September 2014 :

13 PhD positions in different fields :

-Chemistry : synthesis, functionalization of NP -Physics / chemical physics (experimental/theory)-Medical physics/radiation physics-Biology (radiation)

EU PhD training : Marie Curie ITN ARGENTAdvanced Radiotherapy, Generated by Exploiting

Nanoprocesses and TechnologiesUniv Paris Sud-Orsay (FR)

Open university (UK)Queens university Belfast (UK)

Univ of Caen (FR)Univ of Frankfurt FIAS (D)

Univ Madrid (S)GSI (Darmstadt, D)NanoH, SME (FR)

ChemaTech( SME, FR)Quantumwise( SME, Danemrk)

Contact : sandrine.lacombe@u-psud.fr

RESEARCH•Improvement of the hadrontherapy protocols using nanosensitizers (S. Lacombe Orsay)•Uptake dynamics of nanoagents and effect on radioenhancement (Orsay/Belfast)•Development of new modules for ATK code for modelling radiosensitizing nanoagents (A.

Solovyov/industrial in Danemark)•Bond-breaking as a descriptor for nanodosimetry (G. Garcia-Madrid)•Validation of models in medical radiation planning (G. Garcia, Madrid)•Nanoagent functionalization aiming at tumor targeting and biocompatibility (industrial in France) •Nanoscale understanding of cell signalling and biological response (K.Prise, Belfast)•Multiscale understanding of radiation biodamage (A. Solovyov, Frankfurt and F. Curell, Belfast)•Development of Lanthanides based nanosensitizers for theranostic ((industrial in France) •Molecular efficiency of radiosensitizers in ion-induced radiation damage processes (B. Huber, Caen)•OER prediction on the nanoscale for a target tissue in different conditions of irradiation and

oxygenation (E. Scifoni, M. Durante, Darmstadt)•Exploring site specificity, structure and sequence dependence of radiation-induced damage (N.

Mason, Milton Keynes) •Impact of nanoscale processes and agents on biodamage complexity in the presence of

nanoagents (A. Solovyov, Frankfurt)

Contact : sandrine.lacombe@u-psud.fr

RESEARCH•Improvement of the hadrontherapy protocols using nanosensitizers (S. Lacombe Orsay)•Uptake dynamics of nanoagents and effect on radioenhancement (Orsay/Belfast)•Development of new modules for ATK code for modelling radiosensitizing nanoagents (A.

Solovyov/industrial in Danemark)•Bond-breaking as a descriptor for nanodosimetry (G. Garcia-Madrid)•Validation of models in medical radiation planning (G. Garcia, Madrid)•Nanoagent functionalization aiming at tumor targeting and biocompatibility (industrial in France) •Nanoscale understanding of cell signalling and biological response (K.Prise, Belfast)•Multiscale understanding of radiation biodamage (A. Solovyov, Frankfurt and F. Curell, Belfast)•Development of Lanthanides based nanosensitizers for theranostic ((industrial in France) •Molecular efficiency of radiosensitizers in ion-induced radiation damage processes (B. Huber, Caen)•OER prediction on the nanoscale for a target tissue in different conditions of irradiation and

oxygenation (E. Scifoni, M. Durante, Darmstadt)•Exploring site specificity, structure and sequence dependence of radiation-induced damage (N.

Mason, Milton Keynes) •Impact of nanoscale processes and agents on biodamage complexity in the presence of

nanoagents (A. Solovyov, Frankfurt)

Contact : sandrine.lacombe@u-psud.fr

SCIENTIFIC AND SOFT SKILLS:3 months tutorials + soft skills (MBA 3 weeks) + 1 month industrial site

Nigel MasonNigel Mason

The Open UniversityThe Open University

A roadmap for Europe’s research on radiation damage

NANO - IBCT Sopot May 20 - 24 2013

A history A history

How did we get to How did we get to be in SOPOT ?be in SOPOT ?

Question (for Question (for academics) academics)

How many people How many people did you know in did you know in this room in this room in 2003 ?2003 ?

Question for atomic Question for atomic molecular and electron molecular and electron

collisions peoplecollisions people In 2003 what did you know about DNA ? In 2003 what did you know about DNA ?

Cells and radiotherapy ? RBE ? LET ? (Nano) Cells and radiotherapy ? RBE ? LET ? (Nano) dosimetrydosimetry

What molecular targets were you studying ?What molecular targets were you studying ?

ECAMP 2004 only 9/850 papers on biomolecules ! ECAMP 2004 only 9/850 papers on biomolecules ! >20 on N>20 on N2 2 and >100 on rare gasesand >100 on rare gases

Question for biological and Question for biological and clinical peopleclinical people

In 2003 had you heard of DEA ?In 2003 had you heard of DEA ?

Anions and Resonances ?Anions and Resonances ?

Did you know about experimental EU Did you know about experimental EU ion beam facilities (GANIL, Groningen ? ion beam facilities (GANIL, Groningen ? Had you visited one ?Had you visited one ?

The conjecture The conjecture

There has been a big change in what There has been a big change in what we study and why !we study and why !

A new (trans disciplinary) EU A new (trans disciplinary) EU community has developed. community has developed.

It has been useful, successful and It has been useful, successful and

The conjecture The conjecture

There has been a big change in what There has been a big change in what we study and why !we study and why !

A new (trans disciplinary) EU A new (trans disciplinary) EU community has developed. community has developed.

It has been useful, successful and It has been useful, successful and

FUNFUN

Where is all began (for many of Where is all began (for many of us!)us!)

The pioneering work of The pioneering work of Sanche et al Sanche et al and the and the (in)famous Science (in)famous Science paper paper

Resonant Formation of Resonant Formation of DNA Strand Breaks by DNA Strand Breaks by Low-Energy (3 to 20eV) Low-Energy (3 to 20eV) Electrons. Science 287, Electrons. Science 287, 1658-16601658-1660 (2000). B. (2000). B. Boudaiffa, P. Cloutier, Boudaiffa, P. Cloutier, D. Hunting, M.A. Huels D. Hunting, M.A. Huels et L. Sanche.et L. Sanche.

L. Sanche et al. Science, 287 (2000) 1659 and PRL (2004)

Strand breaks of DNA

10

0 5 10 15 20

0

5

10

SSB DSB

Electron Energy (eV)

DN

A b

reak

s pe

r 10

4 in

cide

nt e

lect

rons

e- + DNA → DNA-* → fragments

These ‘fundamental’ studies These ‘fundamental’ studies coincided with new therapiescoincided with new therapies

e.g. carbon ion therapy. (Nano-e.g. carbon ion therapy. (Nano-IBCT)IBCT)

Hence Hence

The idea/development of need to bring The idea/development of need to bring two disparate communities together two disparate communities together

Atomic, molecular physics/ physical Atomic, molecular physics/ physical chemistry chemistry

AndAnd

Radiation chemists/medical physics Radiation chemists/medical physics

This research has been This research has been developed through networksdeveloped through networks

RADAM first COST RADAM first COST ActionAction

Presented 2002 Presented 2002 WARSAWWARSAW

Started 2003 Started 2003

RADAM RADAM 11 Lyons Lyons 20042004

RADAM Meetings RADAM Meetings

1 2004 Lyons (food) 1 2004 Lyons (food) 2 2005 Potsdam ( a tutorial)2 2005 Potsdam ( a tutorial) 3 2006 Groningen (Euro football!)3 2006 Groningen (Euro football!) 4 2007 Dublin (rain!)4 2007 Dublin (rain!) 5 2008 Debrecen (thunder!)5 2008 Debrecen (thunder!) 6 2009 Frankfurt6 2009 Frankfurt 7 2010 Madrid7 2010 Madrid Then Then IBCT Nano IBCT Nano Caen 2011 and Sopot Caen 2011 and Sopot

2013 2013

The exchanges The exchanges

RADAM; ECCL; EIPAM & Nano-RADAM; ECCL; EIPAM & Nano-IBCT has supported IBCT has supported

Over Over 450 450 visits/exchanges !!visits/exchanges !!

They have built the community They have built the community

So what have we learnt ?So what have we learnt ?

DNA damage (key process) needs DNA damage (key process) needs trans disciplinary research trans disciplinary research

Lets look at interconnections in Lets look at interconnections in

‘RADAM’‘RADAM’

communitycommunity

MesoBioNano- Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn)MesoBioNano- Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn)

SSB’s and DSB’s

Energy loss by the incident

particle

Energy loss by the incident

particle

Production of secondary

electrons, holes

Production of secondary

electrons, holes Heating of the mediumHeating of

the medium

Damage of the DNA

Damage of the DNA

Production of Free RadicalsProduction of Free Radicals

Bragg peak, its position, shape, and height

Energy spectrum, number density, plasma

Propagation in a dense medium

Excitation of the mediumExcitation of the medium

April 19, 2023

Solov’yov et al., Phys. Rev. E, v.79, p. 011909-(1-7) (2009)Europhysicsnews, v.40, n.2, p.21-24 (2009)

To understanding DNA Damage To understanding DNA Damage (Solov’yov) (Solov’yov) To understanding DNA Damage To understanding DNA Damage (Solov’yov) (Solov’yov)

Nano-ICBT 2011, Caen

Or view of Werner FriedlandOr view of Werner Friedland

physical track structurecalculation

pre-chemical and chemical stagecalculation

DNA targetmodelling

biologicaleffectsimulation

Nano-ICBT 2011, Caen

Biological effect simulations using track structuresBiological effect simulations using track structures

… has to be complemented by target structure simulation …where damage to DNA in the nucleus is - supposed to be - the main initiating event by which radiation causes long-term harm to organs and tissues of the body after low doses of radiation

… and by radiation effect simulationwhere double-strand breaks (DSB) in genomic DNA are – supposed to be -crucial initial lesions for causing critical damage after irradiation

Track structure simulation …based on cross sections for interactions of primary and secondaryionising particles (electrons, photons, protons, alphas, ions)

Where are we now ?Where are we now ? Our studies in Our studies in the mechanismsthe mechanisms of radiation of radiation

damage has developed rapidly in the last damage has developed rapidly in the last decade.decade.

There has been a lot of work on the There has been a lot of work on the fragmentation (and hence stability) of fragmentation (and hence stability) of biomolecules biomolecules

In particular DEA In particular DEA

(>80% of molecular targets for which DEA has (>80% of molecular targets for which DEA has been explored are biomolecules and studied been explored are biomolecules and studied since 2002 !) since 2002 !)

Bond Selectivity using Electrons

Process of Dissociative Electron Attachment

DEADEA

Is a universal process Is a universal process

Often simple H abstraction Often simple H abstraction (M-H)(M-H)-

and is bond specific !

Thymine + e- → TNI-* →electron attachment

C5H6N2O2-

e-dissociative electron attachment

(T-H)- + H(T-2H)- + neutral(s)

C4H5N2O- + neutral(s)

C2H3N2O- + neutral(s)

C3H2NO- + neutral(s)

CN- + neutral(s)

O- + neutral(s)H- + neutral(s)

OCN- + neutral(s)

→→→

→→

→C3H4N- + neutral(s)

→

→

→

→

DEA to biomolecules typical results -- S

126 amu

125 amu

124 amu

1 amu

16 amu

26 amu

42 amu

54 amu

68 amu

99 amu

73 amu

DEA to biomolecules typical results -- Ptasinska

0 1 2 3 40

2

4

6

8

10

12

Cro

ss s

ectio

n (1

0-20 m

2)

Electron energy (eV)

H loss

e-

DEA in Thymine

(M-H)-

125 amu

DEADEA

But what is real relevance to the cell biology ?

Does it hold in condensed phase ?

Can it explain any radiobiology Can it explain any radiobiology phenomena ?phenomena ?

(e.g radiosensitizers) (e.g radiosensitizers)

Desorption of anions and neutrals from Tetrahydrofuran

THF (4 layers) / Kr / Pt(111)

P (

x 1

0-17 cm

2 )

Energie d'électron incident (eV)2 4 6 8 10 12 14 16 18 20 22 24 26

012345678

Formation de C=O

0

1

2

3

4

Re

nd

em

en

t (

x103 c

ou

nts

)

H3C

2O

-

-200

20406080

100120140

H-

0,00,20,40,60,81,01,21,4

CHO

Uracil Thymine Bromouracil (Radiosensitizer)

+ Br

.

≈ 600 Å2

Freie University Berlin

Ion impactIon impact

Similar story to electrons/DEASimilar story to electrons/DEA

Great progress in number of systems Great progress in number of systems studied and exploration of studied and exploration of fragmentation fragmentation

Stability - necleobases more stable Stability - necleobases more stable than sugarsthan sugars

(e.g. uracil cf deoxyribose) (Hoekstra)(e.g. uracil cf deoxyribose) (Hoekstra)

• Groningen University

• Ion irradiation of biomolecules

• Eg C+ on nucleobasesDeoxyribose and amino acids

• Different fragmentation patterns

Ion impactIon impact

But …. But ….

Can this be extrapolated to cellular Can this be extrapolated to cellular conditions and condensed phase ?)conditions and condensed phase ?)

What is relevance of heavy ions (> What is relevance of heavy ions (> Carbon ?)Carbon ?)

Photon impactPhoton impact

Photostability Photostability

Electronic state Electronic state structure of structure of biomolecules biomolecules

Quantum Quantum chemistry chemistry advances (DFT) advances (DFT)

Three Grand Challenges of Three Grand Challenges of thethe

underpinning fundamental underpinning fundamental sciencescience

1. Moving from the isolated gas phase to the cellular environment

2. Extend study of damage to DNA to other macromolecules in the cell and cell itself

1. Developing models of such damage for use in therapy etc.

Moving from the isolated gas phase to the cellular environment

• Developing cluster sources

• e.g. nucleobases and water (S Eden OU)

• Study spectroscopy

• Collision dynamics

• PDRA post on offerPDRA post on offer

Developments in understanding of Developments in understanding of fundamental processes is used to fundamental processes is used to

develop better modelsdevelop better models

Allowed new track models to be Allowed new track models to be developeddeveloped

Track modelling

2 keV electrons in H2O Pressure: 200 Torr

5 single tracks

Ionisation

Neutral dissociation

Excitation

Auger

Such models needSuch models need

Cross sections !!!!Cross sections !!!!

Real numbers not just Real numbers not just phenomenology !phenomenology !

Data providers * theory * experiment

Data users in variousapplication fields * fusion science * astrophysics * industrial plasmas * environmental physics * medical (radiotherapy) etc.

Data centers data compilation data evaluation (important but not easy) dissemination and updating of database retrievable online database = easy to access, use, find data

Data

requests

Dat

a ne

eds

Data

pro

vid

e

Dat

a pr

ovid

e

Dat

a se

arch

Data requestedD

ata

search

for

check

International A&M data center network IAEA, NIFS, A-PAN, KAERI, NIST, ORNL, GAPHIOR, VAMDC,

Data provided

feed

back

Planning a DatabasePlanning a Database

Electron Electron interactions data in interactions data in

HH22OO

eMOL data review eMOL data review and validation and validation

projectproject

Summary of the Recommended dataSummary of the Recommended data on the electron collision cross section for Hon the electron collision cross section for H22OO

Y. Itikawa and N.J.Mason, J. Phys. Chem. Ref. Data 34 (2005)1 Y. Itikawa and N.J.Mason, J. Phys. Chem. Ref. Data 34 (2005)1

e-H2O integral cross section data (Courtesy of G Garcia)

1 10 100 1000 10000Electron energy (eV)

0.01

0.1

1

10

100

1000

Cro

ss s

ectio

n (a

02)

Total scattering (5%)

Integral elastic and inelastic

(10%)

Ionisation (7%)

Excitation (15%)

Neutral dissociation

(15%)

But such complete data But such complete data sets are raresets are rare

For most biomolecules MOST cross sections For most biomolecules MOST cross sections are missingare missing

Some may be calculated – eg ionisation Some may be calculated – eg ionisation (Theory – Kim (BE) and Deutsch Maerk )(Theory – Kim (BE) and Deutsch Maerk )And compare well with experimentsAnd compare well with experiments

Or for total, elastic, some excitationsOr for total, elastic, some excitationsQuantemol package (J Tennyson)Quantemol package (J Tennyson)

So lots of data needed !So lots of data needed !

How do we co-ordinate data How do we co-ordinate data collection ?collection ?

Where does the user find it ?Where does the user find it ?

When collected how/where is it When collected how/where is it stored and ‘ratified’ ?stored and ‘ratified’ ?

VAMDC will provide a one stop VAMDC will provide a one stop scientific data e-infrastructure scientific data e-infrastructure enabling easy access to A+M dataenabling easy access to A+M data

www.vamdc.orgwww.vamdc.org

To include To include RADAM database RADAM database from from COST Nano-IBCT networkCOST Nano-IBCT network

But beyond this…. But beyond this….

Need to remember the chemistry Need to remember the chemistry

And biology ……..And biology ……..

Nano-ICBT 2011, Caen

eaq

+ eaq

+ 2H2O → H

2 + 2OH-

eaq

+ •OH → OH-

eaq

+ H• + H2O → H

2 + OH-

eaq

+ H3O+ → H• + H

2O

eaq

+ H2O

2 → OH- + •OH

•OH + •OH → H2O

2

•OH + H• → H2O

H• + H• → H2

H

3O+ + OH- → 2H

2O

physical stage

chemical stage

physico-chemical• relax

• auto-ionize• dissociate

• diffuse• react

eaq

, •OH, H•, H2

H3O+ , OH- , H

2O

2

reaction rate constants k

diffusioncoefficients D

10-15 – 10-12 s 10-12 – 10-6 s

esub

,H2O+

A1B1, B1A

1

Ryd, db

H2O+ + H

2O → H

3O+ + •OH 100%

A1B1

→ H2O + E 35%

H• + •OH 65%B1A

1 → H

2O

+ E 30%

H3O+ + •OH + e

aq

55%H2 + •OH + •OH

15%Ryd,db → H

2O + E 50%

H3O+ + •OH + e

aq

50%

Particle tracks during physico-chemical and chemical stageParticle tracks during physico-chemical and chemical stage

Damage of the genome in living cell by ionising radiation is about 1/3 a

direct and 2/3 an indirect processes.

Radiation damage to DNA

DNA damage signalling in bystander cellsDNA damage signalling in bystander cells

Burdak-Rothkamm and Prise, 2009

MesoBioNano- Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn)MesoBioNano- Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn)

Nucleosome damage by shock waveNucleosome damage by shock wave

• R=17.5nm• L=8nm• # atoms ~ 700.000• T0=310 K• NVE ensemble• Z-periodic BC• Integration timestep

0.1 fs• CHARMM22 ForceField• TIP3P model for water• …

Nano-ICBT 2011, Caen

Italic numbers are time constants in seconds(1)Chromatin remodeling(2)DSB formation from labile sites(3)Processing of DSB from labile sites before synapsis(4) Inhibition of Ku70/Ku80 attachment(5) Release from Ku70/Ku80 attachment inhibition(6) Ku70/Ku80 attachment to DNA(7) Ku70/Ku80-DNA dissociation(8) DNA-PKcs attachment to DNA(9) DNA-PK – DNA dissociation(10) Synapsis(11) Phosphorylation, recruitment and action of nucleases, polymerases, ligases(12) Cleaning of single-strand breaks and base lesions(13) Final ligation and removal of repair enzymes(14) Inhibition of final ligation(15) Release form inhibition of final ligation(a)Correct rejoining(b)Incorrect joining other than (c) and (d)(c)Ring formation(d)Chromosomal exchange aberration

DSB repair model adapted to Stenerlöw data DSB repair model adapted to Stenerlöw data

Other challenges

Developing new Developing new radiosensitizers radiosensitizers e.g. Au nanoparticlese.g. Au nanoparticles

MesoBioNano- Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn)MesoBioNano- Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn)

Sensitising effects of GNPs: the role of Auger electronsSensitising effects of GNPs: the role of Auger electrons

19.04.23

Average energy deposit in the vicinity of a 20 nm GNP after a single ionizing event by a photon

Here, the data are used to investigate whether the model presented by Fred J. Currell et al, Nature Scientific Reports (2011) is capable of accurately quantifying the sensitising effects of GNPs.

Fred J. Currell, Kevin M. Prise et al, Nature Scientific Reports (2011)

13 PhD positions in different fields :

Applications procedure starting September 2013

Starting date : September 2014

EU PhD training : Marie Curie ITN ARGENTAdvanced Radiotherapy, Generated by Exploiting

Nanoprocesses and Technologies

Contact : sandrine.lacombe@u-psud.fr

And we have more to explore with new projectiles

• What about damage induced by positrons ??

• How do positrons damage DNA ?

• Role of annihilation and gamma rays ?

What is the role of water and proteins in electron induced damage of DNA?

DNA

Proteins (amino acids)

M. Begusova et al., Int. J.Radiat.Biol. (2003)

bases

sugar

undamage atoms

proteins

undamage atoms

DNA

proteins

• Free electron attachment to amino- acids/nucleobases complexes

• radiation damage of proteins

radiation

What is the effect of damage to the cell membrane ?

• radiation damage of proteins

DNA structures and nanotechnology

• Making DNA wires • Adding metal atoms

to make DNA conduct

• Electron transport = electron induced damage

DNA structures Recent work in the Turberfield group Oxford includes the design and characterization of DNA tetrahedra.Which can serve as rigid building blocks and as molecular cages; and the application of DNA lattices to protein structure determination.

Plasma treatment

DNA Damage (SSB DSB) induced by VUV, electronsIons and plasmas S Ptasinska talk to follow

And related fieldsAnd related fields

ASTROBIOLOGY Stability and development of

biomolecules, cells and DNA

Space medicine Space medicine

Survival in Survival in space space

Travel to Mars Travel to Mars 3 years – lethal 3 years – lethal

dose of radiation dose of radiation to solveto solve

Horizon 2020Horizon 2020

Fast approaching Fast approaching

Programmes in health, Radiation Programmes in health, Radiation (Euratom),(Euratom),

Space and nanomaterials Space and nanomaterials

All relevant to us All relevant to us

Horizon 2020Horizon 2020

So lets be ready to work together to So lets be ready to work together to exploit it exploit it

What is next ?? What is next ?? (COST March 2014 !)(COST March 2014 !)

But more …..But more …..

I propose (through NANO IBCT) we I propose (through NANO IBCT) we copy copy

Astrobiology community and Astrobiology community and

Write a roadmapWrite a roadmap

Awe asking the right questions ?

Roadmap

• Review where we are

• Declare the challenges

• Propose how the challenges are met (by integrated research plan)

• Publish and so define the road ahead