Journal of Literature Pharmacy Sciences

CRISPR-Cas9 Teknolojisi, Güvenliliği ve Etik Açıdan Değerlendirilmesi
CRISPR-Cas9 Technology, Safety and Evaluation from an Ethical Perspective
Selinay Başak ERDEMLİ KÖSEa,b, Ünzile SURa,c, Anıl YİRÜNa,d, Aylin BALCIa, Belma KOÇER GÜMÜŞELe, Pınar ERKEKOĞLUa
aHacettepe Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Ankara, TÜRKİYE
bBurdur Mehmet Akif Ersoy Üniversitesi Fen-Edebiyat Fakültesi, Kimya Bölümü, Burdur, TÜRKİYE
cAtatürk Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Erzurum, TÜRKİYE
dÇukurova Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Adana, TÜRKİYE eLokman Hekim Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Ankara, TÜRKİYE
J Lit Pharm Sci. 2020;9(1):50-64
doi: 10.5336/pharmsci.2019-70581
Article Language: TR
Full Text
ÖZET
Günümüzde bir genom mühendisliği aracı olan 'Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)'-Cas9 (CRISPR associated) sistemi, biyolojik bilimlerde yepyeni bir dönem başlatmıştır. CRISPR-Cas9 sistemi; ilk olarak bakteri ve arkealar gibi prokaryotlarda keşfedilen, bakteriyofaj enfeksiyonları, istilacı plazmidler ve yabancı nükleik asitlere karşı hücreyi korumayı amaçlayan RNA ve protein tabanlı bir sistemdir. DNA sekanslarını kolayca ve hassas bir şekilde yerleştirme, çıkarma ve hatta düzenleme yeteneği, tıp, enerji ve hatta çevre çalışmaları gibi geniş bir yelpazedeki biyoteknoloji alanlarında bilim çevrelerinin ilgisini çekmektedir. Tıbbi açıdan bakıldığında bu teknoloji, klinik öncesi ve klinik çalışmalarla çeşitli hastalıkların tedavisinde kullanılabilir. Bilim adamlarının herhangi bir organizmada herhangi bir geni teorik olarak hedeflemesine ve değiştirmesine olanak sağlayan hedeflenebilir nükleazlar, bu tedavilerin yolunu açmaktadır. Bu sistem embriyoloji, kanser, nörolojik hastalıklar ve enfeksiyon hastalıklarında araştırma aşamasında kullanıma girmiştir. Ancak CRISPRCas9 sisteminin güvenliği ile ilgili konular henüz çözülememiştir. Ayrıca, bu sistemin başta insan embriyolarında kullanımı olmak üzere birçok alanda kullanımı üzerine etik kaygılar devam etmektedir. Bu derleme kapsamında CRISPR-Cas9 teknolojisinin dayandığı prensiplerden ve bu teknolojinin güvenliğinden söz edilecek; sistemin kullanımı ile ortaya çıkabilecek etik kaygılar irdelenecektir.

Anahtar Kelimeler: CRISPR-Cas9; etik; güvenlilik; nörodejeneratif hastalıklar; kanser
ABSTRACT
Today, a genomic engineering tool 'Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)'-Cas9 (CRISPR associated) system has started a new era in biological sciences. CRISPRCas9 system was first discovered in prokaryotes like bacteria and archaea as an RNA and a protein-based system that protects the cell against bacteriophage infections, invading plasmids and foreign nucleic acids. The ability of easy and sensitive replacement of DNA sequences, deletion and most of all arrangement have attracted attention of scientists in a wide range of biotechnology study fields including medicine, energy and environment studies. From a medical perspective, this technology can be used in pre-clinical and clinical studies to treat several diseases. Targetable nucleases that enable the scientist to target and change a gene in an organism can pave the way for these treatments. This system is now being used in researches in embryology, cancer, neurological and infectious diseases. However, problems have not solved for the safety issues of CRISPR-Cas9 system. In addition, ethical concerns are still continuing for the use of this system in several fields, particularly in human embryos. In this review we will mention the main principles and safety issues of CRISPR-Cas9 technology as well as the ethical concerns and toxicological problems.

Keywords: CRISPR-Cas9; ethics; safety; neurodegenerative diseases; cancer
REFERENCES:
  1. Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213): 1258096. [Crossref]  [PubMed] 
  2. Chen S, Yu X, Guo D. CRISPR-cas targeting of host genes as an antiviral strategy. Viruses. 2018;10(1).pii: E40. [Crossref]  [PubMed]  [PMC] 
  3. Cao J, Xiao Q, Yan Q. The multiplexed CRISPR targeting platforms. Drug Discov Today Technol. 2018;28:53-61. [Crossref]  [PubMed]  [PMC] 
  4. Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science. 2007;315(5819):1709-12. [Crossref]  [PubMed] 
  5. Provasi E, Genovese P, Lombardo A, Magnani Z, Liu PQ, Reik A, et al. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat Med. 2012;18(5):807-15. [Crossref]  [PubMed]  [PMC] 
  6. Segal DJ, Meckler JF. Genome engineering at the dawn of the golden age. Annu Rev Genomics Hum Genet. 2013;14:135-58. [Crossref]  [PubMed] 
  7. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8(11):2281-308. [Crossref]  [PubMed]  [PMC] 
  8. Ishino Y, Shinagawa H, Makino K, Amemura M, Nakata A. Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product. J Bacteriol. 1987;169(12):5429-33. [Crossref]  [PubMed]  [PMC] 
  9. Bolotin A, Quinquis B, Sorokin A, Ehrlich SD. Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin. Microbiology. 2005;151(Pt 8):2551-61. [Crossref]  [PubMed] 
  10. Mojica FJ, Díez-Villase-or C, García-Martínez J, Soria E. Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J Mol Evol. 2005;60(2):174-82. [Crossref]  [PubMed] 
  11. Pourcel C, Salvignol G, Vergnaud G. CRISPR elements in Yersinia pestis acquire new repeats by preferential uptake of bacteriophage DNA, and provide additional tools for evolutionary studies. Microbiology. 2005;151(Pt 3):653-63. [Crossref]  [PubMed] 
  12. Horvath P, Barrangou R. CRISPR/Cas, the immune system of bacteria and archaea. Science. 2010;327(5962):167-70. [Crossref]  [PubMed] 
  13. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816-21. [Crossref]  [PubMed]  [PMC] 
  14. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819-23. [Crossref]  [PubMed]  [PMC] 
  15. Walsh RM, Hochedlinger K. A variant CRISPR-Cas9 system adds versatility to genome engineering. Proc Natl Acad Sci USA. 2013;110(39):15514-5. [Crossref]  [PubMed]  [PMC] 
  16. Zetsche B, Gootenberg JS, Abudayyeh OO, Slaymaker IM, Makarova KS, Essletzbichler P, et al. Cpf1 is a single RNA-guided endonuclease of a Class 2 CRISPR-Cas system. Cell. 2015;163(3):759-71. [Crossref]  [PubMed]  [PMC] 
  17. Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F. Rationally engineered Cas9 nucleases with improved specificity. Science. 2016;351(6268):84-8. [Crossref]  [PubMed]  [PMC] 
  18. Kleinstiver BP, Pattanayak V, Prew MS, Tsai SQ, Nguyen NT, Zheng Z, et al. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature. 2016;529(7587):490-5. [Crossref]  [PubMed]  [PMC] 
  19. O'Connell MR, Oakes BL, Sternberg SH, East-Seletsky A, Kaplan M, Doudna JA. Programmable RNA recognition and cleavage by CRISPR/Cas9. Nature. 2014;516(7530):263-6. [Crossref]  [PubMed]  [PMC] 
  20. Taştan C, Sakartepe E. T101 CRISPR Genom Modifikasyonları. AddGene CRISPR 101. Taştan C, çeviri editörü. 2018.
  21. Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, et al. CRISPR-Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015;6(5):363-72. [Crossref]  [PubMed]  [PMC] 
  22. Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, et al. Correction of a pathogenic gene mutation in human embryos. Nature. 2017;548(7668):413-9. [Crossref]  [PubMed] 
  23. Winblad N, Lanner F. Biotechnology: at the heart of gene edits in human embryos. Nature. 2017;548(7668):398-400. [Crossref]  [PubMed] 
  24. Fogarty NME, McCarthy A, Snijders KE, Powell BE, Kubikova N, Blakeley P, et al. Genome editing reveals a role for OCT4 in human embryogenesis. Nature. 2017;550(7674):67-73. [Crossref]  [PubMed]  [PMC] 
  25. Kang X, He W, Huang Y, Yu Q, Chen Y, Gao X, et al. Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas-mediated genome editing. J Assist Reprod Genet. 2016;33(5):581-8. [Crossref]  [PubMed]  [PMC] 
  26. Tang L, Zeng Y, Du H, Gong M, Peng J, Zhang B, et al. CRISPR-Cas9-mediated gene editing in human zygotes using Cas9 protein. Mol Genet Genomics. 2017;292(3):525-33. [Crossref]  [PubMed] 
  27. Mahmoudian-sani MR, Farnoosh G, Mahdavinezhad A, Saidijam M. CRISPR genome editing and its medical applications. Biotechnol Biotechnol Equip. 2018;32(2):286-92. [Crossref] 
  28. Cho SW, Kim S, Kim Y, Kweon J, Kim HS, Bae S, et al. Analysis of off-target effects of CRISPR/Cas-derived RNA-guided endonucleases and nickases. Genome Res. 2014;24(1):132-41. [Crossref]  [PubMed]  [PMC] 
  29. Hsu PD, Scott DA, Weinstein JA, Ran FA, Konermann S, Agarwala V, et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol. 2013;31(9):827-32. [Crossref]  [PubMed]  [PMC] 
  30. Wu X, Scott DA, Kriz AJ, Chiu AC, Hsu PD, Dadon DB, et al. Genome-wide binding of the CRISPR endonuclease Cas9 in mammalian cells. Nat Biotechnol. 2014;32(7):670-6. [Crossref]  [PubMed]  [PMC] 
  31. Guernet A, Grumolato L. CRISPR-Cas9 editing of the genome for cancer modeling. Methods. 2017;121-122:130-7. [Crossref]  [PubMed] 
  32. Xue W, Chen S, Yin H, Tammela T, Papagiannakopoulos T, Joshi NS, et al. CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature. 2014;514(7522):380-4. [Crossref]  [PubMed]  [PMC] 
  33. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546-58. [Crossref]  [PubMed]  [PMC] 
  34. Matano M, Date S, Shimokawa M, Takano A, Fujii M, Ohta Y, et al. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat Med. 2015;21(3):256-62. [Crossref]  [PubMed] 
  35. Drost J, van Jaarsveld RH, Ponsioen B, Zimberlin C, van Boxtel R, Buijs A, et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature. 2015;521(7550):43-7. [Crossref]  [PubMed] 
  36. Zuckermann M, Hovestadt V, Knobbe-Thomsen CB, Zapatka M, Northcott PA, Schramm K, et al. Somatic CRISPR-Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling. Nat Commun. 2015;6:7391. [Crossref]  [PubMed]  [PMC] 
  37. You L, Jianxin X, Tao D, Xiaojuan Z, Kun Y, Meijuan H, et al. A phase I trial of PD-1 deficient engineered T cells with CRISPR-Cas9 in patients with advanced non-small cell lung cancer. J Clin Oncol. 2018;36(15 Suppl):3050. [Crossref] 
  38. Mintz RL, Gao MA, Lo K, Lao YH, Li M, Leong KW. CRISPR technology for breast cancer: diagnostics, modeling, and therapy. Adv Biosys. 2018;2(11):1800132. [Crossref] 
  39. Yan S, Tu Z, Li S, Li XJ. Use of CRISPR-Cas9 to model brain diseases. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:488-92. [Crossref]  [PubMed]  [PMC] 
  40. Heidenreich M, Zhang F. Applications of CRISPR-Cas systems in neuroscience. Nat Rev Neurosci. 2016;17(1):36-44. [Crossref]  [PubMed]  [PMC] 
  41. Walter JM, Chandran SS, Horwitz AA. CRISPR-Cas-Assisted Multiplexing (CAM): simple same-day multi-locus engineering in yeast. J Cell Physiol. 2016;231(12):2563-9. [Crossref]  [PubMed] 
  42. Yu Z, Ren M, Wang Z, Zhang B, Rong YS, Jiao R, et al. Highly efficient genome modifications mediated by CRISPR/Cas9 in drosophila. Genetics. 2013;195(1):289-91. [Crossref]  [PubMed]  [PMC] 
  43. Nakayama T, Fish MB, Fisher M, Oomen-Hajagos J, Thomsen GH, Grainger RM. Simple and efficient CRISPR/Cas9-mediated targeted mutagenesis in Xenopus tropicalis. Genesis. 2013;51(12):835-43. [Crossref]  [PubMed]  [PMC] 
  44. Li D, Qiu Z, Shao Y, Chen Y, Guan Y, Liu M, et al. Heritable gene targeting in the mouse and rat using a CRISPR-Cas system. Nat Biotechnol. 2013;31(8):681-3. [Crossref]  [PubMed] 
  45. Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell. 2013;153(4):910-8. [Crossref]  [PubMed]  [PMC] 
  46. Song Y, Yuan L, Wang Y, Chen M, Deng J, Lv Q, et al. Efficient dual sgRNA-directed large gene deletion in rabbit with CRISPR/Cas9 system. Cell Mol Life Sci. 2016;73(15):2959-68. [Crossref]  [PubMed] 
  47. Giau VV, Lee H, Shim KH, Bagyinszky E, An SSA. Genome-editing applications of CRISPR-Cas9 to promote in vitro studies of Alzheimer's disease. Clin Interv Aging. 2018;13:221-33. [Crossref]  [PubMed]  [PMC] 
  48. Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208-11. [Crossref]  [PubMed]  [PMC] 
  49. Shin JW, Lee JM. The prospects of CRISPR-based genome engineering in the treatment of neurodegenerative disorders. Ther Adv Neurol Disord. 2018;11:1756285617741837. [Crossref]  [PubMed]  [PMC] 
  50. Ye L, Wang J, Beyer AI, Teque F, Cradick TJ, Qi Z, et al. Seamless modification of wildtype induced pluripotent stem cells to the natural CCR5Δ32 mutation confers resistance to HIV infection. Proc Natl Acad Sci USA. 2014;111(26):9591-6. [Crossref]  [PubMed]  [PMC] 
  51. Yin H, Xue W, Chen S, Bogorad RL, Benedetti E, Grompe M, et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol. 2014;32(6):551-3. [Crossref]  [PubMed]  [PMC] 
  52. Long C, Amoasii L, Mireault AA, McAnally JR, Li H, Sanchez-Ortiz E, et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science. 2016;351(6271):400-3. [Crossref]  [PubMed]  [PMC] 
  53. Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Castellanos Rivera RM, et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science. 2016;351(6271):403-7. [Crossref]  [PubMed]  [PMC] 
  54. Tabebordbar M, Zhu K, Cheng JKW, Chew WL, Widrick JJ, Yan WX, et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science. 2016;351(6271):407-11. [Crossref]  [PubMed]  [PMC] 
  55. Lee JM, Gillis T, Mysore JS, Ramos EM, Myers RH, Hayden MR, et al. Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region. Am J Hum Genet. 2012;90(3):434-44. [Crossref]  [PubMed]  [PMC] 
  56. Shin JW, Kim KH, Chao MJ, Atwal RS, Gillis T, MacDonald ME. Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR/Cas9. Hum Mol Genet. 2016;25(20):4566-76. [Crossref]  [PubMed]  [PMC] 
  57. Erkekoğlu P. [ Entry inhibitors for the treatment of human immunodeficiency virus-1 (HIV-1) and their toxic effects]. FABAD J Pharm Sci. 2018;43(1):41-58.
  58. Yuen KS, Chan CP, Wong NH, Ho CH, Ho TH, Lei T, et al. CRISPR-Cas9-mediated genome editing of Epstein-Barr virus in human cells. J Gen Virol. 2015;96(Pt 3):626-36. [Crossref]  [PubMed] 
  59. Zhu W, Lei R, Le Duff Y, Li J, Guo F, Wainberg MA, et al. The CRISPR-Cas9 system inactivates latent HIV-1 proviral DNA. Retrovirology. 2015;12:22. [Crossref]  [PubMed]  [PMC] 
  60. Buchthal J, Evans SW, Lunshof J, Telford SR 3rd, Esvelt KM. Mice against ticks: an experimental communityguided effort to prevent tick-borne disease by altering the shared environment. Philos Trans R Soc Lond B Biol Sci. 2019;374(1772):20180105. [Crossref]  [PubMed]  [PMC] 
  61. Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the United States. CDC; 2013. p.112. https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf
  62. Greene AC. CRISPR-based antibacterials: transforming bacterial defense into offense. Trends Biotechnol. 2018;36(2):127-30. [Crossref]  [PubMed] 
  63. Umeyama T, Hayashi Y, Shimosaka H, Inukai T, Yamagoe S, Takatsuka S, et al. CRISPR-Cas9 genome editing to demonstrate the contribution of Cyp51A Gly138Ser to azole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 2018;62(9).pii:e00894-18. [Crossref]  [PubMed]  [PMC] 
  64. Shabbir MA, Wu Q, Shabbir MZ, Sajid A, Ahmed S, Sattar A, et al. The CRISPR-cas system promotes antimicrobial resistance in Campylobacter jejuni. Future Microbiol. 2018;13:1757-74. [Crossref]  [PubMed] 
  65. Brokowski C, Adli M. CRISPR ethics: moral considerations for applications of a powerful tool. J Mol Biol. 2019;431(1):88-101. [Crossref]  [PubMed]  [PMC] 
  66. Kohn DB, Sadelain M, Glorioso JC. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer. 2003;3(7):477-88. [Crossref]  [PubMed] 
  67. Wang X, Wang Y, Wu X, Wang J, Wang Y, Qiu Z, et al. Unbiased detection of off-target cleavage by CRISPR-Cas9 and TALENs using integrase-defective lentiviral vectors. Nat Biotechnol. 2015;33(2):175-8. [Crossref]  [PubMed] 
  68. Ren X, Yang Z, Xu J, Sun J, Mao D, Hu Y, et al. Enhanced specificity and efficiency of the CRISPR-Cas9 system with optimized sgRNA parameters in Drosophila. Cell Rep. 2014;9(3):1151-62. [Crossref]  [PubMed]  [PMC] 
  69. Xie F, Ye L, Chang JC, Beyer AI, Wang J, Muench MO, et al. Seamless gene correction of β-thalassemia mutations in patient-specific iPSCs using CRISPR-Cas9 and piggyBac. Genome Res. 2014;24(9):1526-33. [Crossref]  [PubMed]  [PMC] 
  70. Polstein LR, Gersbach CA. A light-inducible CRISPR-Cas9 system for control of endogenous gene activation. Nat Chem Biol. 2015;11(3):198-200. [Crossref]  [PubMed]  [PMC] 
  71. Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014;157(6):1262-78. [Crossref]  [PubMed]  [PMC] 
  72. Li X, Burnight ER, Cooney AL, Malani N, Brady T, Sander JD, et al. PiggyBac transposase tools for genome engineering. Proc Natl Acad Sci USA. 2013;110(25):E2279-87. [Crossref]  [PubMed]  [PMC] 
  73. Lockyer EJ. The potential of CRISPR-Cas9 for treating genetic disorders. Bioscience Horizons: The International Journal of Student Research. 2016;9:hzw012. https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw012/2562795
  74. Baltimore D, Berg P, Botchan M, Carroll D, Charo RA, Church G, et al. A prudent path forward for genomic engineering and germline gene modification. Science. 2015;348(6230):36-8. [Crossref]  [PubMed]  [PMC] 
  75. National Academies of Sciences, Engineering, and Medicine (NASEM). Human Genome Editing: Science, Ethics, and Governance. The National Academies Press. Washington, DC, 2017.

.: Up To Date

.: Process List

Login



Contact


Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com