1. 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 ARGENT Advanced Radiotherapy, Generated by Exploiting Nanoprocesses and Technologies Univ 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

2. 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

3. 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

4. Nigel Mason Nigel Mason The Open University A roadmap for Europe’s research on radiation damage NANO - IBCT Sopot May 20 - 24 2013

5. A history How did we get to be in SOPOT ? How did we get to be in SOPOT ? Question (for academics) Question (for academics) How many people did you know in this room in 2003 ? How many people did you know in this room in 2003 ?

6. Question for atomic molecular and electron collisions people In 2003 what did you know about DNA ? In 2003 what did you know about DNA ? Cells and radiotherapy ? RBE ? LET ? (Nano) dosimetry Cells and radiotherapy ? RBE ? LET ? (Nano) dosimetry What molecular targets were you studying ? What molecular targets were you studying ? ECAMP 2004 only 9/850 papers on biomolecules ! >20 on N 2 and >100 on rare gases ECAMP 2004 only 9/850 papers on biomolecules ! >20 on N 2 and >100 on rare gases

7. Question for biological and clinical 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 ion beam facilities (GANIL, Groningen ? Had you visited one ? Did you know about experimental EU ion beam facilities (GANIL, Groningen ? Had you visited one ?

8. The conjecture There has been a big change in what we study and why ! There has been a big change in what we study and why ! A new (trans disciplinary) EU community has developed. A new (trans disciplinary) EU community has developed. It has been useful, successful and It has been useful, successful and

9. The conjecture There has been a big change in what we study and why ! There has been a big change in what we study and why ! A new (trans disciplinary) EU community has developed. A new (trans disciplinary) EU community has developed. It has been useful, successful and FUN It has been useful, successful and FUN

10. Where is all began (for many of us!) The pioneering work of Sanche et al and the (in)famous Science paper The pioneering work of Sanche et al and the (in)famous Science paper Resonant Formation of DNA Strand Breaks by Low-Energy (3 to 20eV) Electrons. Science 287, 1658-1660 (2000). B. Boudaiffa, P. Cloutier, D. Hunting, M.A. Huels et L. Sanche. Resonant Formation of DNA Strand Breaks by Low-Energy (3 to 20eV) Electrons. Science 287, 1658-1660 (2000). B. Boudaiffa, P. Cloutier, D. Hunting, M.A. Huels et L. Sanche.

11. L. Sanche et al. Science, 287 (2000) 1659 and PRL (2004) Strand breaks of DNA  10 05101520 0 5 10 SSB DSB Electron Energy (eV) DNA breaks per 10 4 incident electrons e - + DNA → DNA - * → fragments

12. These ‘fundamental’ studies coincided with new therapies e.g. carbon ion therapy. (Nano-IBCT)

13. Hence The idea/development of need to bring two disparate communities together The idea/development of need to bring two disparate communities together Atomic, molecular physics/ physical chemistry Atomic, molecular physics/ physical chemistry And And Radiation chemists/medical physics Radiation chemists/medical physics

14. This research has been developed through networks

15. RADAM first COST Action Presented 2002 WARSAW Presented 2002 WARSAW Started 2003 Started 2003 RADAM 1 Lyons 2004 RADAM 1 Lyons 2004

16. 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 Frankfurt 6 2009 Frankfurt 7 2010 Madrid 7 2010 Madrid Then IBCT Nano Caen 2011 and Sopot 2013 Then IBCT Nano Caen 2011 and Sopot 2013

17. The exchanges RADAM; ECCL; EIPAM & Nano-IBCT has supported RADAM; ECCL; EIPAM & Nano-IBCT has supported Over 450 visits/exchanges !! Over 450 visits/exchanges !! They have built the community They have built the community

18. So what have we learnt ? DNA damage (key process) needs trans disciplinary research DNA damage (key process) needs trans disciplinary research Lets look at interconnections in ‘RADAM’ Lets look at interconnections in ‘RADAM’community

19. MesoBioNano- Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn) SSB’s and DSB’s Energy loss by the incident particle Production of secondary electrons, holes Heating of the medium Damage of the DNA Production of Free Radicals Bragg peak, its position, shape, and height Energy spectrum, number density, plasma Propagation in a dense medium Excitation of the medium 9 September 2015 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 (Solov’yov) To understanding DNA Damage (Solov’yov)

20. Nano-ICBT 2011, Caen Or view of Werner Friedland physical track structure calculation pre-chemical and chemical stage calculation DNA target modelling biological effect simulation

21. Nano-ICBT 2011, Caen Biological 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 simulation where 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 secondary ionising particles (electrons, photons, protons, alphas, ions)

22. Where are we now ? Our studies in the mechanisms of radiation damage has developed rapidly in the last decade. Our studies in the mechanisms of radiation damage has developed rapidly in the last decade. There has been a lot of work on the fragmentation (and hence stability) of biomolecules There has been a lot of work on the fragmentation (and hence stability) of biomolecules In particular DEA In particular DEA (>80% of molecular targets for which DEA has been explored are biomolecules and studied since 2002 !)

23. Bond Selectivity using Electrons Process of Dissociative Electron Attachment

24. DEA Is a universal process Is a universal process Often simple H abstraction (M-H) Often simple H abstraction (M-H) - and is bond specific !

25. Thymine + e - → TNI - * → electron attachment C5H6N2O2-C5H6N2O2- e-e- dissociative electron attachment (T-H) - + H (T-2H) - + neutral(s) C 4 H 5 N 2 O - + neutral(s) C 2 H 3 N 2 O - + neutral(s) C 3 H 2 NO - + neutral(s) CN - + neutral(s) O - + neutral(s) H - + neutral(s) OCN - + neutral(s) → → → → → → C 3 H 4 N - + 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

26. 01234 0 2 4 6 8 10 12 Cross section (10 -20 m 2 ) Electron energy (eV) H loss e-e- DEA in Thymine (M-H) - 125 amu

27. DEA But what is real relevance to the cell biology ? Does it hold in condensed phase ? Can it explain any radiobiology phenomena ? Can it explain any radiobiology phenomena ? (e.g radiosensitizers) (e.g radiosensitizers)

28. Desorption of anions and neutrals from Tetrahydrofuran

29. UracilThymine Bromouracil (Radiosensitizer )

30. + Br.  ≈ 600 Å 2 Freie University Berlin

31. Ion impact Similar story to electrons/DEA Similar story to electrons/DEA Great progress in number of systems studied and exploration of fragmentation Great progress in number of systems studied and exploration of fragmentation Stability - necleobases more stable than sugars Stability - necleobases more stable than sugars (e.g. uracil cf deoxyribose) (Hoekstra)

32. Groningen University Ion irradiation of biomolecules Eg C + on nucleobases Deoxyribose and amino acids Different fragmentation patterns

33. Ion impact But …. But …. Can this be extrapolated to cellular conditions and condensed phase ?) Can this be extrapolated to cellular conditions and condensed phase ?) What is relevance of heavy ions (> Carbon ?) What is relevance of heavy ions (> Carbon ?)

34. Photon impact Photostability Photostability Electronic state structure of biomolecules Electronic state structure of biomolecules Quantum chemistry advances (DFT) Quantum chemistry advances (DFT)

35. Three Grand Challenges of the underpinning fundamental science 1. 1. Moving from the isolated gas phase to the cellular environment 2. 2. Extend study of damage to DNA to other macromolecules in the cell and cell itself 1. 1. Developing models of such damage for use in therapy etc.

36. 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

37. Developments in understanding of fundamental processes is used to develop better models Allowed new track models to be developed

38. Track modelling 2 keV electrons in H 2 O Pressure: 200 Torr 5 single tracks Ionisation Neutral dissociation Excitation Auger

39. Such models need Cross sections !!!! Cross sections !!!! Real numbers not just phenomenology ! Real numbers not just phenomenology !

40. Data providers * theory * experiment Data users in various application 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 Data needs Data provide Data search Data requested Data search for check International A&M data center network IAEA, NIFS, A-PAN, KAERI, NIST, ORNL, GAPHIOR, VAMDC, Data provided feedback Planning a Database

41. Electron interactions data in H 2 O eMOL data review and validation project

42. Summary of the Recommended data on the electron collision cross section for H 2 O Y. Itikawa and N.J.Mason, J. Phys. Chem. Ref. Data 34 (2005)1

43. e-H 2 O integral cross section data (Courtesy of G Garcia) Total scattering (5%) Integral elastic and inelastic (10%) Ionisation (7%) Excitation (15%) Neutral dissociation (15%)

44. But such complete data sets are rare For most biomolecules MOST cross sections are missing Some may be calculated – eg ionisation (Theory – Kim (BE) and Deutsch Maerk ) And compare well with experiments Or for total, elastic, some excitations Quantemol package (J Tennyson)

45. So lots of data needed ! How do we co-ordinate data collection ? How do we co-ordinate data collection ? Where does the user find it ? Where does the user find it ? When collected how/where is it stored and ‘ratified’ ? When collected how/where is it stored and ‘ratified’ ?

46. VAMDC will provide a one stop scientific data e-infrastructure enabling easy access to A+M data VAMDC will provide a one stop scientific data e-infrastructure enabling easy access to A+M datawww.vamdc.org To include RADAM database from COST Nano-IBCT network To include RADAM database from COST Nano-IBCT network

47. But beyond this…. Need to remember the chemistry Need to remember the chemistry And biology …….. And biology ……..

48. Nano-ICBT 2011, Caen e aq + e aq + 2H 2 O → H 2 + 2OH - e aq + OH → OH - e aq + H + H 2 O → H 2 + OH - e aq + H 3 O + → H + H 2 O e aq + H 2 O 2 → OH - + OH OH + OH → H 2 O 2 OH + H → H 2 O H + H → H 2 H 3 O + + OH - → 2H 2 O physical stage chemical stage physico- chemical relax auto-ionize dissociate diffuse react e aq, OH, H, H 2 H 3 O +, OH -, H 2 O 2 reaction rate constants k diffusion coefficients D 10 -15 – 10 -12 s 10 -12 – 10 -6 s e sub,H 2 O + A 1 B 1, B 1 A 1 Ryd, db H 2 O + + H 2 O → H 3 O + + OH 100% A 1 B 1 →H 2 O +  E35% H + OH65% B 1 A 1 →H 2 O +  E30% H 3 O + + OH + e aq 55% H 2 + OH + OH 15% Ryd,db →H 2 O +  E50% H 3 O + + OH + e aq 50% Particle tracks during physico-chemical and chemical stage

49. 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

50. DNA damage signalling in bystander cells Burdak-Rothkamm and Prise, 2009

51. MesoBioNano- Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn) Nucleosome damage by shock wave R=17.5nm L=8nm # atoms ~ 700.000 T 0 =310 K NVE ensemble Z-periodic BC Integration timestep 0.1 fs CHARMM22 ForceField TIP3P model for water …

52. 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

53. Other challenges

54. Developing new radiosensitizers e.g. Au nanoparticles

55. MesoBioNano- Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn) Sensitising effects of GNPs: the role of Auger electrons 09.09.2015 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)

56. 13 PhD positions in different fields : Applications procedure starting September 2013 Starting date : September 2014 EU PhD training : Marie Curie ITN ARGENT Advanced Radiotherapy, Generated by Exploiting Nanoprocesses and Technologies Contact : sandrine.lacombe@u-psud.fr

57. 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 ?

58. 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

59. What is the effect of damage to the cell membrane ? radiation damage of proteins

60. DNA structures and nanotechnology Making DNA wires Adding metal atoms to make DNA conduct Electron transport = electron induced damage

61. 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.

62. Plasma treatment DNA Damage (SSB DSB) induced by VUV, electrons Ions and plasmas S Ptasinska talk to follow

63. And related fields ASTROBIOLOGY Stability and development of biomolecules, cells and DNA

64. Space medicine Survival in space Survival in space Travel to Mars Travel to Mars 3 years – lethal dose of radiation to solve 3 years – lethal dose of radiation to solve

65. Horizon 2020 Fast approaching Fast approaching Programmes in health, Radiation (Euratom), Programmes in health, Radiation (Euratom), Space and nanomaterials All relevant to us

66. Horizon 2020 So lets be ready to work together to exploit it So lets be ready to work together to exploit it What is next ?? (COST March 2014 !) What is next ?? (COST March 2014 !)

67. But more ….. I propose (through NANO IBCT) we copy Astrobiology community and Write a roadmap

68. Awe asking the right questions ?

69. 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