Maria Grazia Pia,

INFN Genova

DNA

Geant4-DNA

Simulation of Interactions of Radiation with Biological Systems at the Cellular and DNA Level

Based on Partly funded by University of Lund 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.) Maria Grazia Pia,

INFN Genova

Medical applications

PET, SPECT Hadrontherapy Radiotherapy with external beams, IMRT Maria Grazia Pia,

INFN Genova

Brachytherapy

Courtesy of R. Taschereau, UCSF

Biological models in Geant4 Relevance for space: astronaut and aircrew radiation hazards

Maria Grazia Pia,

INFN Genova

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, ...

Maria Grazia Pia,

INFN Genova

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),

of Lund IN2P3

(CENBG, Univ. Clermont-Ferrand),

Univ. 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 Maria Grazia Pia,

INFN Genova

Courtesy A. Brahme INFN Genova

Biological processes

Complexity Multiple disciplines involved – – – physics chemistry biology Still object of active research – – not fully known no general models, only partial/empirical ones

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 Maria Grazia Pia,

INFN Genova

Collection of User Requirements

Known, available Physical processes Biological processes Unknown, not available Process requirements Chemical processes in the cell icals Maria Grazia Pia,

INFN Genova

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 Maria Grazia Pia,

INFN Genova

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 Complexity of software, physics and biology Cellular level – – cell modelling processes for cell survival, damage etc.

addressed with an iterative and incremental software process DNA level – – – DNA modelling physics processes at the eV scale processes for DNA strand breaking, repair etc.

Parallel development at all the three levels (domain decomposition) Maria Grazia Pia,

INFN Genova

Anthropomorphic phantoms

Macroscopic level

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) Maria Grazia Pia,

INFN Genova

Cellular level

Theories and models for cell survival

TARGET THEORY MODELS  Single-hit model  Multi-target single-hit model  Single-target multi-hit model in progress   MOLECULAR THEORY MODELS  Theory of radiation action  Theory of dual radiation action Repair-Misrepair model Lethal-Potentially lethal model Critical evaluation of the models done Requirements Problem domain analysis Maria Grazia Pia,

INFN Genova

Analysis & Design Implementation Test future Experimental validation of Geant4 simulation models

Target theory models

No hits: cell survives One or more hits: cell dies Extension of single-hit model Single-hit model

Cell survival equations

based on model-dependent assumptions S(ρ, Δ ) = P SURV (ρ 0 , h=0, Δ ) = (1- ρ 0 ) Δ = exp[Δ ln (1- ρ 0 )] Multi-target single-hit model n!

P SURV (q,b,n,D) = B(b) (e -q D ) (n-b) (1- e -q D ) b b! (n -b)!

Single-target multi-hit model No assumption on: • Time • Enzymatic repair of DNA Joiner & Johns model S= e -ßD 2

two hits

Maria Grazia Pia,

INFN Genova

S = e -α R [1 + ( α S / α R - D/D C -1) e ] D – ß D

Molecular models for cell death

More sophisticated models Molecular theory of radiation action (linear-quadratic model) Theory of dual radiation action Kellerer and Rossi (1971) Chadwick and Leenhouts (1981) Repair or misrepair of cell survival Tobias et al. (1980) Maria Grazia Pia,

INFN Genova

Lethal-potentially lethal model Curtis (1986)

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!

Maria Grazia Pia,

INFN Genova

TARGET THEORY TARGET THEORY MOLECULAR THEORY MOLECULAR THEORY MOLECULAR THEORY MOLECULAR THEORY MOLECULAR THEORY MOLECULAR THEORY MOLECULAR THEORY MOLECULAR THEORY SINGLE-HIT MULTI-TARGET SINGLE-HIT RADIATION ACTION DUAL RADIATION ACTION REPAIR-MISREPAIR LIN REP / QUADMIS REPAIR-MISREPAIR LIN REP / MIS LETHAL-POTENTIALLY LETHAL LETHAL-POTENTIALLY LETHAL – LOW DOSE LETHAL-POTENTIALLY LETHAL – HIGH DOSE LETHAL-POTENTIALLY LETHAL – LQ APPROX Maria Grazia Pia,

INFN Genova

S= e -D / D 0 S = 1- (1- e -q D ) n S = e –p ( αD + ßD ) REVISED MODEL S = e -q 1 D [ 1- (1- e -q n D ) n ] S = S S = e 0 -αD 2 e - k (ξ D + D ) [1 + (αDT / ε) ] S = e -αD [1 + (αD / ε) ] εΦ ε In progress: calculation of model parameters from clinical data N PL S = exp[ - N TOT [1 + εBAtr ) ] ε ] S = e -η AC D - ln[ S(t)] = (η AC + η AB ) D – ε ln[1 + ( η AB D/ ε)(1 – e -εBA tr )] - ln[ S(t)] = (η AC + η AB e -εBAtr ) D + ( η 2 AB /2 ε)(1 – e -εBA tr ) 2 D 2 ]

Low Energy Physics extensions

DNA level

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 Maria Grazia Pia,

INFN Genova

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

Maria Grazia Pia,

INFN Genova

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 Maria Grazia Pia,

INFN Genova

Scenario for Aurora

Geant4 simulation space environment + spacecraft, shielding etc.

+ anthropomorphic phantom Dose in organs at risk Maria Grazia Pia,

INFN Genova

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

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 Maria Grazia Pia,

INFN Genova