Simulation of Interactions of Radiation with Biological Systems
at the Cellular and DNA Level
Based on
http://www.ge.infn.it/geant4/dna/
Sponsored by
Activity of
S. Agostinelli, S. Chauvie,, G. Cosmo, R. Corvó, N. Crompton D. Emfietzoglou,
J.M. Fernandez Varea, F. Foppiano, S. Garelli, M. Krengli, F. Marchetto, P. Nieminen, M.G. Pia,
V. Rolando, A. Solano, G. Sanguineti
Relevance
Motivations
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)
Relevance for space:
astronaut and airline pilot
radiation hazards, biological
experiments
Applications in radiotherapy,
radiobiology...
Potential later connection to
other than radiation-induced
effects at the cellular and DNA
level
Programme description
-based “sister” activity to the Geant4 Low-E e.m.
Working Group: same rigorous software standards
ESA-sponsored + INFN official activity
Simulation of nano-scale effects of radiation at the DNA level
First year frame: Collection of user requirements and first
prototypes
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
Complexity
Complexity
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It is a complex field
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The complexity is increased by
the multi-disciplinary nature of
the project
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Courtesy A. Brahme (KI)
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ongoing active research
no one masters all the scientific
components (biology, chemistry,
physics etc.)
A rigorous approach to the
collection of the requirements is
essential
A challenge for problem
domain analysis and software
design!
Collection of User Requirements
Biological
processes
Physical
processes
Known,
available
Courtesy Nature
Unknown,
not available
Process user
requirements
Chemical
processes
User requirements on
geometry and visualisation
E.g. generation of free
radicals in the cell
Work programme (1)
Geometry requirements
Processes requirements
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Physics and processes requirements
Heavy ion interactions with molecular
structures
Low-energy electromagnetic interactions
Low-energy hadronic interactions
Step size and energy loss requirements;
secondary particle production
Other physics and processes required in
biological targets in general, and in the
vicinity of cells and DNA molecules in
particular
Consideration of biological processes (such
as DNA repair mechanisms, apoptosis) vs.
physical processes
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Geometry requirements
Implementation of the structure of
the DNA
Implementation of the composition
of the DNA
Other cellular structures
Shielding provided by the biological
tissue
Work programme (2)
Visualisation requirements
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DNA and cellular structures
visualisation; particle tracks
Visualisation of biological and
chemical processes;
visualisation of DNA ruptures
General simulation and data
analysis requirements
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Scaling and zooming
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Hierarchy and scalability of the
simulation
Combination of DNA and
cellular simulation results
ultimately to macroscopic
biological predictions
Run-time requirements
-DNA Collaboration
Multi-disciplinary
collaboration: physicists,
biologists, physicians,
computer scientists
Study of the space radiation environment
Anomalous
cosmic rays
Galactic and extra-galactic
cosmic rays
Jovian
electrons
(Neutrinos)
Solar
X-rays
Induced
emission
Trapped
particles
Solar flare neutrons
and g-rays
Solar flare electrons,
protons, and heavy ions
Study of biological effects of radiation
DNA damage
Base alteration (Ba): the chemical
properties of an organic base are
abnormally modified
Base deletion (Bd): an organic base is
removed from a nucleotide
Sugar alteration (Sa): the chemical
properties of deoxyribose sugar are
abnormally modified
Strand break (Sb): the covalent bond
between the deoxyribose sugar unit and
the phosphate group is broken
Mismatched base: the natural coupling
between complementary bases A-T and
G-C is altered
Reaction to damage
Cell cycle arrest
Apoptosis
Repair
Relative Biological
Effectiveness (RBE)
Different types of ionising radiation
have different effects on cells
High LET radiation (ions, neutrons and
low energy protons) has a higher
efficiency for damaging cells than low
LET radiation
The RBE depends on the processes
taking place (cell death, double strand
break, chromosomal aberration, etc...)
Effects of low doses
Ionising radiation accounts for about 3% of all cancers
High doses of radiation (tens of Gy) all at once on whole body
can be fatal, but spread out over a period of time and/or limited
to a part of the body may be tolerated with little damage to
healthy tissues
Low doses of radiation may cause no acute effects, but increased
risk of late damage on various cell populations due to genetic
mutations
Epidemiology of radiation-induced cancer
 Atomic bomb survivors
 Occupational exposure
 Patients treated with ionising radiation
Other fields of application
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Radiotherapy
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Nuclear medicine
Teletherapy
Brachytherapy
Radio-emitting machinery
Food irradiation
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Doses and effects of radiation
Modifications of irradiated food
Similar issues: biological experiments on the International Space Station
Study of existing Monte Carlo codes
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Continuous-slowing-down (CSD) scheme
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Simplest approach
Condensed-random-walk scheme: class I codes
Condensed-random-walk scheme: class II codes
Event-by-event scheme: class III codes
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Gas-phase approximation
Condensed-water medium
Biopolymer-specific
Requirements engineering
73% of projects are canceled or fail to meet expectations due
to poor requirements definition and analysis
(The Standish Group, The Chaos Report 1995)
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Requirements engineering can be
defined as the systematic process of
developing requirements through an
iterative cooperative process of
The requirements process
includes the following activities:
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analysing the problem
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documenting the resulting observations
checking the accuracy of the
understanding gained
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Requirements Elicitation
Requirements Analysis
Requirements Specification
Requirements Validation
Requirements Management
Requirements
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Requirements are the quantifiable and verifiable
 behaviours that a system must possess
 constraints that a system must work within
Collection, specification
and analysis
URD
Requirements are subject to evolution in the lifetime of a
software project!
 ability to cope with the evolution of the requirements
Capture of user requirements
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Followed PSS-05 recommendations:
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Wide agreement should be established through interviews
and surveys
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UR should be clarified through criticism and experience of
existing software and prototypes
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Knowledge and experience of the potential development
organizations should be used to help decide on
implementation feasibility and build prototypes
Methods for User Requirements capture
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Interviews and surveys
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Use cases and scenarios
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Thinking systematically in a variety of situations
Studies of existing software
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Useful to ensure that UR are complete and there is wide agreement
Good or bad features of existing software can identify requirements for
the new software
Prototyping
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Useful especially if requirements are unclear or incomplete
The prototype is based on tentative requirements, then explore what is
really wanted
Problems in Requirements Elicitation
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Users may know what they want, but are unable to
articulate the requirements
Users may not know what is technologically capable and
may not consider what is possible
Users may have reasons for not wanting to communicate
the requirements
Users and developers sometimes do not speak the same
language
No single user has all the answers, the requirements come
from many sources
The URD
GEANT4-DNA
Simulation of interactions of radiation with biological
systems at the cellular and DNA level
Physical processes
Chemical processes
Biochemical processes
User Requirements Document
Status: Delivered to ESA on 22 February 2001
Version: 1.3
Project: Geant4-DNA
Reference: DNA-URD-V1.03
Created: 28 December 2000
Last modified: 21 February 2001
Prepared by:
Maria Grazia Pia (INFN Genova)
Stéphane Chauvie (Univ. of Torino and INFN Torino and AIRCC)
Gabriele Cosmo (CERN)
José Maria Fernandez Varea (Univ. of Barcelona)
Franca Foppiano (IST Genova - Istituto Nazionale per la Ricerca sul Cancro)
Petteri Nieminen (ESA/ESTEC)
Ada Solano (Univ. of Torino and INFN Torino)
On behalf of the Geant4-DNA Collaboration
Geometry
Materials
Particles
Visualisation
Analysis
Interface to other components
Capability and constraint requirements
5.3 MeV alpha particle in a cylindrical volume inside cell nucleus. The inner cylinder has a
radius of 50 nm.
ISTITUTO NAZIONALE DI FISICA NUCLEARE
Sezione di Genova
Publication
INFN/TC-??/??
31 July 2001
Draft 3
A STUDY OF THE USER REQUIREMENTS FOR THE SIMULATION OF
INTERACTIONS OF RADIATION WITH BIOLOGICAL SYSTEMS AT THE
CELLULAR AND DNA LEVEL
The outcome of the first phase
of the activity will be published
in an INFN report(~summer 2001)
S. Agostinelli, S. Chauvie, G. Cosmo, R. Corvó, N. Crompton, D. Emfietzoglou, J.M.
1
2
Fernandez Varea,
F. Foppiano, S. Garelli, M. Krengli, P. Nieminen , M.G. Pia , G.
Sanguineti, A. Solano
1)
INFN-Sezione di Napoli, Dip. Scienze Fisiche Università di Napoli, I-80125 Napoli, Italy
2)
INFN-Laboratori Nazionali di Frascati Via E. Fermi 40, I-00044 Frascati, Italy
It will contain the URD too
Abstract
This is where the abstract should be placed. Type the abstract in single spaced
paragraphs only for this page, same format (12 pt) and font (times) as text. Title, author names
and abstract should fit in one page. For large collaboration, you need to list individual names
in the next page
PACS.: insert the exact ref. number
Published by SIS–Pubblicazioni
Laboratori Nazionali di Frascati
Future
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The exploratory phase of the project has generated a wide
scientific interest
The current body of knowledge is already adequate for a first
functional product
Well worth continuing the activity
A spiral software process is mandatory in such a complex field
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Incremental and iterative phases of analysis&design, implementation,
testing
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There will certainly be iterations in the requirements too
The continuation depends on the availability of financial resources
http://srhp.jsc.nasa.gov/