Wound healing - Aiming for perfect skin regeneration

Science

Volumn 276, Issue 5309, 1997, Pages 75-81

  Martin, Paul ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

KERATIN; TRANSFORMING GROWTH FACTOR ALPHA;

ANGIOGENESIS; ARTICLE; CELL MIGRATION; CELL PROLIFERATION; CELL REGENERATION; EPITHELIZATION; EXTRACELLULAR MATRIX; FIBRIN CLOT; HAIR GROWTH; HUMAN; NONHUMAN; PRIORITY JOURNAL; SCAR FORMATION; SKIN; SWEAT GLAND; WOUND CONTRACTION; WOUND HEALING;

ANIMALS; BLOOD COAGULATION; CICATRIX; ENDOPEPTIDASES; EPIDERMIS; EPITHELIAL CELLS; EPITHELIUM; GROWTH SUBSTANCES; HAIR; HUMANS; KERATINOCYTES; KERATINS; LEUKOCYTES; NEOVASCULARIZATION, PHYSIOLOGIC; REGENERATION; SKIN; SKIN PHYSIOLOGY; SWEAT GLANDS; TRANSFORMING GROWTH FACTOR BETA; WOUND HEALING;

EID: 0030934532     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.276.5309.75     Document Type: Article

References (135)

1. R. A. F. Clark, Ed., The Molecular and Cellular Biology of Wound Repair (Plenum, New York, 1996). Throughout my article I refer to various of the excellent and detailed chapters in this book for supplementary reading and exhaustive references.
2. _, in (1), pp. 3-50.
3. D. W. H. Riches, in (1), pp. 95-141.
4. T. A. Springer, Cell 76, 301 (1994).
5. T. N. Mayadas et al., ibid. 74, 541 (1993).
6. G. Hubner et al., Cytokine 8, 548 (1996).
7. S. J. Leibovich and R. Ross, Am. J. Pathol. 78, 71 (1975).
8. A. Cavani et al., J. Invest. Dermatol. 101, 600 (1993); J. M. Breuss et al., J. Cell Sci. 108, 2241 (1995); K. M. Yamada and R. A. F. Clark, in (1), pp. 51-93; K. Haapasalmi et al., J. Invest. Dermatol. 106, 42 (1996).
9. A. Cavani et al., J. Invest. Dermatol. 101, 600 (1993); J. M. Breuss et al., J. Cell Sci. 108, 2241 (1995); K. M. Yamada and R. A. F. Clark, in (1), pp. 51-93; K. Haapasalmi et al., J. Invest. Dermatol. 106, 42 (1996).
10. A. Cavani et al., J. Invest. Dermatol. 101, 600 (1993); J. M. Breuss et al., J. Cell Sci. 108, 2241 (1995); K. M. Yamada and R. A. F. Clark, in (1), pp. 51-93; K. Haapasalmi et al., J. Invest. Dermatol. 106, 42 (1996).
11. A. Cavani et al., J. Invest. Dermatol. 101, 600 (1993); J. M. Breuss et al., J. Cell Sci. 108, 2241 (1995); K. M. Yamada and R. A. F. Clark, in (1), pp. 51-93; K. Haapasalmi et al., J. Invest. Dermatol. 106, 42 (1996).
12. T. J. Mitcheson and L. P. Cramer, Cell 84, 371 (1996).
13. F. Grinnell, J. Cell. Sci. 101, 1 (1992).
14. J. A. Garlick and L. B. Taichman, Lab. Invest. 70, 916 (1994)
15. M. D. Hertle, M.-D. Kubler, I. M. Leigh, F. M. Watt, J. Clin. Invest. 89, 1892 (1992).
16. A. G. Matoltsy and C. B. Viziam, J. Invest. Dermatol. 55, 20 (1970); W. S. Krawczyk, J. Cell Biol. 49, 247 (1971).
17. A. G. Matoltsy and C. B. Viziam, J. Invest. Dermatol. 55, 20 (1970); W. S. Krawczyk, J. Cell Biol. 49, 247 (1971).
18. C. C. Compton et al., Lab. Invest. 60, 600 (1989).
19. A. Rochat, K. Kobayashi, Y. Barrandon, Cell 76, 1063 (1994).
20. P. H. Jones and F. M. Watt, ibid. 73, 713 (1993); P. H. Jones, S. Harper, F. M. Watt, ibid. 80, 83 (1995).
21. P. H. Jones and F. M. Watt, ibid. 73, 713 (1993); P. H. Jones, S. Harper, F. M. Watt, ibid. 80, 83 (1995).
22. J. Grondahl-Hansen et al., J. Invest. Dermatol. 90, 790 (1988); J. Romer et al., ibid 97, 803 (1991); J. Romer et al., ibid. 102, 519 (1994).
23. J. Grondahl-Hansen et al., J. Invest. Dermatol. 90, 790 (1988); J. Romer et al., ibid 97, 803 (1991); J. Romer et al., ibid. 102, 519 (1994).
24. J. Grondahl-Hansen et al., J. Invest. Dermatol. 90, 790 (1988); J. Romer et al., ibid 97, 803 (1991); J. Romer et al., ibid. 102, 519 (1994).
25. J. Romer et al., Nature Med. 2, 287 (1996).
26. T. Salo et al., Lab. Invest. 70, 176. (1994).
27. U. K. Saarialho-Kere, E. S. Chang, H. G. Welgus, W. C. Parks, J. Clin. Invest. 90, 1952 (1992).
28. U. K. Saarialho-Kere et al., ibid. 94, 79 (1994).
29. F. Grinnell, C.-H. Ho, A. Wysocki, J. Invest. Dermatol. 98, 410 (1992); R.W. Tarnuzzer and G. S. Schultz, Wound Repair Regen. 4, 321 (1996); B. A. Mast and G. S. Schultz, ibid., p. 411.
30. F. Grinnell, C.-H. Ho, A. Wysocki, J. Invest. Dermatol. 98, 410 (1992); R.W. Tarnuzzer and G. S. Schultz, Wound Repair Regen. 4, 321 (1996); B. A. Mast and G. S. Schultz, ibid., p. 411.
31. F. Grinnell, C.-H. Ho, A. Wysocki, J. Invest. Dermatol. 98, 410 (1992); R.W. Tarnuzzer and G. S. Schultz, Wound Repair Regen. 4, 321 (1996); B. A. Mast and G. S. Schultz, ibid., p. 411.
32. I. K. Gipson, S. J. Spurr-Michaud, A. S. Tisdale, Dev. Biol. 126, 253 (1988); J. Uitto, A. Mauviel, J. McGrath, in (1), pp. 513-560.
33. I. K. Gipson, S. J. Spurr-Michaud, A. S. Tisdale, Dev. Biol. 126, 253 (1988); J. Uitto, A. Mauviel, J. McGrath, in (1), pp. 513-560.
34. G. L. Brown et al., J. Exp. Med. 163, 1319 (1986); G. S. Schultz et al., Science 235, 350 (1987).
35. G. L. Brown et al., J. Exp. Med. 163, 1319 (1986); G. S. Schultz et al., Science 235, 350 (1987).
36. Y. Barrandon and H. Green, Cell 50, 1131 (1987).
37. A. J. Ridley and A. Hall, ibid. 70, 389 (1992); A. J. Ridley, P. M. Comoglio, A. Hall, Mol. Cell. Biol. 15, 1110 (1995); C. D. Nobes and A. Halt, Cell 81, 53 (1995).
38. A. J. Ridley and A. Hall, ibid. 70, 389 (1992); A. J. Ridley, P. M. Comoglio, A. Hall, Mol. Cell. Biol. 15, 1110 (1995); C. D. Nobes and A. Halt, Cell 81, 53 (1995).
39. A. J. Ridley and A. Hall, ibid. 70, 389 (1992); A. J. Ridley, P. M. Comoglio, A. Hall, Mol. Cell. Biol. 15, 1110 (1995); C. D. Nobes and A. Halt, Cell 81, 53 (1995).
40. S. Werner et al., Proc. Natl. Acad. Sci. U.S.A. 89, 6896 (1992).
41. M. Brauchle, R. Fassler, S. Werner, J. Invest. Dermatol. 105, 579 (1995).
42. L. Guo, L. Degenstein, E. Fuchs, Genes Dev. 10, 165 (1996).
43. S. Werner et al., Science 266, 819 (1994).
44. L. Staiano-Coico et al., J. Exp. Med. 178, 865 (1993); G. F. Pierce et al., ibid. 179, 831 (1994).
45. L. Staiano-Coico et al., J. Exp. Med. 178, 865 (1993); G. F. Pierce et al., ibid. 179, 831 (1994).
46. R. Tsuboi et al., J. Invest. Dermatol. 101, 49 (1993); M. Madlener et al., Biochem. J. 320, 659 (1996).
47. R. Tsuboi et al., J. Invest. Dermatol. 101, 49 (1993); M. Madlener et al., Biochem. J. 320, 659 (1996).
48. J. Gailet, M. P. Welch, R. A. F. Clark, J. Invest. Dermatol. 103, 221 (1994); M. D. Hertle et al., ibid. 104, 260 (1995).
49. J. Gailet, M. P. Welch, R. A. F. Clark, J. Invest. Dermatol. 103, 221 (1994); M. D. Hertle et al., ibid. 104, 260 (1995).
50. P. Martin and J. Lewis, Nature 360, 179 (1992); J. McCluskey and P. Martin, Dev. Biol. 170, 102 (1995). J. Brock, K. Midwinter, J. Lewis, P. Martin, J. Cell Biol. 135, 1097 (1996).
51. P. Martin and J. Lewis, Nature 360, 179 (1992); J. McCluskey and P. Martin, Dev. Biol. 170, 102 (1995). J. Brock, K. Midwinter, J. Lewis, P. Martin, J. Cell Biol. 135, 1097 (1996).
52. P. Martin and J. Lewis, Nature 360, 179 (1992); J. McCluskey and P. Martin, Dev. Biol. 170, 102 (1995). J. Brock, K. Midwinter, J. Lewis, P. Martin, J. Cell Biol. 135, 1097 (1996).
53. W. M. Bement, P. Forscher, M. S. Mooseker, Ibid. 121, 565 (1993); J. P. Heath, Cell Biol. Int. 20, 139 (1996).
54. W. M. Bement, P. Forscher, M. S. Mooseker, Ibid. 121, 565 (1993); J. P. Heath, Cell Biol. Int. 20, 139 (1996).
55. L. Guo et al., Cell 81, 233 (1995).
56. R. D. Paladini, K. Takahashi, N. S. Bravo, P. A. Coulombe, J. Cell Biol. 132, 381 (1996).
57. J. Brock, J. McCluskey, H. Baribault, P. Martin, Cell Motil. Cytoskel. 35, 358 (1996).
58. P. Sengel, in Biology of the Integument, J. Bereiter-Hahn, A. G. Matolsty, K. S. Richards, Eds. (Springer-Verlag, Berlin, 1986).
59. P. Zhou, C. Byrne, J. Jacobs, E. Fuchs, Genes Dev. 9, 570 (1995); T. Nohno et al., Biochem. Biophys. Res. Commun. 206, 33 (1995); R. S. Stenn et al. [Dermatol. Clin. 14, 543 (1996)] have a table of all genes expressed in developing hair bud.
60. P. Zhou, C. Byrne, J. Jacobs, E. Fuchs, Genes Dev. 9, 570 (1995); T. Nohno et al., Biochem. Biophys. Res. Commun. 206, 33 (1995); R. S. Stenn et al. [Dermatol. Clin. 14, 543 (1996)] have a table of all genes expressed in developing hair bud.
61. P. Zhou, C. Byrne, J. Jacobs, E. Fuchs, Genes Dev. 9, 570 (1995); T. Nohno et al., Biochem. Biophys. Res. Commun. 206, 33 (1995); R. S. Stenn et al. [Dermatol. Clin. 14, 543 (1996)] have a table of all genes expressed in developing hair bud.
62. N. C. Luetteke et al., Cell 73, 263 (1993); G. B. Mann et al., ibid., p. 249; J. M. Hebert et al, ibid. 78, 1017 (1994).
63. N. C. Luetteke et al., Cell 73, 263 (1993); G. B. Mann et al., ibid., p. 249; J. M. Hebert et al, ibid. 78, 1017 (1994).
64. N. C. Luetteke et al., Cell 73, 263 (1993); G. B. Mann et al., ibid., p. 249; J. M. Hebert et al, ibid. 78, 1017 (1994).
65. C. A. B. Jahoda, Development 115, 1103 (1992).
66. B. Eckes, M. Aumailley, T. Krieg, in (1), pp. 493-512.
67. S. A. McClain et al., Am. J. Pathol. 149, 1257 (1996).
68. A. Eriksson et al., EMBO J. 11, 543 (1992); C.-H. Heldin and B. Westermark, in (1), pp. 249-273.
69. A. Eriksson et al., EMBO J. 11, 543 (1992); C.-H. Heldin and B. Westermark, in (1), pp. 249-273.
70. A. B. Roberts and M. B. Sporn, in (1), pp. 275-308; S. Frank, M. Madlener, S. Werner, J. Biol. Chem. 271, 10188 (1996).
71. A. B. Roberts and M. B. Sporn, in (1), pp. 275-308; S. Frank, M. Madlener, S. Werner, J. Biol. Chem. 271, 10188 (1996).
72. G. Hubner, Q. Hu, H. Smola, S. Werner, Dev. Biol. 173, 490 (1996).
73. A. Igarashi, H. Okochi, D. M. Bradham, G. R. Grotendorst, Mol. Biol. Cell 4, 637 (1993); E. D. Mason, K. D. Conrad, C. D. Webb, J. L. Marsh, Genes Dev. 8, 1489 (1994); G. R. Grotendorst, H. Okochi, N. Hayashi, Cell Growth Differ. 7, 469 (1996); D. Kothapalli et al., ibid. 8, 61 (1997).
74. A. Igarashi, H. Okochi, D. M. Bradham, G. R. Grotendorst, Mol. Biol. Cell 4, 637 (1993); E. D. Mason, K. D. Conrad, C. D. Webb, J. L. Marsh, Genes Dev. 8, 1489 (1994); G. R. Grotendorst, H. Okochi, N. Hayashi, Cell Growth Differ. 7, 469 (1996); D. Kothapalli et al., ibid. 8, 61 (1997).
75. A. Igarashi, H. Okochi, D. M. Bradham, G. R. Grotendorst, Mol. Biol. Cell 4, 637 (1993); E. D. Mason, K. D. Conrad, C. D. Webb, J. L. Marsh, Genes Dev. 8, 1489 (1994); G. R. Grotendorst, H. Okochi, N. Hayashi, Cell Growth Differ. 7, 469 (1996); D. Kothapalli et al., ibid. 8, 61 (1997).
76. A. Igarashi, H. Okochi, D. M. Bradham, G. R. Grotendorst, Mol. Biol. Cell 4, 637 (1993); E. D. Mason, K. D. Conrad, C. D. Webb, J. L. Marsh, Genes Dev. 8, 1489 (1994); G. R. Grotendorst, H. Okochi, N. Hayashi, Cell Growth Differ. 7, 469 (1996); D. Kothapalli et al., ibid. 8, 61 (1997).
77. J. Xu and R. A. F. Clark, J. Cell Biol. 132, 239 (1996).
78. D. Greiling and R. A. F. Clark, J. Cell Sci., in press.
79. C. Ffrench-Constant, L. van de Water, H. F. Dvorak, R. O. Hynes, J. Cell Biol. 109, 903 (1989); L. F. Brown et al., Am. J. Pathol. 142, 793 (1993).
80. C. Ffrench-Constant, L. van de Water, H. F. Dvorak, R. O. Hynes, J. Cell Biol. 109, 903 (1989); L. F. Brown et al., Am. J. Pathol. 142, 793 (1993).
81. W. Witke et al., Cell 81, 41 (1995); see S. O'Kane et al. [Mol. Biol. Cell (suppl. 7). 543a (1996)] for preliminary in vivo wound healing report.
82. W. Witke et al., Cell 81, 41 (1995); see S. O'Kane et al. [Mol. Biol. Cell (suppl. 7). 543a (1996)] for preliminary in vivo wound healing report.
83. J. H. H. Hartwig et al., Cell 82, 643 (1995).
84. A. Desmouliere and G. Gabbiani, in (1), pp. 391-423.
85. A. Desmouliere, A. Geinoz, F. Gabbiani, G. Gabbiani, J. Cell Biol. 122, 103 (1993).
86. F. Grinnell, ibid. 124, 401 (1994).
87. R. Montesano and L. Orci, Proc. Natl. Acad. Sci. U.S.A. 85, 4894 (1988); R. A. F. Clark et al., J. Clin. Invest. 84, 1036 (1989).
88. R. Montesano and L. Orci, Proc. Natl. Acad. Sci. U.S.A. 85, 4894 (1988); R. A. F. Clark et al., J. Clin. Invest. 84, 1036 (1989).
89. Y. He and F. Grinnell, J. Cell Biol. 126, 457 (1994); ibid. 130, 1197 (1995).
90. Y. He and F. Grinnell, J. Cell Biol. 126, 457 (1994); ibid. 130, 1197 (1995).
91. Y.-C. Lin and F. Grinnell, ibid. 122, 663 (1993).
92. A. Desmouliere, M. Redard, I. Darby, G. Gabbiani, Am. J. Pathol. 146, 56 (1995).
93. J. A. Abraham and M. Klagsbrun, in (1), pp. 195-248.
94. K. N. Broadley et al., Lab. Invest. 61, 571 (1989).
95. L. F. Brown et al., J. Exp. Med. 176, 1375 (1992); B. Berse et al., Mol. Biol. Cell 3, 211 (1992).
96. L. F. Brown et al., J. Exp. Med. 176, 1375 (1992); B. Berse et al., Mol. Biol. Cell 3, 211 (1992).
97. S. Frank et al., J. Biol. Chem. 270, 12607 (1995).
98. P. C. Brooks, R. A. F. Clark, D. A. Cheresh, Science 264, 569 (1994); R. A. F. Clark, M. G. Tonnesen, J. Gailit, and D. A. Cheresh, Am. J. Pathol. 148, 1407 (1996).
99. P. C. Brooks, R. A. F. Clark, D. A. Cheresh, Science 264, 569 (1994); R. A. F. Clark, M. G. Tonnesen, J. Gailit, and D. A. Cheresh, Am. J. Pathol. 148, 1407 (1996).
100. C. Fisher et al., Dev. Biol. 162, 499 (1994).
101. M. L. Reynolds and M. Fitzgerald, J. Comp. Neurol. 358, 487 (1995).
102. J. Constantinou et al., Neuroreport 5, 2281 (1994).
103. V. L. Buchman, M. Sporn, A. M. Davies, Development 120, 1621 (1994).
104. L. M. Mullen et al., ibid. 122, 3487 (1996).
105. J. Nilsson, A. von Euler, C.-J. Dalsgaard, Nature 315, 61 (1985).
106. K.-F. Lee et al., Cell 69, 737 (1992).
107. J. M. Estes et al., Differentiation 56, 173 (1994).
108. See chapters in N. S. Adzick and M. T. Longaker, Eds., Fetal Wound Healing (Elsevier, New York, 1992); R. L. McCallion and M. W. J. Ferguson, in (1), pp. 561-600; P. Martin, Curr. Top. Dev. Biol. 32, 175 (1996); S. Nodder and P. Martin, Anat. Embryol. 195, 215 (1997).
109. See chapters in N. S. Adzick and M. T. Longaker, Eds., Fetal Wound Healing (Elsevier, New York, 1992); R. L. McCallion and M. W. J. Ferguson, in (1), pp. 561-600; P. Martin, Curr. Top. Dev. Biol. 32, 175 (1996); S. Nodder and P. Martin, Anat. Embryol. 195, 215 (1997).
110. See chapters in N. S. Adzick and M. T. Longaker, Eds., Fetal Wound Healing (Elsevier, New York, 1992); R. L. McCallion and M. W. J. Ferguson, in (1), pp. 561-600; P. Martin, Curr. Top. Dev. Biol. 32, 175 (1996); S. Nodder and P. Martin, Anat. Embryol. 195, 215 (1997).
111. See chapters in N. S. Adzick and M. T. Longaker, Eds., Fetal Wound Healing (Elsevier, New York, 1992); R. L. McCallion and M. W. J. Ferguson, in (1), pp. 561-600; P. Martin, Curr. Top. Dev. Biol. 32, 175 (1996); S. Nodder and P. Martin, Anat. Embryol. 195, 215 (1997).
112. M. T. Longaker et al., Surg. Forum 41, 639 (1990).
113. J. R. Armstrong and M. W. J. Ferguson, Dev. Biol. 169, 242 (1995).
114. N. S. Adzick et al., J. Pediatr. Surg. 20, 315 (1985); D. J. Whitby and M. W. J. Ferguson, Development 112, 651 (1991); J. Hopkinson-Woolley, D. Hughes, S. Gordon, P. Martin, J. Cell Sci. 107, 1159 (1994).
115. N. S. Adzick et al., J. Pediatr. Surg. 20, 315 (1985); D. J. Whitby and M. W. J. Ferguson, Development 112, 651 (1991); J. Hopkinson-Woolley, D. Hughes, S. Gordon, P. Martin, J. Cell Sci. 107, 1159 (1994).
116. N. S. Adzick et al., J. Pediatr. Surg. 20, 315 (1985); D. J. Whitby and M. W. J. Ferguson, Development 112, 651 (1991); J. Hopkinson-Woolley, D. Hughes, S. Gordon, P. Martin, J. Cell Sci. 107, 1159 (1994).
117. D. J. Whitby and M. W. J. Ferguson, Dev. Biol. 147, 207 (1991); P. Martin, M. C. Dickson, F. A. Millan, R. J. Akhurst, Dev. Genet. 14, 225 (1993).
118. D. J. Whitby and M. W. J. Ferguson, Dev. Biol. 147, 207 (1991); P. Martin, M. C. Dickson, F. A. Millan, R. J. Akhurst, Dev. Genet. 14, 225 (1993).
119. W. A. Noble and N. A. Noble, N. Engl. J. Med. 331, 1286 (1994).
120. M. Shah, D. M. Foreman, M. W. J. Ferguson, Lancet 339, 213 (1992); J. Cell Sci. 107, 1137 (1994).
121. M. Shah, D. M. Foreman, M. W. J. Ferguson, Lancet 339, 213 (1992); J. Cell Sci. 107, 1137 (1994).
122. _, J. Cell Sci. 108, 985 (1995).
123. R. L. McCallion, J. M. Wood, D. M. Foreman, M. W. J. Ferguson, Lancet, in press.
124. B. Verrier, D. Muller, R. Bravo, R. Muller, EMBO. J. 5, 913 (1986); P. Martin and C. D. Nobes, Mech. Dev. 38, 209 (1992); S. Pawar, S. Kartha, F. G. Toback, J. Cell. Physiol. 165, 556 (1995).
125. B. Verrier, D. Muller, R. Bravo, R. Muller, EMBO. J. 5, 913 (1986); P. Martin and C. D. Nobes, Mech. Dev. 38, 209 (1992); S. Pawar, S. Kartha, F. G. Toback, J. Cell. Physiol. 165, 556 (1995).
126. B. Verrier, D. Muller, R. Bravo, R. Muller, EMBO. J. 5, 913 (1986); P. Martin and C. D. Nobes, Mech. Dev. 38, 209 (1992); S. Pawar, S. Kartha, F. G. Toback, J. Cell. Physiol. 165, 556 (1995).
127. J. A. Goliger and D. L. Paul, Mol. Biol. Cell 6, 1491 (1995).
128. L. P. A. Burgess et al., Arch. Otolaryngol. Head Neck Surg. 116, 798 (1990).
129. S. Frank, B. Munz, S. Werner, Oncogene, in press.
130. L. B. Nanney and L. E. King, in (1), pp. 171-194.
131. D. A. Rappolee, D. Mark, M. J. Banda, Z. Werb, Science 241, 708 (1988).
132. M. Marikovsky et al., Proc. Natl. Acad. Sci. U.S.A. 90, 3889 (1993).
133. R. V. Mueller, T. K. Hunt, A. Tokunaga, E. M. Spencer, Arch. Surg. 129, 262 (1994).
134. E. Forsberg et al., Proc. Natl. Acad. Sci. U.S.A. 93, 6594 (1996).
135. Many thanks to R. Clark, M. Ferguson, F. Grinnell, and S. Werner for furnishing preprints of their papers, and to F. Burslem, J. Clarke, M. Ferguson, G. Grotendorst, S. Harsum, K. Hooper, C. Jahoda, J. Lewis, K. Nobes, G. Schultz, and S. Werner for critically reading parts or all of this article at short notice. Thanks to M. Turmaine for electron microscopy expertise. I am especially grateful to J. Lewis for continuous encouragement and support over the years. Work from my lab is funded by the Wellcome Trust, the Medical Research Council, and Pfizer UK.