Genomic instability in pluripotent stem cells: Implications for clinical applications

Journal of Biological Chemistry

Volumn 289, Issue 8, 2014, Pages 4578-4584

  Peterson, Suzanne E ^a   Loring, Jeanne F ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

STEM CELLS;

CELL THERAPY; CLINICAL APPLICATION; GENOMIC CHANGES; GENOMIC INSTABILITY; GENOTYPING; HIGH-RESOLUTION METHODS; PLURIPOTENT STEM CELLS;

GENES;

CARCINOGENESIS; CELL CULTURE; CELL DIFFERENTIATION; CELL LINE; CHROMOSOME 20; CLINICAL TRIAL (TOPIC); FOOD AND DRUG ADMINISTRATION; GENETIC VARIABILITY; GENOMIC INSTABILITY; GENOTYPE; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; MOSAICISM; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; REGENERATION; REVIEW; RISK ASSESSMENT; SINGLE NUCLEOTIDE POLYMORPHISM;

CELL DIFFERENTIATION; CELL THERAPY; EMBRYONIC STEM CELL; GENOMICS; INDUCED PLURIPOTENT STEM CELLS;

CARCINOGENESIS; CLINICAL TRIALS AS TOPIC; GENETIC VARIATION; GENOMIC INSTABILITY; HUMANS; PLURIPOTENT STEM CELLS; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84894469509     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.R113.516419     Document Type: Review

References (71)

1. Baylis, F. (2011) Geron's discontinued stem cell trial: what about the research participants? The Hastings Center Report, Vol. 43, No. 3, The Hastings Center, Garrison, NY
2. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., and Jones, J. M. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282, 1145-1147
3. Cowan, C. A., Klimanskaya, I., McMahon, J., Atienza, J., Witmyer, J., Zucker, J. P., Wang, S., Morton, C. C., McMahon, A. P., Powers, D., and Melton, D. A. (2004) Derivation of embryonic stem-cell lines from human blastocysts. N. Engl. J. Med. 350, 1353-1356
4. Draper, J. S., Smith, K., Gokhale, P., Moore, H. D., Maltby, E., Johnson, J., Meisner, L., Zwaka, T. P., Thomson, J. A., and Andrews, P. W. (2004) Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nat. Biotechnol. 22, 53-54
5. Enver, T., Soneji, S., Joshi, C., Brown, J., Iborra, F., Orntoft, T., Thykjaer, T., Maltby, E., Smith, K., Abu Dawud, R., Jones, M., Matin, M., Gokhale, P., Draper, J., and Andrews, P. W. (2005) Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum. Mol. Genet. 14, 3129-3140
6. Mitalipova, M. M., Rao, R. R., Hoyer, D. M., Johnson, J. A., Meisner, L. F., Jones, K. L., Dalton, S., and Stice, S. L. (2005) Preserving the genetic integrity of human embryonic stem cells. Nat. Biotechnol. 23, 19-20
7. Lund, R. J., Närvä, E., and Lahesmaa, R. (2012) Genetic and epigenetic stability of human pluripotent stem cells. Nat. Rev. Genet. 13, 732-744
8. Martins-Taylor, K., and Xu, R. H. (2012) Concise review: genomic stability of human induced pluripotent stem cells. Stem Cells 30, 22-27
9. Ronen, D., and Benvenisty, N. (2012) Genomic stability in reprogramming. Curr. Opin. Genet. Dev. 22, 444-449
10. International Stem Cell Initiative, Amps, K., Andrews, P. W., Anyfantis, G., Armstrong, L., Avery, S., Baharvand, H., Baker, J., Baker, D., Munoz, M. B., Beil, S., Benvenisty, N., Ben-Yosef, D., Biancotti, J. C., Bosman, A., Brena, R. M., Brison, D., Caisander, G., Camarasa, M. V., Chen, J., Chiao, E., Choi, Y. M., Choo, A. B., Collins, D., Colman, A., Crook, J. M., Daley, G. Q., Dalton, A., De Sousa, P. A., Denning, C., Downie, J., Dvorak, P., Montgomery, K. D., Feki, A., Ford, A., Fox, V., Fraga, A. M., Frumkin, T., Ge, L., Gokhale, P. J., Golan-Lev, T., Gourabi, H., Gropp, M., Lu, G., Hampl, A., Harron, K., Healy, L., Herath, W., Holm, F., Hovatta, O., Hyllner, J., Inamdar, M. S., Irwanto, A. K., Ishii, T., Jaconi, M., Jin, Y., Kimber, S., Kiselev, S., Knowles, B. B., Kopper, O., Kukharenko, V., Kuliev, A., Lagarkova, M. A., Laird, P. W., Lako, M., Laslett, A. L., Lavon, N., Lee, D. R., Lee, J. E., Li, C., Lim, L. S., Ludwig, T. E., Ma, Y., Maltby, E., Mateizel, I., Mayshar, Y., Mileikovsky, M., Minger, S. L., Miyazaki, T., Moon, S. Y., Moore, H., Mummery, C., Nagy, A., Nakatsuji, N., Narwani, K., Oh, S. K., Olson, C., Otonkoski, T., Pan, F., Park, I. H., Pells, S., Pera, M. F., Pereira, L. V., Qi, O., Raj, G. S., Reubinoff, B., Robins, A., Robson, P., Rossant, J., Salekdeh, G. H., Schulz, T. C., Sermon, K., Sheik Mohamed, J., Shen, H., Sherrer, E., Sidhu, K., Sivarajah, S., Skottman, H., Spits, C., Stacey, G. N., Strehl, R., Strelchenko, N., Suemori, H., Sun, B., Suuronen, R., Takahashi, K., Tuuri, T., Venu, P., Verlinsky, Y., Wardvan Oostwaard, D., Weisenberger, D. J., Wu, Y., Yamanaka, S., Young, L., and Zhou, Q. (2011) Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat. Biotechnol. 29, 1132-1144
11. Laurent, L. C., Ulitsky, I., Slavin, I., Tran, H., Schork, A., Morey, R., Lynch, C., Harness, J. V., Lee, S., Barrero, M. J., Ku, S., Martynova, M., Semechkin, R., Galat, V., Gottesfeld, J., Izpisua Belmonte, J. C., Murry, C., Keirstead, H. S., Park, H. S., Schmidt, U., Laslett, A. L., Muller, F. J., Nievergelt, C. M., Shamir, R., and Loring, J. F. (2011) Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8, 106-118
12. Peterson, S. E., Westra, J. W., Rehen, S. K., Young, H., Bushman, D. M., Paczkowski, C. M., Yung, Y. C., Lynch, C. L., Tran, H. T., Nickey, K. S., Wang, Y. C., Laurent, L. C., Loring, J. F., Carpenter, M. K., and Chun, J. (2011) Normal human pluripotent stem cell lines exhibit pervasive mosaic aneuploidy. PLoS ONE 6, e23018
13. Taapken, S. M., Nisler, B. S., Newton, M. A., Sampsell-Barron, T. L., Leonhard, K. A., McIntire, E. M., and Montgomery, K. D. (2011) Karotypic abnormalities in human induced pluripotent stem cells and embryonic stem cells. Nat. Biotechnol. 29, 313-314
14. Mayshar, Y., Ben-David, U., Lavon, N., Biancotti, J. C., Yakir, B., Clark, A. T., Plath, K., Lowry, W. E., and Benvenisty, N. (2010) Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521-531
15. Ben-David, U., Mayshar, Y., and Benvenisty, N. (2011) Large-scale analysis reveals acquisition of lineage-specific chromosomal aberrations in human adult stem cells. Cell Stem Cell 9, 97-102
16. Martins-Taylor, K., Nisler, B. S., Taapken, S. M., Compton, T., Crandall, L., Montgomery, K. D., Lalande, M., and Xu, R. H. (2011) Recurrent copy number variations in human induced pluripotent stem cells. Nat. Biotechnol. 29, 488-491
17. Bock, C., Kiskinis, E., Verstappen, G., Gu, H., Boulting, G., Smith, Z. D., Ziller, M., Croft, G. F., Amoroso, M. W., Oakley, D. H., Gnirke, A., Eggan, K., and Meissner, A. (2011) Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144, 439-452
18. Nazor, K. L., Altun, G., Lynch, C., Tran, H., Harness, J. V., Slavin, I., Garitaonandia, I., Müller, F. J., Wang, Y. C., Boscolo, F. S., Fakunle, E., Dumevska, B., Lee, S., Park, H. S., Olee, T., D'Lima, D. D., Semechkin, R., Parast, M. M., Galat, V., Laslett, A. L., Schmidt, U., Keirstead, H. S., Loring, J. F., and Laurent, L. C. (2012) Recurrent variations inDNAmethylation in human pluripotent stem cells and their differentiated derivatives. Cell Stem Cell 10, 620-634
19. Hussein, S. M., Batada, N. N., Vuoristo, S., Ching, R. W., Autio, R., Närvä, E., Ng, S., Sourour, M., Hämäläinen, R., Olsson, C., Lundin, K., Mikkola, M., Trokovic, R., Peitz, M., Brüstle, O., Bazett-Jones, D. P., Alitalo, K., Lahesmaa, R., Nagy, A., and Otonkoski, T. (2011) Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58-62
20. Abyzov, A., Mariani, J., Palejev, D., Zhang, Y., Haney, M. S., Tomasini, L., Ferrandino, A. F., Rosenberg Belmaker, L. A., Szekely, A., Wilson, M., Kocabas, A., Calixto, N. E., Grigorenko, E. L., Huttner, A., Chawarska, K., Weissman, S., Urban, A. E., Gerstein, M., and Vaccarino, F. M. (2012) Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492, 438-442
21. Young, M. A., Larson, D. E., Sun, C. W., George, D. R., Ding, L., Miller, C. A., Lin, L., Pawlik, K. M., Chen, K., Fan, X., Schmidt, H., Kalicki-Veizer, J., Cook, L. L., Swift, G. W., Demeter, R. T., Wendl, M. C., Sands, M. S., Mardis, E. R., Wilson, R. K., Townes, T. M., and Ley, T. J. (2012) Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. Cell Stem Cell 10, 570-582
22. Gore, A., Li, Z., Fung, H. L., Young, J. E., Agarwal, S., Antosiewicz-Bourget, J., Canto, I., Giorgetti, A., Israel, M. A., Kiskinis, E., Lee, J. H., Loh, Y. H., Manos, P. D., Montserrat, N., Panopoulos, A. D., Ruiz, S., Wilbert, M. L., Yu, J., Kirkness, E. F., Izpisua Belmonte, J. C., Rossi, D. J., Thomson, J. A., Eggan, K., Daley, G. Q., Goldstein, L. S., and Zhang, K. (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63-67
23. Ji, J., Ng, S. H., Sharma, V., Neculai, D., Hussein, S., Sam, M., Trinh, Q., Church, G. M., McPherson, J. D., Nagy, A., and Batada, N. N. (2012) Elevated coding mutation rate during the reprogramming of human somatic cells into induced pluripotent stem cells. Stem Cells 30, 435-440
24. Bai, H., Chen, K., Gao, Y. X., Arzigian, M., Xie, Y. L., Malcosky, C., Yang, Y. G., Wu, W. S., and Wang, Z. Z. (2012) Bcl-xL enhances single-cell survival and expansion of human embryonic stem cells without affecting self-renewal. Stem Cell Res. 8, 26-37
25. Varela, C., Denis, J. A., Polentes, J., Feyeux, M., Aubert, S., Champon, B., Piétu, G., Peschanski, M., and Lefort, N. (2012) Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells. J. Clin. Invest. 122, 569-574
26. Ku, S., Soragni, E., Campau, E., Thomas, E. A., Altun, G., Laurent, L. C., Loring, J. F., Napierala, M., and Gottesfeld, J. M. (2010) Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA-TTC triplet repeat instability. Cell Stem Cell 7, 631-637
27. Sheridan, S. D., Theriault, K. M., Reis, S. A., Zhou, F., Madison, J. M., Daheron, L., Loring, J. F., and Haggarty, S. J. (2011) Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS ONE 6, e26203
28. Devys, D., Biancalana, V., Rousseau, F., Boué, J., Mandel, J. L., and Oberlé, I. (1992) Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. Am. J. Med. Genet. 43, 208-216
29. Dion, V., and Wilson, J. H. (2009) Instability and chromatin structure of expanded trinucleotide repeats. Trends Genet. 25, 288-297
30. Li, L. B., Chang, K. H., Wang, P. R., Hirata, R. K., Papayannopoulou, T., and Russell, D. W. (2012) Trisomy correction in Down syndrome induced pluripotent stem cells. Cell Stem Cell 11, 615-619
31. Maclean, G. A., Menne, T. F., Guo, G., Sanchez, D. J., Park, I. H., Daley, G. Q., and Orkin, S. H. (2012) Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells. Proc. Natl. Acad. Sci. U.S.A. 109, 17567-17572
32. Hultén, M. A., Jonasson, J., Nordgren, A., and Iwarsson, E. (2010) Germinal and somatic trisomy 21 mosaicism: how common is it, what are the implications for individual carriers and how does it come about? Curr. Genomics 11, 409-419
33. Lee, A. S., Tang, C., Cao, F., Xie, X., van der Bogt, K., Hwang, A., Connolly, A. J., Robbins, R. C., and Wu, J. C. (2009) Effects of cell number on teratoma formation by human embryonic stem cells. Cell Cycle 8, 2608-2612
34. Arnhold, S., Klein, H., Semkova, I., Addicks, K., and Schraermeyer, U. (2004) Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest. Ophthalmol. Vis. Sci. 45, 4251-4255
35. Seminatore, C., Polentes, J., Ellman, D., Kozubenko, N., Itier, V., Tine, S., Tritschler, L., Brenot, M., Guidou, E., Blondeau, J., Lhuillier, M., Bugi, A., Aubry, L., Jendelova, P., Sykova, E., Perrier, A. L., Finsen, B., and Onteniente, B. (2010) The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors. Stroke 41, 153-159
36. Doi, D., Morizane, A., Kikuchi, T., Onoe, H., Hayashi, T., Kawasaki, T., Motono, M., Sasai, Y., Saiki, H., Gomi, M., Yoshikawa, T., Hayashi, H., Shinoyama, M., Refaat, M. M., Suemori, H., Miyamoto, S., and Takahashi, J. (2012) Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson's disease. Stem Cells 30, 935-945
37. Roy, N. S., Cleren, C., Singh, S. K., Yang, L., Beal, M. F., and Goldman, S. A. (2006) Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat. Med. 12, 1259-1268
38. Atkin, N. B., and Baker, M. C. (1982) Specific chromosome change, i(12p), in testicular tumours? Lancet 320, 1349
39. Rodriguez, E., Houldsworth, J., Reuter, V. E., Meltzer, P., Zhang, J., Trent, J. M., Bosl, G. J., and Chaganti, R. S. (1993) Molecular cytogenetic analysis of i(12p)-negative human male germ cell tumors. Genes Chromosomes Cancer 8, 230-236
40. Skotheim, R. I., Monni, O., Mousses, S., Fossa, S. D., Kallioniemi, O. P., Lothe, R. A., and Kallioniemi, A. (2002) New insights into testicular germ cell tumorigenesis from gene expression profiling. Cancer Res. 62, 2359-2364
41. Wang, N., Trend, B., Bronson, D. L., and Fraley, E. E. (1980) Nonrandom abnormalities in chromosome 1 in human testicular cancers. Cancer Res. 40, 796-802
42. Looijenga, L. H., Rosenberg, C., van Gurp, R. J., Geelen, E., van Echten-Arends, J., de Jong, B., Mostert, M., and Wolter Oosterhuis, J. (2000) Comparative genomic hybridization of microdissected samples from different stages in the development of a seminoma and a non-seminoma. J. Pathol. 191, 187-192
43. Mostert, M., Rosenberg, C., Stoop, H., Schuyer, M., Timmer, A., Oosterhuis, W., and Looijenga, L. (2000) Comparative genomic and in situ hybridization of germ cell tumors of the infantile testis. Lab. Invest. 80, 1055-1064
44. Schneider, D. T., Schuster, A. E., Fritsch, M. K., Calaminus, G., Harms, D., Göbel, U., and Perlman, E. J. (2001) Genetic analysis of childhood germ cell tumors with comparative genomic hybridization. Klinische Padiatrie 213, 204-211
45. Baker, D. E., Harrison, N. J., Maltby, E., Smith, K., Moore, H. D., Shaw, P. J., Heath, P. R., Holden, H., and Andrews, P. W. (2007) Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat. Biotechnol. 25, 207-215
46. Werbowetski-Ogilvie, T. E., Bossé, M., Stewart, M., Schnerch, A., Ramos-Mejia, V., Rouleau, A., Wynder, T., Smith, M. J., Dingwall, S., Carter, T., Williams, C., Harris, C., Dolling, J., Wynder, C., Boreham, D., and Bhatia, M. (2009) Characterization of human embryonic stem cells with features of neoplastic progression. Nat. Biotechnol. 27, 91-97
47. Ben-Porath, I., Thomson, M. W., Carey, V. J., Ge, R., Bell, G. W., Regev, A., and Weinberg, R. A. (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 40, 499-507
48. Yang, S., Lin, G., Tan, Y. Q., Zhou, D., Deng, L. Y., Cheng, D. H., Luo, S. W., Liu, T. C., Zhou, X. Y., Sun, Z., Xiang, Y., Chen, T. J., Wen, J. F., and Lu, G. X. (2008) Tumor progression of culture-adapted human embryonic stem cells during long-term culture. Genes Chromosomes Cancer 47, 665-679
49. Werbowetski-Ogilvie, T. E., Morrison, L. C., Fiebig-Comyn, A., and Bhatia, M. (2012) In vivo generation of neural tumors from neoplastic pluripotent stem cells models early human pediatric brain tumor formation. Stem Cells 30, 392-404
50. Chen, K., Chmait, R. H., Vanderbilt, D., Wu, S., and Randolph, L. (2013) Chimerism in monochorionic dizygotic twins: case study and review. Am. J. Med. Genet. Part A 161, 1817-1824
51. Lupski, J. R. (2013) Genetics. Genome mosaicism-one human, multiple genomes. Science 341, 358-359
52. Poduri, A., Evrony, G. D., Cai, X., and Walsh, C. A. (2013) Somatic mutation, genomic variation, and neurological disease. Science 341, 1237758
53. Biesecker, L. G., and Spinner, N. B. (2013) A genomic view of mosaicism and human disease. Nat. Rev. Genet. 14, 307-320
54. Ambartsumyan, G., and Clark, A. T. (2008) Aneuploidy and early human embryo development. Hum. Mol. Genet. 17, R10-R15
55. Frumkin, T., Malcov, M., Yaron, Y., and Ben-Yosef, D. (2008) Elucidating the origin of chromosomal aberrations in IVF embryos by preimplantation genetic analysis. Mol. Cell. Endocrinol. 282, 112-119
56. Lavon, N., Narwani, K., Golan-Lev, T., Buehler, N., Hill, D., and Benvenisty, N. (2008) Derivation of euploid human embryonic stem cells from aneuploid embryos. Stem Cells 26, 1874-1882
57. Vanneste, E., Voet, T., Le Caignec, C., Ampe, M., Konings, P., Melotte, C., Debrock, S., Amyere, M., Vikkula, M., Schuit, F., Fryns, J. P., Verbeke, G., D'Hooghe, T., Moreau, Y., and Vermeesch, J. R. (2009) Chromosome instability is common in human cleavage-stage embryos. Nat. Med. 15, 577-583
58. Forni, P. E., Scuoppo, C., Imayoshi, I., Taulli, R., Dastrù, W., Sala, V., Betz, U. A., Muzzi, P., Martinuzzi, D., Vercelli, A. E., Kageyama, R., and Ponzetto, C. (2006) High levels of Cre expression in neuronal progenitors cause defects in brain development leading to microencephaly and hydrocephaly. J. Neurosci. 26, 9593-9602
59. Rajendran, R. S., Zupanc, M. M., Lösche, A., Westra, J., Chun, J., and Zupanc, G. K. (2007) Numerical chromosome variation and mitotic segregation defects in the adult brain of teleost fish. Dev. Neurobiol. 67, 1334-1347
60. Rehen, S. K., McConnell, M. J., Kaushal, D., Kingsbury, M. A., Yang, A. H., and Chun, J. (2001) Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc. Natl. Acad. Sci. U.S.A. 98, 13361-13366
61. Rehen, S. K., Yung, Y. C., McCreight, M. P., Kaushal, D., Yang, A. H., Almeida, B. S., Kingsbury, M. A., Cabral, K. M., McConnell, M. J., Anliker, B., Fontanoz, M., and Chun, J. (2005) Constitutional aneuploidy in the normal human brain. J. Neurosci. 25, 2176-2180
62. Yurov, Y. B., Iourov, I. Y., Monakhov, V. V., Soloviev, I. V., Vostrikov, V. M., and Vorsanova, S. G. (2005) The variation of aneuploidy frequency in the developing and adult human brain revealed by an interphase FISH study. J. Histochem. Cytochem. 53, 385-390
63. McConnell, M. J., Lindberg, M. R., Brennand, K. J., Piper, J. C., Voet, T., Cowing-Zitron, C., Shumilina, S., Lasken, R. S., Vermeesch, J. R., Hall, I. M., and Gage, F. H. (2013) Mosaic copy number variation in human neurons. Science 342, 632-637
64. Kaushal, D., Contos, J. J., Treuner, K., Yang, A. H., Kingsbury, M. A., Rehen, S. K., McConnell, M. J., Okabe, M., Barlow, C., and Chun, J. (2003) Alteration of gene expression by chromosome loss in the postnatal mouse brain. J. Neurosci. 23, 5599-5606
65. Muotri, A. R., Chu, V. T., Marchetto, M. C., Deng, W., Moran, J. V., and Gage, F. H. (2005) Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435, 903-910
66. Perrat, P. N., DasGupta, S., Wang, J., Theurkauf, W., Weng, Z., Rosbash, M., and Waddell, S. (2013) Transposition-driven genomic heterogeneity in the Drosophila brain. Science 340, 91-95
67. Thomas, C. A., and Muotri, A. R. (2012) LINE-1: creators of neuronal diversity. Front. Biosci. 4, 1663-1668
68. Wissing, S., Muñoz-Lopez, M., Macia, A., Yang, Z., Montano, M., Collins, W., Garcia-Perez, J. L., Moran, J. V., and Greene, W. C. (2012) Reprogramming somatic cells into iPS cells activates LINE-1 retroelement mobility. Hum. Mol. Genet. 21, 208-218
69. Lee, A. S., Tang, C., Rao, M. S., Weissman, I. L., and Wu, J. C. (2013) Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat. Med. 19, 998-1004
70. Stolberg, S. G. (November 28, 1999) The biotech death of Jesse Gelsinger. New York Times Magazine
71. Weiss, R. (March 4, 2005) Boy's cancer prompts FDA to halt gene therapy. Washington Post, p. A02