Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Timeline
  • Published:

From teratocarcinomas to embryonic stem cells and beyond: a history of embryonic stem cell research

Nature Reviews Genetics volume 7, pages 319–327 (2006)Cite this article

Abstract

We are currently facing an unprecedented level of public interest in research on embryonic stem cells, an area of biomedical research that until recently was small, highly specialized and of limited interest to anyone but experts in the field. Real and imagined possibilities for the treatment of degenerative and other diseases are of special interest to our rapidly ageing population; real and imagined associations of stem cells to cloning, embryos and reproduction stir deeply held beliefs and prejudices. The conjunction of these factors could explain the recent sudden interest in embryonic stem cells but we ought to remember that this research has a long and convoluted history, and that the findings described today in the scientific and popular press are firmly grounded in research that has been going on for several decades. Here I briefly recapitulate this fascinating history.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mouse and human teratomas and teratocarcinomas.
Figure 2: Mouse and human embryonal carcinoma and embryonic stem cells in vitro.
Figure 3: Somatic cell nuclear transfer procedure.

References

  1. Stevens, L. C. Jr & Little, C. C. Spontaneous testicular teratomas in an inbred strain of mice. Proc. Natl Acad. Sci. USA 40, 1080–1087 (1954).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Stevens, L. C. Experimental production of testicular teratomas in mice. Proc. Natl Acad. Sci. USA 52, 654–661 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kleinsmith, L. J. & Pierce, G. B. Jr. Multipotentiality of single embryonal carcinoma cells. Cancer Res. 24, 1544–1551 (1964).

    CAS  PubMed  Google Scholar 

  4. Solter, D., Skreb, N. & Damjanov, I. Extrauterine growth of mouse egg-cylinders results in malignant teratoma. Nature 227, 503–504 (1970).

    Article  CAS  PubMed  Google Scholar 

  5. Stevens, L. C. The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos. Dev. Biol. 21, 364–382 (1970).

    Article  CAS  PubMed  Google Scholar 

  6. Stevens, L. C. A new inbred subline of mice (129/terSv) with a high incidence of spontaneous congenital testicular teratomas. J. Natl Cancer Inst. 50, 235–242 (1973).

    Article  CAS  PubMed  Google Scholar 

  7. Youngren, K. K. et al. The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature 435, 360–364 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Stevens, L. C. & Varnum, D. S. The development of teratomas from parthenogenetically activated ovarian mouse eggs. Dev. Biol. 37, 369–380 (1974).

    Article  CAS  PubMed  Google Scholar 

  9. Pierce, G. B., Verney, E. L. & Dixon, F. J. The biology of testicular cancer. I. Behavior after transplantation. Cancer Res. 17, 134–138 (1957).

    CAS  PubMed  Google Scholar 

  10. Sherman, M. I. & Solter, D. (eds) Teratomas and Differentiation (Academic Press, New York, 1975).

    Google Scholar 

  11. Pierce, G. B. & Verney, E. L. An in vitro and in vivo study of differentiation in teratocarcinomas. Cancer 14, 1017–1029 (1961).

    Article  PubMed  Google Scholar 

  12. Rosenthal, M. D., Wishnow, R. M. & Sato, G. H. In vitro growth and differentiation of clonal populations of multipotential mouse cells derived from a transplantable testicular teratocarcinoma. J. Natl Cancer Inst. 44, 1001–1014 (1970).

    CAS  PubMed  Google Scholar 

  13. Kahan, B. W. & Ephrussi, B. Developmental potentialities of clonal in vitro cultures of mouse testicular teratoma. J. Natl Cancer Inst. 44, 1015–1029 (1970).

    CAS  PubMed  Google Scholar 

  14. Evans, M. J. The isolation and properties of a clonal tissue culture strain of pluripotent mouse teratoma cells. J. Embryol. Exp. Morph. 28, 163–176 (1972).

    CAS  PubMed  Google Scholar 

  15. Jakob, H., Boon, T., Gaillard, J., Nicolas, J. -F. & Jacob, F. Tératocarcinome de la souris: Isolement, culture et propriétés de cellules à potentialités multiples. Ann. Microbiol. (Paris) 124, 269–282 (1973) (in French).

    CAS  Google Scholar 

  16. Nicolas, J. F., Dubois, P., Jakob, H., Gaillard, J. & Jacob, F. Tératocarcinome de la souris: différenciation en culture d'une lignée de cellules primitives à potentialités multiples. Ann. Microbiol. (Paris) 126, 3–22 (1975) (in French).

    CAS  Google Scholar 

  17. Martin, G. R. & Evans, M. J. The morphology and growth of a pluripotent teratocarcinoma cell line and its derivatives in tissue culture. Cell 2, 163–172 (1974).

    Article  CAS  PubMed  Google Scholar 

  18. Martin, G. R. & Evans, M. J. Differentiation of clonal lines of teratocarcinoma cells: Formation of embryoid bodies in vitro. Proc. Natl Acad. Sci. USA 72, 1441–1445 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Martin, G. R. & Evans, M. J. Multiple differentiation of clonal teratocarcinoma stem sells following embryoid body formation in vitro. Cell 6, 467–474 (1975).

    Article  Google Scholar 

  20. Martin, G. R. Teratocarcinomas as a model system for the study of embryogenesis and neoplasia. Cell 5, 229–243 (1975).

    Article  CAS  PubMed  Google Scholar 

  21. Fogh, J. & Trempe, G. in Human Tumor Cells In Vitro (ed. Fogh, J.) 115–159 (Plenum, New York, 1975).

    Book  Google Scholar 

  22. Hogan, B., Fellous, M., Avner, P. & Jacob, F. Isolation of a human teratoma cell line which expresses F9 antigen. Nature 270, 515–518 (1977).

    Article  CAS  PubMed  Google Scholar 

  23. Andrews, P. W., Bronson, D. L., Benham, F., Strickland, S. & Knowles, B. B. A comparative study of eight cell lines derived from human testicular teratocarcinoma. Int. J. Cancer 26, 269–280 (1980).

    Article  CAS  PubMed  Google Scholar 

  24. Andrews, P. W., Goodfellow, P. N., Shevinsky, L. H., Bronson, D. L. & Knowles, B. B. Cell-surface antigens of a clonal human embryonal carcinoma cell line: morphological and antigenic differentiation in culture. Int. J. Cancer 29, 523–531 (1982).

    Article  CAS  PubMed  Google Scholar 

  25. Andrews, P. W. et al. Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line tera-2. Lab. Invest. 50, 147–162 (1984).

    CAS  PubMed  Google Scholar 

  26. Lee, V. M. -Y. & Andrews, P. W. Differentiation of NTERA-2 clonal human embryonal carcinoma cells into neurons involves the induction of all three neurofilament proteins. J. Neurosci. 6, 514–521 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Andrews, P. W., Goodfellow, P. N. & Damjanov, I. Human teratocarcinoma cells in culture. Cancer Surv. 2, 41–73 (1983).

    Google Scholar 

  28. Andrews, P. W. From teratocarcinomas to embryonic stem cells. Phil. Trans. R. Soc. Lond. B 357, 405–417 (2002).

    Article  Google Scholar 

  29. Bernstine, E. G., Hooper, M. L., Grandchamp, S. & Ephrussi, B. Alkaline phosphatase activity in mouse teratoma. Proc. Natl Acad. Sci. USA 70, 3899–3903 (1973).

    Article  CAS  PubMed Central  Google Scholar 

  30. Benham, F. J., Andrews, P. W., Knowles, B. B., Bronson, D. L. & Harris, H. Alkaline phosphatase isozymes as possible markers of differentiation in human testicular teratocarcinoma cell lines. Dev. Biol. 88, 279–287 (1981).

    Article  CAS  PubMed  Google Scholar 

  31. Stern, P. L. et al. Monoclonal antibodies as probes for differentiation and tumor-associated antigens: a Forssman specificity on teratocarcinoma stem cells. Cell 14, 775–783 (1978).

    Article  CAS  PubMed  Google Scholar 

  32. Solter, D. & Knowles, B. B. Monoclonal antibody defining a stage-specific mouse embryonic antigen (SSEA-1). Proc. Natl Acad. Sci. USA 75, 5565–5569 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gooi, H. C. et al. Stage-specific embryonic antigen involves α1→3 fucosylated type 2 blood group chains. Nature 292, 156–158 (1981).

    Article  CAS  PubMed  Google Scholar 

  34. Shevinsky, L. H., Knowles, B. B., Damjanov, I. & Solter, D. Monoclonal antibody to murine embryos defines a stage-specific embryonic antigen expressed on mouse embryos and human teratocarcinoma cells. Cell 30, 697–705 (1982).

    Article  CAS  PubMed  Google Scholar 

  35. Kannagi, R. et al. Stage-specific embryonic antigens (SSEA-3 and -4) are epitopes of a unique globo-series ganglioside isolated from human teratocarcinoma cells. EMBO J. 2, 2355–2361 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kannagi, R. et al. New globoseries glycosphingolipids in human teratocarcinoma reactive with the monoclonal antibody directed to a developmentally regulated antigen, stage-specific embryonic antigen 3. J. Biol. Chem. 258, 8934–8942 (1983).

    CAS  PubMed  Google Scholar 

  37. Fenderson, B. A., Andrews, P. W., Nudelman, E., Clausen, H. & Hakomori, S. -I. Glycolipid core structure switching from globo- to lacto- and ganglio-series during retinoic acid-induced differentiation of TERA-2-derived human embryonal carcinoma cells. Dev. Biol. 122, 21–34 (1987).

    Article  CAS  PubMed  Google Scholar 

  38. Henderson, J. K. et al. Preimplantation human embryos and embryonic stem cells show comparable expression of stage-specific embryonic antigens. Stem Cells 20, 329–337 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Strickland, S. & Mahdavi, V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell 15, 393–403 (1978).

    Article  CAS  PubMed  Google Scholar 

  40. Jakob, H., Dubois, P., Eisen, H. & Jacob, F. Effets de l'hexaméthylènebisacétamide sur la différenciation de cellules de carcinome embryonnaire. C. R. Acad. Sci. Hebd. Seances Acad. Sci. D 286, 109–111 (1978) (in French).

    CAS  PubMed  Google Scholar 

  41. Andrews, P. W. Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro. Dev. Biol. 103, 285–293 (1984).

    Article  CAS  PubMed  Google Scholar 

  42. Simeone, A. et al. Sequential activation of HOX2 homeobox genes by retinoic acid in human embryonal corcinoma cells. Nature 346, 763–66 (1990).

    Article  CAS  PubMed  Google Scholar 

  43. Brinster, R. L. The effect of cells transferred into the mouse blastocyst on subsequent development. J. Exp. Med. 140, 1049–1056 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mintz, B. & Illmensee, K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc. Natl Acad. Sci. USA 72, 3585–3589 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Illmensee, K. & Mintz, B. Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc. Natl Acad. Sci. USA 73, 549–553 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Stewart, T. A. & Mintz, B. Successive generations of mice produced from an established culture line of euploid teratocarcinoma cells. Proc. Natl Acad. Sci. USA 78, 6314–6318 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Stewart, T. A. & Mintz, B. Recurrent germ-line transmission of the teratocarcinoma genome from the METT-1 culture line to progeny in vivo. J. Exp. Zool. 224, 465–469 (1982).

    Article  CAS  PubMed  Google Scholar 

  48. Papaioannou, V. E., McBurney, M. W., Gardner, R. L. & Evans, M. J. Fate of teratocarcinoma cells injected into early mouse embryos. Nature 258, 70–73 (1975).

    Article  CAS  PubMed  Google Scholar 

  49. Papaioannou, V. E., Gardner, R. L., McBurney, M. W., Babinet, C. & Evans, M. J. Participation of cultured teratocarcinoma cells in mouse embryogenesis. J. Embryol. Exp. Morph. 44, 93–104 (1978).

    CAS  PubMed  Google Scholar 

  50. Rossant, J. & McBurney, M. W. The developmental potential of a euploid male teratocarcinoma cell line after blastocyst injection. J. Embryol. Exp. Morph. 70, 99–112 (1982).

    CAS  PubMed  Google Scholar 

  51. Blelloch, R. H. et al. Nuclear cloning of embryonal carcinoma cells. Proc. Natl Acad. Sci. USA 101, 13985–13990 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Silver, L. M., Martin, G. R. & Strickland, S. (eds) Teratocarcinoma Stem Cells (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1983).

    Google Scholar 

  53. Cole, R. J. & Paul, J. in Ciba Foundation Symposium on Preimplantation Stages of Pregnancy (eds Wolstenholme, G. E. W. & O'Conner, M.) 82–122 (J. & A. Churchill Ltd, 1965).

    Google Scholar 

  54. Edwards, R. G. in Handbook of Stem Cells (eds Lanza, R. et al.) 1–14 (Elsevier Academic Press, Burlington, Massachusetts, 2004).

    Book  Google Scholar 

  55. Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).

    Article  CAS  PubMed  Google Scholar 

  56. Martin, G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634–7638 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Doetschman, T. C., Eistetter, H., Katz, M., Schmidt, W. & Kemler, R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J. Embryol. Exp. Morph. 87, 27–45 (1985).

    CAS  PubMed  Google Scholar 

  58. Williams, R. L. et al. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336, 684–687 (1988).

    Article  CAS  PubMed  Google Scholar 

  59. Smith, A. G. et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336, 688–690 (1988).

    Article  CAS  PubMed  Google Scholar 

  60. Matsui, Y., Zsebo, K. & Hogan, B. L. M. Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70, 841–847 (1992).

    Article  CAS  PubMed  Google Scholar 

  61. Resnick, J. L., Bixler, L. S., Cheng, L. & Donovan, P. J. Long-term proliferation of mouse primordial germ cells in culture. Nature 359, 550–551 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Kanatsu-Shinohara, M. et al. Generation of pluripotent stem cells from neonatal mouse testis. Cell 119, 1001–1012 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Hübner, K. et al. Derivation of oocytes from mouse embryonic stem cells. Science 300, 1251–1256 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Toyooka, Y., Tsunekawa, N., Akasu, R. & Noce, T. Embryonic stem cells can form germ cells in vitro. Proc. Natl Acad. Sci. USA 100, 11457–11462 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Geijsen, N. et al. Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature 427, 148–154 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Bradley, A., Evans, M., Kaufman, M. H. & Robertson, E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature 309, 255–256 (1984).

    Article  CAS  PubMed  Google Scholar 

  67. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J. C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gossler, A., Doetschman, T., Korn, R., Serfling, E. & Kemler, R. Transgenesis by means of blastocyst-derived embryonic stem cell lines. Proc. Natl. Acad. Sci. USA 83, 9065–9069 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Robertson, E., Bradley, A., Kuehn, M. & Evans, M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature 323, 445–448 (1986).

    Article  CAS  PubMed  Google Scholar 

  70. Thomas, K. R. & Capecchi, M. R. Introduction of homologous DNA sequences into mammalian cells induces mutations in the cognate gene. Nature 324, 34–38 (1986).

    Article  CAS  PubMed  Google Scholar 

  71. Thomas, K. R., Folger, K. R. & Capecchi, M. R. High frequency targeting of genes to specific sites in the mammalian genome. Cell 44, 419–428 (1986).

    Article  CAS  PubMed  Google Scholar 

  72. Kuehn, M. R., Bradley, A., Robertson, E. J. & Evans, M. J. A potential animal model for Lesch–Nyhan syndrome through introduction of HPRT mutations into mice. Nature 326, 295–298 (1987).

    Article  CAS  PubMed  Google Scholar 

  73. Doetschman, T. et al. Targetted correction of a mutant HPRT gene in mouse embryonic stem cells. Nature 330, 576–578 (1987).

    Article  CAS  PubMed  Google Scholar 

  74. Thomas, K. R. & Capecchi, M. R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51, 503–512 (1987).

    Article  CAS  PubMed  Google Scholar 

  75. Thompson, S., Clarke, A. R., Pow, A. M., Hooper, M. L. & Melton, D. W. Germ line transmission and expression of a corrected HPRT gene produced by gene targeting in embryonic stem cells. Cell 56, 313–321 (1989).

    Article  CAS  PubMed  Google Scholar 

  76. Smithies, O. Many little things: one geneticist's view of complex diseases. Nature Rev. Genet. 6, 419–425 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Capecchi, M. R. Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century. Nature Rev. Genet. 6, 507–512 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Ying, Q. -L., Nichols, J., Chambers, I. & Smith, A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115, 281–292 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. McBurney, M. W., Jones-Villeneuve, E. M. V., Edwards, M. K. S. & Anderson, P. J. Control of muscle and neuronal differentiation in a cultured embryonal carcinoma cell line. Nature 299, 165–167 (1982).

    Article  CAS  PubMed  Google Scholar 

  80. Wichterle, H., Lieberam, I., Porter, J. A. & Jessell, T. M. Directed differentiation of embryonic stem cells into motor neurons. Cell 110, 385–397 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Kim, J. -H. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50–56 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Li, H., Roblin, G., Liu, H. & Heller, S. Generation of hair cells by stepwise differentiation of embryonic stem cells. Proc. Natl Acad. Sci. USA 100, 13495–13500 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Schmitt, T. M. et al. Induction of T cell development and establishment of T cell competence from embryonic stem cells differentiated in vitro. Nature Immunol. 5, 410–417 (2004).

    Article  CAS  Google Scholar 

  84. Loebel, D. A. F., Watson, C. M., De Young, R. A. & Tam, P. P. L. Lineage choice and differentiation in mouse embryos and embryonic stem cells. Dev. Biol. 264, 1–14 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Conti, L. et al. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol. 3, 1594–1606 (2005).

    Article  CAS  Google Scholar 

  86. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Shamblott, M. J. et al. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc. Natl Acad. Sci. USA 95, 13726–13731 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Thomson, J. A. et al. Isolation of a primate embryonic stem cell line. Proc. Natl Acad. Sci. USA 92, 7844–7848 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Amit, M. et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev. Biol. 227, 271–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Hovatta, O. & Skottman, H. Feeder-free derivation of human embryonic stem-cell lines. Lancet 365, 1601–1603 (2005).

    Article  PubMed  Google Scholar 

  91. Klimanskaya, I. et al. Human embryonic stem cells derived without feeder cells. Lancet 365, 1636–1641 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Xu, R. -H. et al. Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nature Methods 2, 185–190 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Schuldiner, M., Yanuka, O., Itskovitz-Eldor, J., Melton, D. A. & Benvenisty, N. Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc. Natl Acad. Sci. USA 97, 11307–11312 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Odorico, J. S., Kaufman, D. S. & Thomson, J. A. Multilineage differentiation from human embryonic stem cell lines. Stem Cells 19, 193–204 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Xu, R. -H. et al. BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nature Biotechnol. 20, 1261–1264 (2002).

    Article  CAS  Google Scholar 

  96. Maitra, A. et al. Genomic alterations in cultured human embryonic stem cells. Nature Genet. 37, 1099–1103 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Gardner, R. L. in Handbook of Stem Cells (eds Lanza, R. et al.) 15–26 (Elsevier Academic Press, Burlington, Massachusetts, 2004).

    Book  Google Scholar 

  98. Iannaccone, P. M., Taborn, G. U., Garton, R. L., Caplice, M. D. & Brenin, D. R. Pluripotent embryonic stem cells from the rat are capable of producing chimeras. Dev. Biol. 163, 288–292 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. Brenin, D., Look, J., Hübner, N., Levan, G. & Iannaccone, P. Correction to: Pluripotent embryonic stem cells from the rat are capable of producing chimeras. Dev. Biol. 185, 124–125 (1997).

    Article  CAS  Google Scholar 

  100. Bavister, B. D., Wolf, D. P. & Brenner, C. A. Challenges of primate embryonic stem cell research. Cloning Stem Cells 7, 82–94 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Wolf, D. P., Kuo, H. -C., Pau, K. -Y. F. & Lester, L. Progress with nonhuman primate embryonic stem cells. Biol. Reprod. 71, 1766–1771 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Takagi, Y. et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J. Clin. Invest. 115, 102–109 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Solter, D. & Gearhart, J. Putting stem cells to work. Science 283, 1468–1470 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Munsie, M. J. et al. Isolation of pluripotent embryonic stem cells from reprogrammed adult somatic cell nuclei. Curr. Biol. 10, 989–992 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Kawase, E., Yamazaki, Y., Yagi, T., Yanagimachi, R. & Pedersen, R. A. Mouse embryonic stem (ES) cell lines established from neuronal cell- derived cloned blastocysts. Genesis 28, 156–163 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Wakayama, T. et al. Differentiation of embryonic stem cell lines generated from adult somatic cells by nuclear transfer. Science 292, 740–743 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Hwang, W. S. et al. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science 303, 1669–1674 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Hwang, W. S. et al. Patient-specific embryonic stem cells derived from human SCNT blastocysts. Science 308, 1777–1783 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Chung, Y. et al. Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres. Nature 439, 216–219 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Meissner, A. & Jaenisch, R. Generation of nuclear transfer-derived pluripotent ES cells from cloned Cdx2-deficient blastocysts. Nature 439, 212–215 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Solter, D. Politically correct human embryonic stem cells? N. Engl. J. Med. 353, 2321–2323 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Simonsson, S. & Gurdon, J. DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nature Cell Biol. 6, 984–990 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Sullivan, E. J., Kasinathan, S., Kasinathan, P., Robl, J. M. & Collas, P. Cloned calves from chromatin remodeled in vitro. Biol. Reprod. 70, 146–153 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Park, K. -S. et al. Phenotypic alteration of eukaryotic cells using randomized libraries of artificial transcription factors. Nature Biotechnol. 21, 1208–1214 (2003).

    Article  CAS  Google Scholar 

  115. Ding, S. et al. Synthetic small molecules that control stem cell fate. Proc. Natl Acad. Sci. USA 100, 7632–7637 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ding, S. & Schultz, P. G. A role for chemistry in stem cell biology. Nature Biotechnol. 22, 833–840 (2004).

    Article  CAS  Google Scholar 

  117. Anderson, D. G., Levenberg, S. & Langer, R. Nanoliter-scale synthesis of arrayed biomaterials and application to human embryonic stem cells. Nature Biotechnol. 22, 863–866 (2004).

    Article  CAS  Google Scholar 

  118. Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I wish to thank P. Andrews, I. Damjanov, R. Kemler and M. Stemmler for help with the illustrations.

Author information

Authors and Affiliations

  1. Max Planck Institute of Immunobiology, Stübeweg 51, Freiburg, 79108, Germany

    Davor Solter

Authors
  1. Davor Solter
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Max-Planck-Institute of Immunobiology

Glossary

Blastocyst

A mammalian embryo that is at the end of cleavage and is ready for implantation into the uterine epithelium. Depending on the species, it contains a hundred or more cells and is composed of: a continuous outside layer called the trophectoderm, which gives rise to the placenta; an inner cell mass, which gives rise to the embryo proper; and some extra-embryonic membrane. The cells of the inner cell mass can give rise to embryonic stem cells in culture.

Cell feeder layer

Cells, usually fibroblasts, that are incapable of division but provide physical support and soluble factors for the cells growing on them. The feeder layer was essential for the early derivation of embryonic stem cells.

Inner cell mass

A small clump of apparently undifferentiated cells in the blastocyst, which gives rise to the entire fetus plus some of its extra-embryonic membranes.

Intraperitoneal

Refers to injection or insertion between the viscera and the abdominal wall.

Karyotype

The chromosomal complement of a given cell.

Matrix material

Solid support surrounding and secreted by cells. Known components of extracellular matrix (for example, collagen) can be used as support for in vitro cell culture.

Meiotic check-point

An event during meiosis that can only proceed if some earlier event has been completed. The fully grown mammalian oocyte is arrested in the prophase of the first meiotic division (first meiotic check-point). Following hormonal stimulation the oocyte undergoes maturation by completing first meiotic division and arresting in the metaphase of the second meiotic division (second meiotic check-point). The oocyte is released from this check-point on fertilization and can complete the second meiotic division.

Monolayer culture

Growth of cells in vitro as a single cell layer that is attached to the bottom of a culture dish.

Parietal endoderm

One of the extra-embryonic membranes. It participates in the formation of the maternal–fetal barrier.

Primordial germ cells

Cells that are localized in a specific part of the early post-implantation embryo that will eventually migrate into gonads and give rise to germ cells (eggs and sperm). They are also probable precursors of embryonic germ cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Solter, D. From teratocarcinomas to embryonic stem cells and beyond: a history of embryonic stem cell research. Nat Rev Genet 7, 319–327 (2006). https://doi.org/10.1038/nrg1827

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1827

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing