Radiobiologcal Research at the JINR Accelerators

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1 Radiobiologcal Research at the JINR Accelerators Е. А. Krasavin Laboratory of Radiation Biology

2 Академик Н.М.Сисакян Академик В.В.Парин Академик О.Г.Газенко

3 β What fundamental problems were solved by the classical radiobiology?

4 Survival cells, % Interpretation of Radiobiological Paradox 100 Why the small doses in thermal equivalent (10 Gy) does kill all kinds mammalians? This dose increases the temperature of human organism barely up to C ,1 0,01 1E-3 1E-4 1E-5 S = ē D 1E Dose, Gy

5 Discovery of mutagenic effect of irradiation Ionizing radiation induces the different types of mutations with high frequency Guanine

6 Ionizing radiation induces a cancer Solid cancer

7 The DNA is a target in irradiated cells Ionizing radiation induces the different DNA damages

8 Discovery of complicated hierarchy of DNA repair mechanisms The DNA repair system is the main mechanism of the genome stability

9 Investigation of biological effects of accelerated heavy ions forms the new radiobiology

10 On Earth - accelerators of heavy charged particles The sources of heavy ions of high energies In space cosmic rays from Galaxy

11 The JINR accelerators Accelerator Particles Energy Lab (up to) Phasotron Protons 660MeV LNP U-200 Heavy ions 10MeV/amu LNR U-400M Heavy ions 50 MeV/amu LNR Sinchrophasotron Protons, 10 GeV/amu LHE Heavy ions Nuclotron Protons, 6 GeV/amu LPHE Heavy ions

12 The nuclotron beams Intensity (particles per cycle) Beam p, d 4 He 12 C 24 Mg 56 Fe 84 Kr Present status In The maximal energy of particles up to 6 GeV/amu

13 Tracks of heavy ions in nuclear emulsion Сегменты треков тяжелых ионов в ядерной эмульсии 50 um Fe

14 The dose distribution of radiation in matter 1 unit of the dose 1 unit of the dose X-rays Fe ion

15 D o s e, G y Exp. Varma Katz.. Chatterjee Radial dose distribution in track of heavy ion ( 12 C, 2,57 MeV/u) Радиус трека, см Радиус трека, см r, cм

16 What radiobiological problems can be solved at use of the accelerated heavy particles?

17 A. Heavy ions is a powerful tool for the solve of fundamental problems of radiation genetics

18 The RBE problem was solved at the Flerov Lab accelerators block of DNA repair normal repair super fast repair DNA repair capacity of the living cells determines the type of RBE on LET dependence Bacterial cells

19 Single DNA damages Single strand break Повреждение основания Base damage Повреждение сахара Sugar damage

20 Clustered DNA damages Fragment of DNA

21 Clustered DNA damages Double strand break of DNA Base damages Sugar damage Base damages

22 Clustered DNA damages in nucleosome

23 Yield of clustered damages on both DNA strands versus LET

24 LRB LABORATORY OF RADIATION BIOLOGY Double strand break of DNA Consequences of DSB induction in cell genome Lethals Cell transformation DSB Mutations Chromosomal aberrations PAC 08

25 Comet assay for detection of DNA lesions Li 2500 ДР/геном D = 0 Гр D = 5 Гр D =10 Гр Доза, Гр D = 20 Гр D = 40 Гр D = 60 Гр

26 mt LRB LABORATORY OF RADIATION BIOLOGY DSB induction in human lymphocytes by γ-rays and accelerated 11 B (40 kev/mm) ions B Dose, Gy

- 40 Гр Gamma - 40 Гр 50 45 40 S G2 G0 G1

4 5 6 Time, h 10 5 0 0 1 2 3 4 5 Доза, Гр

72 ч 96 ч 20 20 15 15 10 10 5 5 PAC 08 0 0

27 Mt Mt mt mt LRB LABORATORY OF RADIATION BIOLOGY Kinetics of DNA repair Li - 40 Гр Gamma - 40 Гр S G2 G0 G Time, h Доза, Гр Гр 1Гр 3Гр 4Гр ч 24 ч 48 ч 72 ч 96 ч PAC Время, ч Доза, Гр

28 The mechanism of DSB DNA repair in human cells MRE11 белок Ku70-Ku80 + ДНК PK связывает концы ДНК Rad50/Mre11/NBS1 резицирует 5 концы. 3 концы защищены RPA Rad51соединяет 3 концы Rad50/Mre11/NBS1 заполняет гэп Rad51/52/54 обеспечивает поиск гомологии и миграцию ветвей XRCC4/lig4 зачищает и связывает концы Синтез гомологичных ветвей Нити восстановлены (репарация с ошибками) Завершение репарации лигированием концов и разрешение структуры

29 DSB ( -H2AX) in human cells after X-ray (А) and heavy ion irradiation (B) А B

30 3 D dimension of human chromosome 2 chromosomes 1 fragment Chromosome 1 of human lymphocyte nucleus in interphase with fragment after irradiation 1 GeV protons at synchrophasotron. The 3 D dimension picture was obtained by using FISH technique and confocal microscopy.

31 Radiation induced mutagenesis Guanine

32 Nm/N 10-5 Nm/N The frequency of tonb and colb mutation induction after γ-ray and heavy ion irradiation tonb colb tonb Dose, Gy Dose, Gy Dose, Gy

33 Induction of mutagenic DNA repair by heavy ions luciferase FMNH 2 + RCHO + O 2 FMN + RCOOH +H 2 O + h

34 Mutagenic belt of heavy particle track Cor

35 Induction of tonb - trp - deletion mutations by heavy ions - -rays; - 4 He (20 kev/μm); - 4 He (50 kev/μm); - 4 He (78 kev/μm); - 12 C (200 kev/μm)

36 R B E RBE on LET dependence 3,2 2 3,0 2,8 3 2,6 2,4 2,2 2,0 1,8 1,6 1,4 1,2 1,0 x 1 x x x x 1 tonb mutations 2 tonbtrp - deletions 3 lethal effect 0,8 0, L E T, kev/mm

37 Formation of unstable chromosomal aberration after heavy ion irradiation of human cells Unstable chromosomal aberration Block of cell division

38 Formation of stable chromosomal aberration after heavy ion irradiation of human cells Stable chromosomal aberration -rays Successful of cell division

39 R B E RBE as a function of LET on induction of mutations, chromosomal aberrations and cell inactivation survival 2 - chromosomal aberrations 3 - mutagenesis , L E T

40 B. Accelerated heavy ions is a tool for modeling of biological action of space radiation

41 Heavy charged particles from Galaxy are the most dangerous type of cosmic radiation Земля

42 The GCR flux The integral flux of GCR particles of carbon and iron groups equals to 10 5 part cm-2 per year

43 Относительный поток The relative flux of GCR particles Заряд ядра (Z)

44 The energy spectrum of GCR and Nuclotron accelerator

45 Consequences of action of Galactic heavy ions Induction of cancer; Formation of gene and structural mutations; Violation of visual functions: lesions of retina; cataract induction. CNS violation

46 Gardner tumors Relative Risk Harderian Gland Tumor Prevalence Gamma proton helium neon iron (600 MeV/u) iron (350 MeV/u) Iron ions -rays Dose, Gy Nelson, 2006

47 Burns, Albert, 1986 Skin cancer (rats)

48 Cataract induction

49 0,25 Гр 40 Ar 0,05 Гр 40 Ar 0,01 Гр 40 Ar Worgul et al., 2006

50 Cataract ratio RBE Cataract ratio after irradiation by iron ions and X-rays 10 Iron iona X-rays Iron ions 1 10 RBE = D x /D Fe Worgul et al., Dose, Gy Dose, Gy

51 Latent damages of β L -crystalline after irradiation by He ions and UV irradiation UV aggregation of β L -crystalline after irradiation by He ions (30 MeV) Spectrum of β L -crystalline fluorescence after irradiation by He ions (30 MeV) 4 Не+UV UV 4 Не UV UV irradiation, min λ, nm

52 Diffuse cataract, relative units Diffuse opacification of lens in mice in vivo UV irradiation Control UV 2 Gy 2 Gy+UV 4 Gy 4 Gy+UV Experimental groups

53 Accelerated heavy ions and CNS

54 Cosmic ray hit frequencies in CNS critical areas A A B B CNS in General Fe 2 or 13% cells will be hit at least one Fe p particle 8 or 46% would be hit by at least one p particle with Z 15 p Every nucleus will be traversed by a proton once every 3 days and a alpha particle once every 30 days. Mixed Field FE ION TRACKS VISUALIZED BY MARKERS OF DNA DSBs (γh2ax) Multi-hit 0 cgy 50 cgy e 100 cgy 200 cgy TRACK DIRECTION

55 Damages of large number cells in tissue by the single track of heavy ion

56 Arbitr. Units (pixel number/explant area) In Vitro Neurotoxic Effects of 56 Fe Ions on Retinal Explants DOSE vs NEURITE GROWTH INDEX * * 0 cgy 5 cgy 10 cgy ** ** cgy 100 cgy 200 cgy Dose (cgy) apoptosis Vazquez, 2006

57 Control 56 Fe ions, 1 GeV/amu 1.5 Gy Cognitive tests (Morris Water Maze: DAY 4, REVERSAL) 1 month after irradiation

58 Thank you for the attention!

Accelerated heavy ions as a tool for solving problems in fundamental and space radiobiology

Accelerated heavy ions as a tool for solving problems in fundamental and space radiobiology E. Krasavin Round Table 2 Italy-Russia@Dubna on SPACE PHISICS and BIOLOGY On Earth - accelerators of heavy charged