Maria Grazia Pia, INFN Genova DNA. Based on Partly funded by Geant4-DNA Simulation of Interactions of Radiation with Biological Systems at the Cellular.

Maria Grazia Pia, INFN Genova

DNADNA


Based onBased on

Partly funded byPartly funded by

Geant4-DNAGeant4-DNASimulation of Interactions of Radiation with Biological Simulation of Interactions of Radiation with Biological

Systems Systems at the Cellular and DNA Levelat 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.)

University of Lund


MedicalMedical applicationsapplications

Courtesy of R. Taschereau, UCSF

Radiotherapy with external beams, IMRT

Brachytherapy

PET, SPECT

Hadrontherapy


Biological models in Geant4 Biological models in Geant4

Relevance for space: Relevance for space: astronaut and aircrew radiation hazardsastronaut and aircrew radiation hazards


RelevanceRelevance

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, ...


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

ProgrammeProgramme


Cou

rtes

y A

. Bra

hme

(KI)

Courtesy A. Brahme (Karolinska Institute)

Biological Biological processesprocesses

Complexity

Multiple disciplines involved– physics– chemistry– biology

Still object of active research– not fully known– no general models, only

partial/empirical ones


First phaseFirst phaseCollection 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


PhysicalPhysicalprocessesprocesses

BiologicalBiologicalprocessesprocesses

ChemicalChemicalprocessesprocesses

Process Process requirementrequirementss

Cou

rtes

y N

atur

e

Known, available

Unknown, not available

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

User requirements User requirements on geometry and on geometry and visualisationvisualisation

Collection of User RequirementsCollection of User Requirements


Second phaseSecond 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


ScopeScopeRe-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 biologysoftware, physics and biology

addressed with an iterative and incremental software process

Parallel development at all the three levels

(domain decomposition)


Anthropomorphic phantomsAnthropomorphic phantomsDevelopment 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)

Macroscopic Macroscopic level level

Macroscopic Macroscopic level level


RequirementsProblem domain analysis

Theories and models for cell survivalTheories and models for cell survivalTARGET THEORY MODELSTARGET THEORY MODELS Single-hit model Multi-target single-hit model Single-target multi-hit model

MOLECULAR THEORY MODELSMOLECULAR THEORY MODELS Theory of radiation action Theory of dual radiation action Repair-Misrepair model Lethal-Potentially lethal model

Analysis & DesignImplementationTest

Experimental validation of Geant4 simulation models

Critical evaluation of the models

done

in progress

future

Cellular level Cellular level Cellular level Cellular level


Target theory modelsTarget theory models

Single-hitmodel

Multi-targetsingle-hit

model

Single-targetmulti-hitmodel

Joiner & Johns model

No hits: cell survivesOne or more hits: cell dies

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

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

b! (n -b)!

Extension of single-hit model

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

Cell survival equationsCell survival equations based on

model-dependent assumptions

S= e-ßD 2

two hits

No assumption on: • TimeTime• Enzymatic repair of DNAEnzymatic repair of DNA


Molecular theory of radiation action

(linear-quadratic model)

Theory of dualradiation action

Repair or misrepair of cell survival

Lethal-potentiallylethal model

Chadwick and Leenhouts (1981)

Tobias et al. (1980)

Kellerer and Rossi (1971)

Curtis (1986)

Molecular models for cell Molecular models for cell deathdeath

More sophisticated modelsMore sophisticated models


Current statusCurrent 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!


TARGET

THEORY

SINGLE-HIT

TARGET

THEORY

MULTI-TARGET

SINGLE-HIT

MOLECULAR

THEORY

RADIATION ACTION

MOLECULAR

THEORY

DUAL RADIATION ACTION

MOLECULAR

THEORY

REPAIR-MISREPAIR

LIN REP / QUADMIS

MOLECULAR

THEORY

REPAIR-MISREPAIR

LIN REP / MIS

MOLECULAR

THEORY

LETHAL-POTENTIALLY LETHAL

MOLECULAR

THEORY

LETHAL-POTENTIALLY LETHAL – LOW DOSE

MOLECULAR

THEORY

LETHAL-POTENTIALLY LETHAL – HIGH DOSE

MOLECULAR

THEORY

LETHAL-POTENTIALLY LETHAL – LQ APPROX

S= e-D / D0

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

S = e –p ( αD + ßD )2

S = S0 e - k (ξ D + D ) 2

S = e-αD[1 + (αD / ε)]εΦ

S = e-αD[1 + (αDT / ε)]ε

S = exp[ - NTOT[1 + ]ε ] ε (1 – e- εBAtr)NPL

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]

S = e-q1D [ 1- (1- e-qn D)n ]

REVISED MODEL

In progress: calculation of

model parameters from clinical

data


Low Energy Physics extensionsLow 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

DNA levelDNA levelDNA levelDNA level


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


SummarySummary

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 AuroraScenario for Aurora

Geant4 simulationspace environment

+spacecraft, shielding etc.

+anthropomorphic phantom

Dose in organs at risk

Geant4 simulation with biological

processes at cellular level (cell survival,

cell damage…)

Phase space input to nano-simulation

Geant4 simulation with physics at eV scale

+DNA processes

Oncological risk to Oncological risk to astronautsastronauts

Risk of nervous Risk of nervous system damagesystem damage


By-productsBy-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 Area-Wide Control of Insect PestsPests:

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 DNA. Based on Partly funded by Geant4-DNA Simulation of Interactions of Radiation with Biological Systems at the Cellular.

Documents

maria grazia pia

infn genova dna slide

infn genova courtesy

infn genova relevance

infn genova biological

nm slide

cell user requirements

geant4 relevance