 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
16Molecular 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)
17Low 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
18http//www.ge.infn.it/geant4/dna
19Summary
- 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