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.

  • Innovation
  • Published:

Advances in tomography: probing the molecular architecture of cells

Nature Reviews Molecular Cell Biology volume 13, pages 736–742 (2012)Cite this article

Subjects

Abstract

Visualizing the dynamic molecular architecture of cells is instrumental for answering fundamental questions in cellular and structural biology. Although modern microscopy techniques, including fluorescence and conventional electron microscopy, have allowed us to gain insights into the molecular organization of cells, they are limited in their ability to visualize multicomponent complexes in their native environment. Cryo-electron tomography (cryo-ET) allows cells, and the macromolecular assemblies contained within, to be reconstructed in situ, at a resolution of 2–6 nm. By combining cryo-ET with super-resolution fluorescence microscopy approaches, it should be possible to localize proteins with high precision inside cells and so elucidate a more realistic view of cellular processes. Thus, cryo-ET may bridge the resolution gap between cellular and structural biology.

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: The principles of cryo-electron tomography.
Figure 2: Structural analysis of the nuclear pore complexes using cryo-electron tomography.
Figure 3: Correlated light microscopy and cryo-electron tomography can reveal the architecture of macromolecular complexes.
Figure 4: Cryo-electron tomography can be combined with super-resolution microscopy to characterize macromolecular architecture.

Similar content being viewed by others

References

  1. Lodish, H. F. et al. Molecular Cell Biology, 4th edition (W. H. Freeman, 2000).

    Google Scholar 

  2. Palade, G. E. An electron microscope study of the mitochondrial structure. J. Histochem. Cytochem. 1, 188–211 (1953).

    Article  CAS  PubMed  Google Scholar 

  3. Palade, G. E. The fine structure of mitochondria. Anat. Rec. 114, 427–451 (1952).

    Article  CAS  PubMed  Google Scholar 

  4. Wolken, J. J. & Palade, G. E. Fine structure of chloroplasts in two flagellates. Nature 170, 114–115 (1952).

    Article  CAS  PubMed  Google Scholar 

  5. Wolken, J. J. & Palade, G. E. An electron microscope study of two flagellates, chloroplast structure and variation. Ann. NY Acad. Sci. 56, 873–889 (1953).

    Article  CAS  PubMed  Google Scholar 

  6. Palade, G. E. Intracellular aspects of the process of protein secretion. Nobelprize.org[online], (1974).

  7. Sali, A., Glaeser, R., Earnest, T. & Baumeister, W. From words to literature in structural proteomics. Nature 422, 216–225 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Tocheva, E. I., Li, Z. & Jensen, G. J. Electron cryotomography. Cold Spring Harb. Perspect. Biol 2, a003442 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ben-Harush, K., Maimon, T., Patla, I., Villa, E. & Medalia, O. Visualizing cellular processes at the molecular level by cryo-electron tomography. J. Cell Sci. 123, 7–12 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Pilhofer, M., Ladinsky, M. S., McDowall, A. W. & Jensen, G. J. in Methods in Cell Biology (ed. Thomas, M.-R.) 21–45 (Academic Press, 2010).

    Google Scholar 

  11. Dutcher, S. K. Finding treasures in frozen cells: new centriole intermediates. Bioessays 29, 630–634 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Cramer, P., Bushnell, D. A. & Kornberg, R. D. Structural basis of transcription: RNA polymerase II at 2.8 ångstrom resolution. Science 292, 1863–1876 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. van der Feltz, C., Anthony, K., Brilot, A. & Pomeranz Krummel, D. A. Architecture of the spliceosome. Biochemistry 51, 3321–3333 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Bochtler, M., Ditzel, L., Groll, M., Hartmann, C. & Huber, R. The proteasome. Annu. Rev. Biophys. Biomol. Struct. 28, 295–317 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Korostelev, A. & Noller, H. F. The ribosome in focus: new structures bring new insights. Trends Biochem. Sci. 32, 434–441 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Yahav, T., Maimon, T., Grossman, E., Dahan, I. & Medalia, O. Cryo-electron tomography: gaining insight into cellular processes by structural approaches. Curr. Opin. Struct. Biol. 21, 670–677 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Mader, A., Elad, N. & Medalia, O. Cryoelectron tomography of eukaryotic cells. Methods Enzymol. 483, 245–265 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Medalia, O. et al. Macromolecular architecture in eukaryotic cells visualized by cryoelectron tomography. Science 298, 1209–1213 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Chang J., Liu, X., Rochat, R. H., Baker, M. L., Chiu, W. Reconstructing virus structures from nanometer to near-atomic resolutions with cryo-electron microscopy and tomography. Adv. Exp. Med. Biol. 726, 49–90 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dubochet, J. et al. Cryo-electron microscopy of vitrified specimens. Q. Rev. Biophys. 21, 129–228 (1988).

    Article  CAS  PubMed  Google Scholar 

  21. McDonald, K. L. A review of high-pressure freezing preparation techniques for correlative light and electron microscopy of the same cells and tissues. J. Microsc. 235, 273–281 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Hsieh, C. E., Marko, M., Frank, J. & Mannella, C. A. Electron tomographic analysis of frozen-hydrated tissue sections. J. Struct. Biol. 138, 63–73 (2002).

    Article  PubMed  Google Scholar 

  23. Al-Amoudi, A., Norlen, L. P. & Dubochet, J. Cryo-electron microscopy of vitreous sections of native biological cells and tissues. J. Struct. Biol. 148, 131–135 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Bokstad, M., Sabanay, H., Dahan, I., Geiger, B. & Medalia, O. Reconstructing adhesion structures in tissues by cryo-electron tomography of vitrified frozen sections. J Struct. Biol 178, 76–83 (2011).

    Article  PubMed  Google Scholar 

  25. Marko, M., Hsieh, C., Schalek, R., Frank, J. & Mannella, C. Focused-ion-beam thinning of frozen-hydrated biological specimens for cryo-electron microscopy. Nature Methods 4, 215–217 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Rigort, A. et al. Focused ion beam micromachining of eukaryotic cells for cryoelectron tomography. Proc. Natl Acad. Sci. USA 109, 4449–4454 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Frank, J. in Electron tomography (ed. Frank, J), 1–13 (Plenum Press, 1992).

    Book  Google Scholar 

  28. Radermacher, M. in Electron tomography (ed. Frank, J), 91–115 (Plenum Press, 1992).

    Book  Google Scholar 

  29. Koster, A. J. et al. Perspectives of molecular and cellular electron tomography. J. Struct. Biol. 120, 276–308 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Frank, J. et al. Three-dimensional imaging of biological complexity. J. Struct. Biol. 138, 85–91 (2002).

    Article  PubMed  Google Scholar 

  31. Dierksen, K., Typke, D., Hegerl, R. & Baumeister, W. Towards automatic electron tomography II. Implementation of autofocus and low-dose procedures. Ultramicroscopy 49, 109–120 (1993).

    Article  Google Scholar 

  32. Dierksen, K., Typke, D., Hegerl, R., Koster, A. J. & Baumeister, W. Towards automatic electron tomography. Ultramicroscopy 40, 71–87 (1992).

    Article  Google Scholar 

  33. Grimm, R. et al. Electron tomography of ice-embedded prokaryotic cells. Biophys. J. 74, 1031–1042 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Grimm, R., Koster, A. J., Ziese, U., Typke, D. & Baumeister, W. Zero-loss energy filtering under low-dose conditions using a post-column energy filter. J. Microsc. 183, 60–68 (1996).

    Article  CAS  Google Scholar 

  35. Förster, F. Medalia, O., Zauberman, N., Baumeister, W., Fass, D. Retrovirus envelope protein complex structure in situ studied by cryo-electron tomography. Proc. Natl Acad. Sci. USA 102, 4729–4734 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li, S., Fernandez, J.-J., Marshall, W. F. & Agard, D. A. Three-dimensional structure of basal body triplet revealed by electron cryo-tomography. EMBO J. 31, 552–562 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kourˇil, R., Oostergetel, G. T. & Boekema, E. J. Fine structure of granal thylakoid membrane organization using cryo electron tomography. Biochim. Biophys. Acta 1807, 368–374 (2011).

    Article  CAS  Google Scholar 

  38. Bartesaghi, A. & Subramaniam, S. Membrane protein structure determination using cryo-electron tomography and 3D image averaging. Curr. Opin. Struct. Biol. 19, 402–407 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schmid, M. F. & Booth, C. R. Methods for aligning and for averaging 3D volumes with missing data. J. Struct. Biol. 161, 243–248 (2008).

    Article  PubMed  Google Scholar 

  40. Bartesaghi, A. et al. Classification and 3D averaging with missing wedge correction in biological electron tomography. J. Struct. Biol. 162, 436–450 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Al-Amoudi, A., Diez, D. C., Betts, M. J. & Frangakis, A. S. The molecular architecture of cadherins in native epidermal desmosomes. Nature 450, 832–837 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Castaño-Díez, D., Al-Amoudi, A., Glynn, A. M., Seybert, A. & Frangakis, A. S. Fiducial-less alignment of cryo-sections. J. Struct. Biol. 159, 413–423 (2007).

    Article  PubMed  Google Scholar 

  43. Gruska, M., Medalia, O., Baumeister, W. & Leis, A. Electron tomography of vitreous sections from cultured mammalian cells. J. Struct. Biol. 161, 384–392 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Al-Amoudi, A., Studer, D. & Dubochet, J. Cutting artefacts and cutting process in vitreous sections for cryo-electron microscopy. J. Struct. Biol. 150, 109–121 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Salje, J., Zuber, B. & Lowe, J. Electron cryomicroscopy of E. coli reveals filament bundles involved in plasmid DNA segregation. Science 323, 509–512 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Lieber, A., Leis, A., Kushmaro, A., Minsky, A. & Medalia, O. Chromatin organization and radio resistance in the bacterium Gemmata obscuriglobus. J. Bacteriol. 191, 1439–1445 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Gobbi, P. et al. Scanning electron microscopic detection of nuclear structures involved in DNA replication. Arch. Histol. Cytol. 62, 317–326 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Giannuzzi, L. A. & Stevie, F. A. Introduction to focused ion beams: instrumentation, theory, techniques and practice (Springer, 2005).

  49. Elad, N., Abramovitch, S., Sabanay, H. & Medalia, O. Microtubule organization in the final stages of cytokinesis as revealed by cryo-electron tomography. J. Cell Sci. 124, 207–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Maurer, U. E., Sodeik, B. & Grunewald, K. Native 3D intermediates of membrane fusion in herpes simplex virus 1 entry. Proc. Natl Acad. Sci. USA 105, 10559–10564 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cyrklaff, M. et al. Hemoglobins S and C interfere with actin remodeling in Plasmodium falciparum-infected erythrocytes. Science 334, 1283–1286 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Gan, L., Ladinsky, Mark, S. & Jensen, Grant, J. Organization of the smallest eukaryotic spindle. Curr. Biol. 21, 1578–1583 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Grossman, E., Medalia, O. & Zwerger, M. Functional architecture of the nuclear pore complex. Ann. Rev. Biophys. 41, 557–584 (2012).

    Article  CAS  Google Scholar 

  54. Elad, N., Maimon, T., Frenkiel-Krispin, D., Lim, R. Y. & Medalia, O. Structural analysis of the nuclear pore complex by integrated approaches. Curr. Opin. Struct. Biol. 19, 226–232 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Rout, M. P. & Blobel, G. Isolation of the yeast nuclear pore complex. J. Cell Biol. 123, 771–783 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. Reichelt, R. et al. Correlation between structure and mass distribution of the nuclear pore complex and of distinct pore complex components. J. Cell Biol. 110, 883–894 (1990).

    Article  CAS  PubMed  Google Scholar 

  57. Callan, H. G. & Tomlin, S. G. Experimental studies on amphibian oocyte nuclei. I. Investigation of the structure of the nuclear membrane by means of the electron microscope. Proc. R. Soc. Lond. B Biol. Sci. 137, 367–378 (1950).

    Article  CAS  PubMed  Google Scholar 

  58. Akey, C. W. Structural plasticity of the nuclear pore complex. J. Mol. Biol. 248, 273–293 (1995).

    CAS  PubMed  Google Scholar 

  59. Akey, C. W. & Radermacher, M. Architecture of the Xenopus nuclear pore complex revealed by three-dimensional cryo-electron microscopy. J. Cell Biol. 122, 1–19 (1993).

    Article  CAS  PubMed  Google Scholar 

  60. Beck, M. et al. Nuclear pore complex structure and dynamics revealed by cryoelectron tomography. Science 306, 1387–1390 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Stoffler, D. et al. Cryo-electron tomography provides novel insights into nuclear pore architecture: implications for nucleocytoplasmic transport. J. Mol. Biol. 328, 119–130 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Frenkiel-Krispin, D., Maco, B., Aebi, U. & Medalia, O. Structural analysis of a metazoan nuclear pore complex reveals a fused concentric ring architecture. J. Mol. Biol. 395, 578–586 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Maimon, T., Elad, N., Dahan, I. & Medalia, O. The human nuclear pore complex as revealed by cryo-electron tomography. Structure 20, 998–1006 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Beck, M., Lucic, V., Forster, F., Baumeister, W. & Medalia, O. Snapshots of nuclear pore complexes in action captured by cryo-electron tomography. Nature 449, 611–615 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Winey, M., Yarar, D., Giddings, T. H. Jr & Mastronarde, D. N. Nuclear pore complex number and distribution throughout the Saccharomyces cerevisiae cell cycle by three-dimensional reconstruction from electron micrographs of nuclear envelopes. Mol. Biol. Cell 8, 2119–2132 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gerace, L. & Burke, B. Functional organization of the nuclear envelope. Annu. Rev. Cell Biol. 4, 335–374 (1988).

    Article  CAS  PubMed  Google Scholar 

  67. Melcak, I., Hoelz, A. & Blobel, G. Structure of Nup58/45 suggests flexible nuclear pore diameter by intermolecular sliding. Science 315, 1729–1732 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Alber, F. et al. The molecular architecture of the nuclear pore complex. Nature 450, 695–701 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Abercrombie, M. & Dunn, G. A. Adhesions of fibroblasts to substratum during contact inhibition observed by interference reflection microscopy. Exp. Cell Res. 92, 57–62 (1975).

    Article  CAS  PubMed  Google Scholar 

  70. Wiesner, S., Lange, A. & Fässler, R. Local call: from integrins to actin assembly. Trends Cell Biol. 16, 327–329 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Medalia, O. & Geiger, B. Frontiers of microscopy-based research into cell–matrix adhesions. Curr. Opin. Cell Biol. 22, 659–668 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Chen, W. T. Mechanism of retraction of the trailing edge during fibroblast movement. J. Cell Biol. 90, 187–200 (1981).

    Article  CAS  PubMed  Google Scholar 

  73. Geiger, B. A 130K protein from chicken gizzard: its localization at the termini of microfilament bundles in cultured chicken cells. Cell 18, 193–205 (1979).

    Article  CAS  PubMed  Google Scholar 

  74. Burridge, K. & Connell, L. Talin: a cytoskeletal component concentrated in adhesion plaques and other sites of actin–membrane interaction. Cell. Motil. 3, 405–417 (1983).

    Article  CAS  PubMed  Google Scholar 

  75. Burridge, K. & Feramisco, J. R. Microinjection and localization of a 130K protein in living fibroblasts: a relationship to actin and fibronectin. Cell 19, 587–595 (1980).

    Article  CAS  PubMed  Google Scholar 

  76. Turner, C. E., Glenney, J. R. Jr & Burridge, K. Paxillin: a new vinculin-binding protein present in focal adhesions. J. Cell Biol. 111, 1059–1068 (1990).

    Article  CAS  PubMed  Google Scholar 

  77. Burridge, K., Fath, K., Kelly, T., Nuckolls, G. & Turner, C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu. Rev. Cell Biol. 4, 487–525 (1988).

    Article  CAS  PubMed  Google Scholar 

  78. Singer, I. I. The fibronexus: a transmembrane association of fibronectin-containing fibers and bundles of 5 nm microfilaments in hamster and human fibroblasts. Cell 16, 675–685 (1979).

    Article  CAS  PubMed  Google Scholar 

  79. Heath, J. P. & Dunn, G. A. Cell to substratum contacts of chick fibroblasts and their relation to the microfilament system. A correlated interference-reflexion and high-voltage electron-microscope study. J. Cell Sci. 29, 197–212 (1978).

    CAS  PubMed  Google Scholar 

  80. Patla, I. et al. Dissecting the molecular architecture of integrin adhesion sites by cryo-electron tomography. Nature Cell Biol. 12, 909–915 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Kanchanawong, P. et al. Nanoscale architecture of integrin-based cell adhesions. Nature 468, 580–584 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Muller, D. A. et al. Structure of the Dengue virus glycoprotein NS1 by electron microscopy and single particle analysis. J. Gen. Virol. 93, 771–779 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Bharat, T. A. M. et al. Structural dissection of Ebola virus and its assembly determinants using cryo-electron tomography. Proc. Natl Acad. Sci. USA 109, 4275–4280 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Pigino, G. et al. Comparative structural analysis of eukaryotic flagella and cilia from Chlamydomonas, Tetrahymena, and sea urchins. J. Struct. Biol. 178, 199–206 (2012).

    Article  PubMed  Google Scholar 

  85. Höög, J. L., Bouchet-Marquis, C., McIntosh, J. R., Hoenger, A. & Gull, K. Cryo-electron tomography and 3D analysis of the intact flagellum in Trypanosoma brucei. J. Struct. Biol. 178, 189–198 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Huang, B., Babcock, H. & Zhuang, X. Breaking the diffraction barrier: super-resolution imaging of cells. Cell 143, 1047–1058 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Galbraith, C. G. & Galbraith, J. A. Super-resolution microscopy at a glance. J. Cell Sci. 124, 1607–1611 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Schermelleh, L. et al. Subdiffraction multicolor imaging of the nuclear periphery with 3D structured illumination microscopy. Science 320, 1332–1336 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Loschberger, A. et al. Super-resolution imaging visualizes the eightfold symmetry of gp210 proteins around the nuclear pore complex and resolves the central channel with nanometer resolution. J. Cell Sci. 125, 570–575 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Barr, F. A. & Gruneberg, U. Cytokinesis: placing and making the final cut. Cell 131, 847–860 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Eggert, U. S., Mitchison, T. J. & Field, C. M. Animal cytokinesis: from parts list to mechanisms. Annu. Rev. Biochem. 75, 543–566 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Guizetti, J. et al. Cortical constriction during abscission involves helices of ESCRT-III-dependent filaments. Science 331, 1616–1620 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Schiel, J. A. et al. Endocytic membrane fusion and buckling-induced microtubule severing mediate cell abscission. J. Cell Sci. 124, 1411–1424 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Elia, N., Sougrat, R., Spurlin, T. A., Hurley, J. H. & Lippincott-Schwartz, J. Dynamics of endosomal sorting complex required for transport (ESCRT) machinery during cytokinesis and its role in abscission. Proc. Natl Acad. Sci. USA 108, 4846–4851 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wollert, T. et al. The ESCRT machinery at a glance. J. Cell Sci. 122, 2163–2166 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Raiborg, C. & Stenmark, H. Cell biology. A helix for the final cut. Science 331, 1533–1534 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Caballe, A. & Martin-Serrano, J. ESCRT machinery and cytokinesis: the road to daughter cell separation. Traffic 12, 1318–1326 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Elia, N., Fabrikant, G., Kozlov, M. & Lippincott-Schwartz, J. Computational model of cytokinetic abscission driven by ESCRT-III polymerization and remodeling. Biophys. J. 102, 2309–2320 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Guizetti, J. & Gerlich, D. W. ESCRT-III polymers in membrane neck constriction. Trends Cell Biol. 22, 133–140 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Betzig, E. et al. Imaging intracellular fluorescent proteins at nanometer resolution. Science 313, 1642–1645 (2006).

    Article  PubMed  Google Scholar 

  101. Rust, M. J., Bates, M. & Zhuang, X. Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nature Methods 3, 793–795 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hell, S. W. & Wichmann, J. Breaking the diffraction resolution limit by stimulated emission: stimulated-emission-depletion fluorescence microscopy. Opt. Lett. 19, 780–782 (1994).

    Article  CAS  PubMed  Google Scholar 

  103. Westphal, V. & Hell, S. W. Nanoscale resolution in the focal plane of an optical microscope. Phys. Rev. Lett. 94, 143903 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Gustafsson, M. G. Surpassing the lateral resolution limit by a factor of two using structured illumination microscopy. J. Microsc. 198, 82–87 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Heintzmann, R. & Cremer, C. G. Laterally modulated excitation microscopy: improvement of resolution by using a diffraction grating. Proc. SPIE. 3568, 185–196 (1999).

    Article  Google Scholar 

Download references

Acknowledgements

The authors work is supported by the Swiss National Science Foundation (SNSF), the National Center for Competence in Research in Structural Biology, a Swiss National Science Foundation grant (SNSF 31003A_141083/1) and an European Research Council (ERC) Starting Grant (243047 INCEL).

Author information

Authors and Affiliations

  1. Natalie Elia and Ohad Medalia are at the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Karen Fridman, Asaf Mader, Ben-Gurion University, Beer-Sheva, 84105 Israel.,

    Karen Fridman, Asaf Mader, Natalie Elia & Ohad Medalia

  2. Monika Zwerger and Ohad Medalia are at Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.,

    Monika Zwerger & Ohad Medalia

Authors
  1. Karen Fridman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asaf Mader
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monika Zwerger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natalie Elia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ohad Medalia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ohad Medalia.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Ohad Medalia's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fridman, K., Mader, A., Zwerger, M. et al. Advances in tomography: probing the molecular architecture of cells. Nat Rev Mol Cell Biol 13, 736–742 (2012). https://doi.org/10.1038/nrm3453

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3453

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