INFN Seminar

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Simulation of Interactions of Radiation with
Biological Systems at the Cellular and DNA Level
http//www.ge.infn.it/geant4/dna/
Activity of
Sponsored by
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
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Motivations
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)

• 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

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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

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Complexity
Complexity

• It is a complex field
• ongoing active research
• The complexity is increased by the
  multi-disciplinary nature of the project
• 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!

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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
Chemicalprocesses
Courtesy Nature
User requirements on geometry and visualisation
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Work programme (1)
Geometry requirements
Processes requirements

• 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

• 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

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Work programme (2)

• General simulation and data
• analysis requirements
• Hierarchy and scalability of the simulation
• Combination of DNA and cellular simulation
  results ultimately to macroscopic biological
  predictions
• Run-time requirements

• Visualisation requirements
• DNA and cellular structures visualisation
  particle tracks
• Visualisation of biological and chemical
  processes visualisation of DNA ruptures
• Scaling and zooming

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-DNA Collaboration
Multi-disciplinary collaboration physicists,
biologists, physicians, computer scientists
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Study of the space radiation environment
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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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

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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...)

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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

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Other fields of application

• Radiotherapy
• Nuclear medicine
• Teletherapy
• Brachytherapy
• Radio-emitting machinery
• Food irradiation
• Doses and effects of radiation
• Modifications of irradiated food
• Similar issues biological experiments on the
  International Space Station

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Study of existing Monte Carlo codes

• Continuous-slowing-down (CSD) scheme
• Simplest approach
• Condensed-random-walk scheme class I codes
• Condensed-random-walk scheme class II codes
• Event-by-event scheme class III codes
• Gas-phase approximation
• Condensed-water medium
• Biopolymer-specific

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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)

• The requirements process includes the following
  activities
• Requirements Elicitation
• Requirements Analysis
• Requirements Specification
• Requirements Validation
• Requirements Management

• Requirements engineering can be defined as the
  systematic process of developing requirements
  through an iterative cooperative process of
• analysing the problem
• documenting the resulting observations
• checking the accuracy of the understanding gained

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Requirements

• 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

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Capture of user requirements

• Followed PSS-05 recommendations
• Wide agreement should be established through
  interviews and surveys
• UR should be clarified through criticism and
  experience of existing software and prototypes
• Knowledge and experience of the potential
  development organizations should be used to help
  decide on implementation feasibility and build
  prototypes

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Methods for User Requirements capture

• Interviews and surveys
• Useful to ensure that UR are complete and there
  is wide agreement
• Use cases and scenarios
• Thinking systematically in a variety of
  situations
• Studies of existing software
• Good or bad features of existing software can
  identify requirements for the new software
• Prototyping
• Useful especially if requirements are unclear or
  incomplete
• The prototype is based on tentative requirements,
  then explore what is really wanted

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Problems in Requirements Elicitation

• 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

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The URD
Physical processes Chemical processes Biochemical
processes Geometry Materials Particles Visualisati
on Analysis Interface to other components
Capability and constraint requirements
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Prototyping
5.3 MeV alpha particle in a cylindrical volume
inside cell nucleus. The inner cylinder has a
radius of 50 nm.
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Publication
draft
The outcome of the first phase of the activity
will be published in an INFN report(summer
2001) It will contain the URD too
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Future

• 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
• Incremental and iterative phases of
  analysisdesign, implementation, testing
• There will certainly be iterations in the
  requirements too
• The continuation depends on the availability of
  financial resources

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http//srhp.jsc.nasa.gov/