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.

  • Review Article
  • Published:

Epigenesis: The Missing Beat in Biotechnology?

Bio/Technology volume 12, pages 156–164 (1994)Cite this article

Abstract

The range of human phenotypes/diseases for which our burgeoning bio–molecular data base is sufficient to provide understanding, diagnosis, and therapy is small. Only 2 percent of our total disease load is related to monogenic causality, and even here the final phenotype is modulated by many factors. Monogenic logic cannot, moreover, be applied to the 98 percent of our most important sources of premature disability and death. This article provides an analysis of the limits of genetic thinking in biotechnology and describes the outline for another approach to understanding complex cellular/physiological systems. In this outline, rules governing physiological regulation and cellular and higher levels of organization are located not in the genome, but in interactive epigenetic networks which themselves organize genomic response to environmental signaling.

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

Similar content being viewed by others

References

  1. Hood, L. 1992. In: The Code of Codes. D. J. Kevles and L. Hood. (Eds.) Harvard University Press, Cambridge, Massachusetts.

    Google Scholar 

  2. Mckeown, T. 1979. The Role of Medicine: Dream, Mirage or Nemesis? Princeton University Press, Princeton, New Jersey.

    Google Scholar 

  3. Casky, T. 1992. In: The Code of Codes. D. J. Kevles and L. Hood. (Eds.) Harvard University Press, Cambridge, Massachusetts.

    Google Scholar 

  4. Strohman, R.C. 1993. Ancient Genomes, Wise Bodies, Unhealthy People: Limits of Genetic Thinking in Biology and Medicine. Perspectives in Biology & Medicine 37(1): 112–145

    CAS  Google Scholar 

  5. Lewontin, R.C. 1992. Biology As Ideology. Harper Perennial, New York.

    Google Scholar 

  6. Wahlsten, D. 1990. Insensitivity of the analysis of variance to heredity-environment interaction. Behav. and Brain Sci. 13: 109–161.

    Google Scholar 

  7. Tautz, D. 1992. Redundancies, development and the flow of information. BioEssays 14: 263–266.

    CAS  PubMed  Google Scholar 

  8. Wilkins, A.S. 1993. Genetic Analysis of Animal Development, 2nd Ed., p. 473. Wiley-Liss Press, New York.

    Google Scholar 

  9. Wright, S. 1941. The physiology of the gene. Physiological Reviews. 21: 487–527.

    Google Scholar 

  10. Kuhn, T. 1962. The Structure of Scientific Revolutions. The University ofChicago Press, Chicago, Illinois.

    Google Scholar 

  11. Brenner, S., Dove, W., Hewrskowitz, I. and Thomas, R. 1990. Genes and development: molecular and logical themes. Genetics 126: 479–486.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Weatherall, D.J. 1982. The new genetics and clinical practice. Nuffield Provincial Hospitals Trust, London.

  13. Coggan, A.R., Spina, R.J., Rogers, M.A., King, D.S., Brown, M., Nemeth, P.M. and Holloszy, J.O. 1990. Histochemical and enzymatic characteristics of skeletal muscle in master athletes. J. Applied Physiology 68: 1896–1901.

    CAS  Google Scholar 

  14. Pette, D. and Dusterhoft, S. 1992. Altered gene expression in fast-twitch muscle induced by chronic low-frequency stimulation. Am. J. Physiol. 262: 333–338.

    Google Scholar 

  15. Kaufmann, S. 1993. The Origins of Order. Oxford University Press, Oxford.

    Google Scholar 

  16. Skinner, J.E., Molnar, M., Vybiral, T. and Mitra, M. 1992. Application of chaos theory to biology and medicine. Integ. Physiol. & Behav. Sci. 27: 39–53.

    CAS  Google Scholar 

  17. Sing, C.F. and Reilley, S.L. 1993. Genetics of common diseases that aggregate but do not segregate in families. p. 140–161. In: Genetics of Cellular, Individual, Family and Population Variability. Sing, C. F., Hanis, C. L. (Eds.). Oxford Univ. Press, Oxford.

    Google Scholar 

  18. Nathan, C. and Sporn, M. 1991. Cytokines in context. J. Cell Biol. 113: 981–986.

    CAS  PubMed  Google Scholar 

  19. McKeown, T. 1988. The Origins of Human Disease. Basil Blackwell, Inc., Oxford.

    Google Scholar 

  20. Feldman, M.W. and Lewontin, R.C. 1975. The heritability hang-up. Science 190: 1163–1168.

    CAS  PubMed  Google Scholar 

  21. Gillespie, J.H. and Turelli, M. 1989. Genotype-environment interactions and the maintenance of polygenic variation. Genetics 121: 129–138.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lander, E.S. and Botstein, D. 1986. Strategies for studying heterogeneous genetic traits in humans by using a linkage map of restriction fragment length polymorphisms. Proc. Natl. Acad. Sci. USA 83: 735–737.

    Google Scholar 

  23. Jacob, H.J., Linkpaintner, K., Lincoln, S.E., Kusumi, K., Bunker, R.K., Mao, Y.P., Ganten, D., Dzau, V.J. and Lander, E.S. 1991. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67: 213–224.

    Article  CAS  PubMed  Google Scholar 

  24. Cambien, F., Poirier, O., Lecref, L., Evans, A., Cambou, J.P., Arveiler, D., Luc, G., Bard, J.M., Bara, L., Ricard, S., Tiret, L., Amouyel, P., AlhencGerlas, F. and Soubrier, F. 1992. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for mycardial infarction. Nature 359: 641–644.

    CAS  PubMed  Google Scholar 

  25. Myers, M.M., Branelli, S.A., Squire, J.M., Shindeldecker, R.D. and Hofer, M.A. 1989. Maternal behavior of SHR rats and its relationship to offspring blood pressures. Develop. Psychobiol. 22(1): 29–53.

    CAS  Google Scholar 

  26. Urata, H., Healy, B., Stewart, R.W., Bumpus, F.M. and Husain, A. Angiotensin. 1990. II-forming pathways in normal and failing human hearts. Circulation Res. 66: 883–890.

    CAS  PubMed  Google Scholar 

  27. Peterson, L.H. 1972. Neural and Psychological Mechanisms in Cardiovascular Disease. Casa Editrice, Milano, Italy.

    Google Scholar 

  28. Kurtz, T.W. 1992. The ACE of hearts. Nature 359: 588–589.

    CAS  PubMed  Google Scholar 

  29. Sherringtion, R., Brynjolfsson, J., Petursson, H., Potter, M., Dudleston, K., Barraclough, B., Wasmuth, J., Dobbs, M. and Gurling, H. 1988. Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature 336: 164–167.

    Google Scholar 

  30. Kennedy, J.L., Giuffra, L.A., Moises, H.W., Cavalli-Sforza, L.L., Pakstis, A.J., Kidd, J.R., Catiglione, C.M., Sjogren, B., Wetterberg, L. and Kidd, K.K. 1988. Evidence against linkage of schizophrenia to markers on chromosome 5 in a northern Swedish pedigree. Nature 336: 167–170.

    CAS  PubMed  Google Scholar 

  31. Ayala, F.J. and Kiger, J.A. Jr. 1984. Modern Genetics, 2nd ed. Benjamin/Cummings Pub. Co., Menlo Park, California.

    Google Scholar 

  32. Stent, G. 1981. Strength and weakness of the genetic approach to the development of the nervous system. Ann. Rev. Neurosci. 4: 163–194.

    CAS  PubMed  Google Scholar 

  33. Phillips, D.I.W. 1993. Twin studies in medical research: can they tell us whether diseases are genetically determined? The Lancet 341: 1008–1009.

    CAS  Google Scholar 

  34. Bracha, H.S., Torrey, E.F., Bigelow, L.B., Lohr, J.B. and Linigton, B.B. 1991. Subtle signs of prenatal maldevelopment of the hand ectoderm in schizophrenia: a preliminary monozygotic twin study. Biol. Psychiatry. 30: 719–725.

    CAS  PubMed  Google Scholar 

  35. Egeland, J.A., Gerhard, D.S., Pauls, D.L., Sussex, J.N., Kidd, K.K., Alien, C.R., Hosteller, A.M. and Housman, D.E. 1987. Biopolar affective disorders linked to DNA markers on chromosome 11. Nature 325: 783–787.

    CAS  PubMed  Google Scholar 

  36. Kelsoe, J.R., Ginns, E.I., Egeland, J.A., Gerhard, D.S., Goldstein, A.M., Bale, S. J., Pauls, D.L., Long, R.T., Kidd, K.K., Conte, G., Housman, D.E. and Paul, S.M. 1989. Re-evaluation of Ihe linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish. Nature 342: 238–243.

    CAS  PubMed  Google Scholar 

  37. Hodgkinson, S., Sherrington, R., Gurling, H., Marchbanks, R., Reeders, S., Mallet, J., Mcinnis, M., Peturrson, H., and Brynjolfsson, J. 1987. Molecular genetic evidence for heterogenity in manic depression. Nature 325: 805–806.

    CAS  PubMed  Google Scholar 

  38. Baron, M. 1991. X-linkage and manic-depressive illness: a reassessment. Social Biol. 38: 179–88.

    CAS  Google Scholar 

  39. New hunt on for bipolar genes. 1993. Science 262: 651.

    PubMed  Google Scholar 

  40. Gottlieb, G. 1992. Individual Developmenl and Evolution, p. xxx–xxx?. In: The Genesis of Novel Behavior. Oxford University Press, Oxford.

    Google Scholar 

  41. Levine, A.J., Momand, J. and Finlay, C.A. 1991. The p53 tumour suppressor gene. Nature 351: 453–456.

    CAS  PubMed  Google Scholar 

  42. Jacks, T., Faneli, A., Schmitt, E.M., Bronson, R.T. Goodell, M.A. and Weinberg, R.A. 1992. Effects of an Rb mutation in the mouse. Nature 359: 295–300.

    CAS  PubMed  Google Scholar 

  43. Donehower, L.A., Harvey, M., Slagle, B.L., Mcarthur, M.J., Montgomery, C.A. Jr., Butel, J.S. and Bradley, A. 1992. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356: 215–221.

    CAS  PubMed  Google Scholar 

  44. Baker, S.J., Markowitz, S., Fearon, E.R., Willson, J.K. and Vogelstein, B. 1990. Suppression of human coloreclal carcinoma cell growth by wild-type p53. Science 249: 912–915.

    CAS  PubMed  Google Scholar 

  45. Pietenpol, J.A. and Vogelstein, B. 1993. No room at the p53 inn. Nature 356: 17–18.

    Google Scholar 

  46. Dutta, A., Ruppert, J.M., Aster, J.C. and Winchester, E. 1993. Inhibition of DNA replication factor RPA by p53. Nature 365: 79–82.

    CAS  PubMed  Google Scholar 

  47. Duesberg, P.H. and Schwartz, J.R. 1992. Latent viruses and mutated oncogenes: no evidence for pathogenicity. Progress in Nucleic Acid Research and Molecular Biology 43: 135–204.

  48. Knudson, A. 1985. Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 45: 1437–43.

    CAS  PubMed  Google Scholar 

  49. Benedict, W.F., Banetjee, A., Mark, C. and Murphee, A. 1983. Nonrandom chromosomal changes in untreated retinoblastoma. Cancer Genetics and Cyotgenetics 10: 311–333.

    CAS  Google Scholar 

  50. Gardner, H.A., Gallie, B.L., Knight, L.A. and Phillips, R.A. 1982. Multiple karyotypic changes in relinoblastoma tumor cells: presence of normal chromosome No. 13 in most tumors. Cancer Genetics and Cyotgenetics 6: 201–211.

    CAS  Google Scholar 

  51. Bookstein, R., Shew, J.Y, Chen, P.L., Scully, P. and Lee, W.H. 1990. Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science 247: 712–715.

    CAS  PubMed  Google Scholar 

  52. Xu, H.J., Sumegi, J., Hu, S.X., Banerjee, A., Uzvolgyi, E., Klein, G. and Benedict, W.F. 1991. Intraocular tumor function of RB reconstituted retinoblastoma cells. Cancer Research 51: 4481–4485.

    CAS  PubMed  Google Scholar 

  53. Colditz, G.A., Willett, W.C., Hunter, D.J., Stampfer, M.J., Manson, J.E., Hennekens, C.H., Rosner, B.A. and Speizer, F.E. 1993. Family history, age, and risk of breast cancer. JAMA 270: 338–343.

    CAS  PubMed  Google Scholar 

  54. Rubin, H. 1985. Cancer as a dynamic developmental disease. Cancer Res. 45: 2935–2942.

    CAS  PubMed  Google Scholar 

  55. Farber, E. and Rubin, H. 1991. Cellular adaptation in the origin and development of cancer. Cancer Res. 51: 2751–2761.

    CAS  PubMed  Google Scholar 

  56. Hall, J.M., Lee, M.K., Newman, B., Morrow, J.E., Anderson, L.A., Huey, B. and King, M.C. 1990. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250: 1684–1689.

    CAS  PubMed  Google Scholar 

  57. Tsui, L. 1992. The spectrum of cystic fibrosis mutations. Trends in Genet. 8: 392–398.

    CAS  Google Scholar 

  58. The Cystic Fibrosis Genolype-Phenotype Consortium, 1993. Correlation between genotype and phenotype in patients with cystic fibrosis. N. Engl. J. Med. 329: 1308–1313.

  59. Collins, F.S. 1992. Cystic Fibrosis: Molecular biology and therapeutic implications. Science 256: 774–777.

    CAS  PubMed  Google Scholar 

  60. Miller, S.S., Jiang, C., Finkbeiner, W.E., Widdicombe, J.H. and McCray,Jr. P.B. Altered fluid transport across airway epithelium in cystic fibrosis. Science 262: 424–427.

  61. Black, W.C. and Welch, H.G. 1993. Advances in diagnostic imaging and overestimation of disease prevalence and Ihe benefits of therapy. NEJM. 328: 1237–1243.

    CAS  PubMed  Google Scholar 

  62. Harach, H.R., Franssila, K.O. and Wasenius, V.M. 1985. Occult papillary carcinoma of the thyroid: a “normal” finding in Finland: a systematic autopsy study. Cancer 56: 531–538.

    CAS  PubMed  Google Scholar 

  63. Moertel, C.G., Fleming, T.R., Macdonald and J.S. et al. 1993. An evaluation of the carcinoembryonic antigen (CEA) lesl for monitoring patients with resected colon cancer. JAMA 270: 943–947.

    CAS  PubMed  Google Scholar 

  64. Fortuin, M., Chotard, J., Jack, A.D., Maine, N.P., Mendy, M., Hall, A.J., Inskip, H.M., George, M.O. and Whittle, H.C. 1993. Efficacy of hepatitis B vaccine in the Gambian expanded programme on immunisation. Lancet 341: 1129–1131.

    CAS  PubMed  Google Scholar 

  65. Tabor, E., Gerety, R.J. and Drucker, J.A. 1978. Transmission of non-A, non-B hepatitis from man to chimpanzee. Lancet 1: 463–465.

    CAS  PubMed  Google Scholar 

  66. Reyes, G.R. and Baroudy, B.M. 1991. Molecular biology of non-A, non-B, hepatitis agents: Hepatitis C and Hepatitis E viruses. Advances in Virus Research 40: 57–102.

    CAS  PubMed  Google Scholar 

  67. Choo, Q.L., Kuo, G., Weiner, A.J., Overby, L.R., Bradley, D.W. and Houghton. M. 1989. Isolation of a cDNA clone derived from a blood-born non-A, non-B viral hepatatitis genome. Science 244: 359–362.

    CAS  PubMed  Google Scholar 

  68. Weiner, A.J., Kuo, G., Bradley, D.W., Bonino, F., Saracco, G., Lee, C., Rosenblatt, J., Choo, Q.L. and Houghton, M. 1990. Detection of hepatitis C viral sequences in non-A, non-B hepatitis. Lancet 335: 1–3.

    CAS  PubMed  Google Scholar 

  69. Selby, M.J., Choo, Q., Berger, K., Kuo, G., Glazer, E., Eckart, M., Lee, C., Chien, D., Kuo, C. and Houghton, M. 1993. Expression, identification and subcellular localization of the proteins encoded by the hepatitis C viral genome. J. of Gen. Virol. 74: 1103–1113.

    CAS  Google Scholar 

  70. Seeff, L.B., Buskell-Bales, Z., Wright, E.C., Durako, S.J., Alter, H.J., Iber, F.L., Hollinger, F.B., Gitnick, G., Knodell, R.G., Perrillo, R.P., Stevens, C.E. and Hollingsworth, C.G. 1992. Long-term mortality after transfusion-associated non-A, non-B hepatitis. NEJM 327: 1906–1911.

    CAS  PubMed  Google Scholar 

  71. Czaja, A.J. 1992. Chronic hepatitis C virus infection—A disease in waiting? NEJM 327: 1949–1950.

    CAS  PubMed  Google Scholar 

  72. Thomas,C., Mullis, K.B., Ellison, B.J. and Johnson, P. 1993. Why there is still an HIV controversy. Nature, submitted in November 1993; rejected December 1993, manuscript available upon request (RS).

  73. Duesberg, P.H. 1992. AIDS acquired by drug consumption and other noncontagious risk factors. Pharmac. Ther. 55: 201–277.

    CAS  Google Scholar 

  74. Aldhous, P. 1992 The promise and pitfalls of molecular genetics. Science 257: 164–165.

    CAS  PubMed  Google Scholar 

  75. Plomin, R., DeFries, J.C. and McClearn, G.E. 1990. Behavioral Genetics, 2nd ed. W. H. Freeman, New York.

    Google Scholar 

  76. Garber, A.M., Littenberg, B., Sox, H.C., Wagner, J.L. and Gluck, M. 1991. Costs and health consequences of cholesterol screening for asymptomatic older Americans. Arch. Internal Med. 151: 1089–1095.

    CAS  Google Scholar 

  77. Moore, T.J. 1989. Heart Failure: A Critical Inquiry Into American Medicine and The Revolution in Heart Care. Random House, Inc., New York.

  78. Fishel, R., Lescoe, M.K., Rao, M.R.S., Copeland, N.G., Jenkins, N.A., Garber, J. and Kolodner, R.D. 1993. The human imitator gene homologue MSH2 and its association with hereditary non-polyposis colon cancer. Cell 75: 1027–1038.

    CAS  PubMed  Google Scholar 

  79. Sapp, J. 1987. Beyond the Gene: Cytoplasmic Inheritance and the Struggle for Authority in Genetics. Oxford University Press, Oxford.

    Google Scholar 

  80. Clark, M.M., Karpluk, P. and Galef, B.G. 1993. Hormonally mediated inheritance of acquired characteristics in Mongolian gerbils. Nature 364: 712.

    CAS  PubMed  Google Scholar 

  81. Nanny, D.L. 1982. Genes andphenes in Tetrahymena. BioScience. 32: 783–788.

    Google Scholar 

  82. Wilson, A.C., Carlson, S.S. and White, T.J. 1977. Biochemical Evolution. Ann. Rev. Biochem. 46: 573–639.

    CAS  PubMed  Google Scholar 

  83. Maddox, J. 1992. Is molecular biology yet a science? Nature 355: 201.

    CAS  PubMed  Google Scholar 

  84. Maddox, J. 1992. Finding wood among the trees. Nature 356: 11.

    Google Scholar 

  85. Elsasser, W. 1987. Reflections on the Theory of Organisms, Orbis Publishing, Quebec.

    Google Scholar 

  86. McClintock, B. 1984. The significance of responses of the genome to challenge. Science 226: 792–801.

    CAS  PubMed  Google Scholar 

  87. Bond, W.C., Bohs, C., Ebey, J. and Wolf, S. 1973. Rhythmic heart rate variability (sinus arrhythmia) related to stages of sleep. Conditional Reflex 8: 98–107.

    CAS  PubMed  Google Scholar 

  88. Skinner, J.E., Goldberger, Mayer-Kress, G. and Ideker, R.E. 1990. Chaos in the heart: implications for clinical cardiology. Bio/Technology 8: 1018–1033.

    Google Scholar 

  89. Cripps, T.R., Malik, M., Farrell, T.G. and Camm, A.J. 1991. Prognostic value of reduced heart rate variability after myocardial infarction: clinical evaluation of a new analysis method. Br. Heart J. 65: 14–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Basar, E. 1993. Chaotic dynamics and resonance phenomena in brain function: progress, perspectives, & thoughts. In: Chaos in Brain Function. E. Basar (Ed.). Springer-Verlag. Berlin.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular & Cell Biology, University of California, Berkeley, CA, 94720

    Richard Strohman

Authors
  1. Richard Strohman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strohman, R. Epigenesis: The Missing Beat in Biotechnology?. Nat Biotechnol 12, 156–164 (1994). https://doi.org/10.1038/nbt0294-156

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt0294-156

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