Nigel MasonNigel Mason

The Open UniversityThe Open University

Radiation Damage; The Database – What we know and what we need to explore

What is the current status of What is the current status of

the field of radiation damge ?the field of radiation damge ? Our studies in Our studies in the mechanismsthe mechanisms of of

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

For example role of DEA in DNA For example role of DEA in DNA damage damage

What is the current status of What is the current status of

the field of radiation damge ?the field of radiation damge ? Development of new cancer therapies Development of new cancer therapies

eg carbon ion therapy.eg carbon ion therapy.

HENCEHENCE

Recent research has stressed the Recent research has stressed the need to understand radiation need to understand radiation damage at damage at the molecular level the molecular level This This was aim of RADAM action 2003-was aim of RADAM action 2003-20082008

This has been coupled with the This has been coupled with the

need to understand effects of low need to understand effects of low dose long term exposure (EU dose long term exposure (EU RISCRAD programme)RISCRAD programme)

AAnd is one of the aims of nd is one of the aims of

COST MP1003COST MP1003

NANO-IBCTNANO-IBCT

Three Grand Challenges of Three Grand Challenges of thethe

underpinning fundamental underpinning fundamental sciencescience

1.1. Understanding fundamental Understanding fundamental interactions between different interactions between different types of radiation and biomoleculestypes of radiation and biomolecules

2.2. Study of damage to DNA and other Study of damage to DNA and other macromolecules in the cellmacromolecules in the cell

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

Grand challenges for Grand challenges for exploitation of exploitation of

knowledgeknowledge Making new knowledge relevant to Making new knowledge relevant to

the clinicthe clinic

Adoption as clinical tool – changing Adoption as clinical tool – changing dose delivery protocolsdose delivery protocols

both require discussions and both require discussions and engagement as in this COST action.engagement as in this COST action.

Radiation Damage – the Radiation Damage – the mechanismmechanism

What we need to understand is the What we need to understand is the mechanisms by which strand breaks mechanisms by which strand breaks in DNA occur.in DNA occur.

Can this be understood by single Can this be understood by single collisions ?collisions ?

Is the damage located at specific sites Is the damage located at specific sites in the DNA chain ?in the DNA chain ?

Can we ‘control’ the site & amount of Can we ‘control’ the site & amount of damage ? damage ?

or X e-

<20 eV

Single and double strand breaks may be induced by secondary

species: a large number of secondary electron with kinetic energies

below about 20 eV, are produced along the radiation track

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

Electron induced damage of DNAElectron induced damage of DNA

V(R)

0

A + B + e-

A- + B

R

D(A-B)

EA(A)

e- + AB → (AB)-*

Transit negative ion (TNI)

→ AB-

→ AB + e-

→ A- + B

autodetachment

molecular anion

dissociative electron attachment

Dissociative Electron Attachment

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

126 amu

125 amu

124 amu

1 amu

16 amu

26 amu

42 amu

54 amu

68 amu

99 amu

73 amu

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

Site selectivity and Chemical control

• Such site selectivity appears to be maintained in larger biomolecules

• Eg if add sugar to base (thymidine) can still target thymine site

DEA and radiosensitizers

• Can we exploit such site specific damage ?

• Eg in developing new cancer therapies?

• Consider radiosensitizers

• Au nanoparticles

E.g exploit enhanced DEA to develop new radiosensitizers

5-nitrouracil

So exploit enhanced DEA to develop new radiosensitizers 5-nitrouracil

0 1 2 30

5000

10000

0 5 100

3

6

0 5 100

30

60

0 5 100

100

200

0 1 2 30

30000

60000

0 1 2 3 40

5000

10000

0 2 4 6 80

25

50

0 2 4 6 8 100

500

1000

(5NU-H)-

156 Da

a b (5NU-2H)-

155 Da

c(5NU-O)-

141 Da

d (5NU-OH)-

140 Da

e f (5NU-NO2-H)-

110 Da

0 5 10 15 20

gC

3N

2OH-

82 DaC

3N

2O

2

-

96 Da

h

(5NU-NO2)-

111 Da

Ion

yie

ld (

cp

s)

Electron energy (eV)

0 5 10 15 20

SO !!!

• We are now developing a picture of radiation damage that is based on fundamental collision physics

• Such an understanding may/is leading to opportunity for controlling damage pathways

• Exploitation for new radiotherapy techniques ?

But are we asking the right questions ?

We need to provide data that is useful in setting clinical protocols

• Medical applications require accurate dose evaluation performed using models

• Available simulation codes (MCNPX, PARTRAC, PENELOPE, GEANT-4): Based on high-energy particle approximations, few molecular details are included

Energy degradation of electrons in H2O

Energy scale (eV)

H2O , 200 Torr

5 mm

2 keV incident energy

(5 single tracks)

Different types of interactions

2 keV electrons in H2O Pressure: 200 Torr

5 single tracks

Ionisation

Neutral dissociation

Excitation

Auger

Such models need

• Cross sections !!!!

• Real numbers not just phenomenology !

Database assessment --What data is needed ?

Electron impact processes• Energy resolved cross sections• Dissociation/ionisation processesIon molecule interactions • Charge state • Energy dependence• Fragmentation – branching ratiosPhoton interactions X-ray to UVSpectroscopy – photostability

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

Views from Database assessed data on cross sections

Electron interactions data in H2O

Summary of the Recommended data on the electron collision cross section for H2O

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

Total electron scattering and ionisation cross sections in H2O

Total

Ionisation

100%Discrepancy below 5eV

*Muñoz et al., Phys. Rev. A

(2007)

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

1 10 100 1000 10000Electron energy (eV)

0.01

0.1

1

10

100

1000C

ross

sec

tion

(a02

)Total scattering

(5%)

Integral elastic and inelastic

(10%)

Ionisation (7%)

Excitation (15%)

Neutral dissociation

(15%)

Elastic scattering - H2O

1

10

0 30 60 90 120 150 180

Present

Rescigno & Lengsfield (1992)

Okamoto et al (1993)

Gianturco et al (1998)

Varella et al (1999)

DC

S (

10-1

6 cm

2 sr-1

)

Scattering Angle (degrees)

10 eVElastic

0.1

1

10

0 30 60 90 120 150 180

Present (CNU)Johnstone & NewellRescigno & LengsfieldOkamoto et alGianturco et alVarella et al

DC

S (

10-1

6 cm

2 sr-1

)

Scattering Angle (degrees)

6 eVElastic

0.1

1

10

0 30 60 90 120 150 180

Present

Shyn & Cho

Varella et al.

Dif

fere

nti

al C

ross

Sec

tion

(10

-16 c

m2 s

r-1)

Scattering Angle (degrees)

4 eVElastic

Cho, Park, Tanaka, BuckmanJPB 37 625 (2004)

But what is the measurable in clinic ?

The stopping power: (-dE/dx)

Mass stopping power of electrons in water: -dE/ dx (Munoz et al)

But such complete data sets are rare

For most biomoleules MOST cross sections are missing

Some may be calculated – eg ionisation (Theory – Kim (BE) and Deutsch Maerk )And compare well with experiments(But note kinetic effects in products)

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

But….

• To date most of the ideas are based on knowledge in gas phase

• The cell is not a gas !! For example electronic states are shifted !

• So are gas phase cross sections relevant in modelling radiation damage in a cell ?

Water ice Note : Blue shift in the solid phase

0.0E+00

2.0E-18

4.0E-18

6.0E-18

8.0E-18

1.0E-17

1.2E-17

1.4E-17

1.6E-17

1.8E-17

2.0E-17

6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5

Photon Energy / eV

Cro

ss S

ectio

n

/ cm2

Carbon dioxide Note : Blue shift in the solid phase

0.0E+00

2.0E-19

4.0E-19

6.0E-19

8.0E-19

1.0E-18

1.2E-18

1.4E-18

6.5 7 7.5 8 8.5 9 9.5 10 10.5

Photon Energy / eV

Cro

ss S

ectio

n / c

m2

Comparison of gas and solid phase Methylamine

Note absence of low lying bands in solid phase

Energy (eV)

5 6 7 8 9 10 11

Cro

ss S

ectio

n (

cm

2 )

0

1e-18

2e-18

3e-18

4e-18

5e-18

6e-18

7e-18

Gas PhaseSolid Phase

Cross sections in condensed phase

• TRK sum rule still holds !!

• So where does ’lost flux’ go ?

• How to measure cross sections in condensed phase ?

Studies in condensed phase

• Evidence is that same site selectivity etc holds in condensed films

GCAT

GCAT

G+C+A+TG+C+A+T

EA - electron affinityEA(CN)= 3.82 eVEA(CNO)= 3.61 eV

DEA to oligomers

O

PO-

NH2

N N

NNHO O

O

O

NH2

O

N

N

P

OO OO-

O

O NH2

N

N

N

N

NN

O

O

O

OO

O

O-

O

OH

G

C

A

Toligomertetramer

(1172 amu)

P

CN- CNO-Gas phase

Condensed phase

Studies in condensed phase

• Evidence is that same site selectivity etc holds in condensed films

• Cross sections in ice have been defined (Sanche)

But a cell is not a solid either !

• So what is the best mimic of the environment of biomolecules in a cell ?

• What can be explored in the Lab ?

Experiments with clusters • Groningen University

T Schladtholter et al)

• Ion irradiation of biomolecular clusters

• Eg C+ on nucleobasesDeoxyribose and amino acids

Uracil and Thymine Different fragmentation

patterns

Experiments with clusters

• Experiments in He droplets (Innsbruck)

• But is this a mimic of ‘real conditions’ ?

But what about other biomolecules ?

• DNA is not the only target in the cell !!!

• What about other molecules ?

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

But what about other biomolecules ?

How do we study Lipids and proteins ?

In gas phase or on surfaces ?

Damage may change ion transport through cell membrane !

Direct damage vs Indirect

• All of the discussion so far is based on direct damage but this is only 1/3 of the damage !

• What about mechanisms of indirect damage ?

And no description can ignore repair

• So in reality we are only exploring one part (important though it is) of the radiation damage process

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 ?

And we have more to explore with new projectiles

• We now have carbon ions !

• And at CERN antiprotons !

So lots of data needed !

• How do we co-ordinate data collection ?

• Where does the user find it ?

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

The Database portal for Atomic and Molecular data

Who are VAMDC What are aims of VAMDC ?

VAMDC -- the product

VAMDC -- the culture

Who are VAMDC ?CNRS (France): ML Dubernet, V. Boudon, C. Joblin, P. Le Sidaner, B. Schmitt, V. Tyuterev, V. Wakelam, C. Zeippen [LPMAA, ICB, CESR, VOPARIS Data Centre, LPG, GSMA, L3AB, LERMA]UK: N. Mason (Open University), J. Tennyson, L. Culhane (UCL), T. Millar (Belfast University), H. Mason, G. Del Zanna, N. Walton, (Cambridge University)VALD Consortium: U. Heiter, N. Piskunov (Uppsalla University, Sweden), T. Ryabchikova (INASAN, Russian Federattion), A. Ryabtsev (ISAN, Russian Federation), F. Kupka, W. Weiss, C. Stuetz (Vienna University)Germany (Cologne Univ): S. SchlemmerBelgrade (Astronomical Observatory): M. DimitrijevicINAF (Italy): G. Mulas, G. Malloci (Observatory of Catania, of Cagliori)Russian Federation: V. Perevalov, A. Fazliev (IAO, Tomsk), Russian Federation: P. Loboda (RFNC-VNIITF, Moscow)Venezuela: C. Mendoza, L. Nunez IVIC, Caracas)USA: Y. Ralchenko (NIST), L Rothman (CFA)

What is VAMDC ?

Funded under the “Combination of Collaborative Projects and Coordination and Support Actions” FundingScheme of The Seventh Framework Program.

42 months from July 2009 with 3,2 million Euros

Grant Agreement number: 239108

What is VAMDC ?

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

Http://www.vamdc.eu/

Why VAMDC ?

•Atomic & Molecular data underpins a wide range of basic and applied research and industrial development

•Thus there is a need to collect, assess and allow access to a wide range of data

•Hence there are DATABASES but….

Why VAMDC ? Databases are dispersed

Often in different formats

Access maybe restricted or ‘regional’

So need a common portal ‘single point entry’

KEY VAMDC OUTCOMES Develop or/and extend standards for

interoperability of AM resources Implementation of selected databases /

Compatibility with existing extraction tools

Find resources easily Registries at a fine granularity

Query those resources Query protocols or/and languages

Transfer large quantities of data, Asynchronous Queries

Create a safe environment where latest AM data can be easily published (even small sets)

Linking producers and users

KEY BENEFITSKEY BENEFITS Find any type of AM with a Find any type of AM with a

“click”“click” Uniform access, i.e. saving Uniform access, i.e. saving

time with format of data, time with format of data, tools developmenttools development

Increase level of scientific Increase level of scientific analysis of ground/space analysis of ground/space missions or experimentsmissions or experiments good standardisation good standardisation

implies Documentationimplies Documentation allows cross-matching allows cross-matching

of different sets of AM of different sets of AM datadata

allows wide access to allows wide access to the latest published AM the latest published AM datadata

At present all the above At present all the above items are not fulfilleditems are not fulfilled

What is VAMDC ?

VAMDC does not collect or commission data but…

Will be a ‘one stop shop’ access to databases (currently some 17 are planned)

What is VAMDC ?Current planned databases

Vienna Atomic Line Database (VALD)

CHIANTI

Cologne Database for Molecular Spectroscopy (CDMS) and Jet Propulsion

Laboratory Submillimeter Catalogue

BASECOLGhoSST

UMIST database for astrochemistry

KInetic Database for Astrochemistry (KIDA)

Polycyclic Aromatic Hydrocarbon spectral database

LASP Database

Stark-B

Spectr-W3

TIPTOPbaseHITRAN

NIST atomic database

• For collisions need to collate/assemble databases

• IAEA willing to develop role but ….

les

• Only for fusion relevant data

• So up to someone else to do for biomolecules …..

• Data (bases) is stated role of NANO-IBCT

• So who will help compile data and write review of

• Ion interactions

• Electron collisions

• Spectroscopy

Over to you….