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.

  • Commentary
  • Published:

The Clonal Selection Theory: what it really is and why modern challenges are misplaced

Nature Immunology volume 3, pages 793–796 (2002)Cite this article

Historical insight: The clonal selection theory of antibody formation has recently been subjected to challenge from many quarters. A review of its history and that of scientific theories in general points to the importance of distinguishing between the central hypotheses of a theory and its subsidiary implications.

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

Relevant articles

Open Access articles citing this article.

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: Burnet's illustration of the CST.

K. R.

References

  1. Burnet, F.M. Cold Spring Harbor Symp. 32, 1–8 (1967), see p. 1.

    Article  CAS  Google Scholar 

  2. Burnet, F.M. Aust. J. Sci. 20, 67–69 (1957); Talmage, D.W. Annu. Rev. Med. 8, 239–257 (1957).

    Google Scholar 

  3. Cohen, I.R. Immunol. Today 13, 441–444 & 490–494 (1992). See also Cohen's Tending Adam's Garden (Academic Press, San Diego, 2000).

    Google Scholar 

  4. The concept first appeared in Matzinger, P. Annu. Rev. Immunol. 12, 991–1045 (1994), but CST was not yet threatened. The claims against CST were exposed most prominently in connection with the publicity attendant on the publication of three papers from Matzinger's and two other labs: Ridge, A.P., Fuchs, E.J. & Matzinger, P. Science 271, 1723–1726 (1996); Sarzotti, M., Robbins, D.S. & Hoffman, P.M. Science 271, 1726–1728 (1996); and Forsthuber, T., Hualin, H.C. & Lehmann, P.V. Science 271, 1728–1730 (1996). See also the commentaries by Pennisi, E. Science 271, 1665–1667 (1996), Johnson, G. The New York Times p. C1 (March 26 1996) and Dreifus, C. The New York Times p. F4 (June 16 1998).

    Article  CAS  Google Scholar 

  5. Birgitta Stockinger has also pointed out the exaggeration of these claims for the overthrow of CST (Immunol. Today 17, 241 (1996)).

  6. Tauber, A.I. The Immune Self: Theory or metaphor? p. 93 (Cambridge University Press, New York, 1994).

    Book  Google Scholar 

  7. Podolsky, S.H. & Tauber, A.I. The Generation of Diversity: Clonal selection theory and the rise of modern immunology p. 369 (Harvard University Press, Cambridge, 1997).

    Google Scholar 

  8. Lederberg's name has been closely associated with CST because of his paper “Genes and antibodies” ( Lederberg, J. Science 129, 1649–1653 (1959)). In this, however, he gave genetic substance to Burnet's ideas, but added little to the core hypotheses of clonal selection.

    Article  CAS  Google Scholar 

  9. Schaffner, K.F. Discovery and Explanation in Biology and Medicine (University of Chicago Press, Chicago, 1993). See also Schaffner's discussion of CST in Theor. Med. 13, 175–216 (1992).

    Google Scholar 

  10. Breinl, F. & Haurowitz, F.Z. Physiol. Chem. 192, 45–57 (1930). They pictured the antigen as determining specificity by controlling the order of addition of the amino acids to the polypeptide chain of the nascent protein.

    Article  CAS  Google Scholar 

  11. Pauling, L. J. Am. Chem. Soc. 62, 2643–2657 (1940). Pauling argued that specificity was based upon an antigen-directed folding of the nascent polypeptide chain to achieve a uniquely molded combining site.

    Article  CAS  Google Scholar 

  12. Burnet advanced two instructionist theories. In the context of the times, the first—The Production of Antibodies (Macmillan, Melbourne, 1941)—involved adaptive enzymes, and the second— Burnet, F.M. & Fenner, F. The Production of Antibodies edn. 2. (Macmillan, New York, 1949)—postulated a genomic “indirect template”. These are outlined briefly in the text.

    Google Scholar 

  13. For a discussion of the dominant phases of the discipline, see Silverstein, A.M. Cell. Immunol. 132, 515–531 (1991).

    Article  CAS  Google Scholar 

  14. Jerne, N.K. Proc. Natl. Acad. Sci. USA 41, 849–857 (1955).

    Article  CAS  Google Scholar 

  15. Ehrlich, P. Klin. Jahrb. 6, 299–326 (1897); also published in English in Collected Papers of Paul Ehrlich edn. 2, pp. 107–125 (Pergamon, London, 1958). Ehrlich's theory is explored at length in Silverstein, A.M. Paul Ehrlich's Receptor Immunology: The magnificent obsession (Academic Press, New York, 2002).

    Google Scholar 

  16. Talmage, D.W. Annu. Rev. Med. 8, 239–257 (1957), see p. 247.

    Article  CAS  Google Scholar 

  17. Burnet, F.M. The Production of Antibodies (Macmillan, Melbourne, 1941).

    Google Scholar 

  18. Burnet, F.M. & Fenner, F. The Production of Antibodies edn. 2 (Macmillan, New York, 1949).

    Google Scholar 

  19. Medawar, P.B. J. Anat. 78, 176–199 (1944); Medawar, P.B. J. Anat. 79, 157–176 (1945); also Medawar, P.B. Brit. J. Exp. Pathol. 27, 9–14 & 15–24 (1946).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Owen, R.D. Science 102, 400–401 (1945).

    Article  CAS  PubMed Central  Google Scholar 

  21. Burnet, F.M. Changing Patterns: An atypical autobiography p. 206 (Heinemann, Melbourne, 1968).

    Google Scholar 

  22. These are not exactly the same as the five “slightly modernized and simplified” principles given in Burnet's 1968 book Changing Patterns: An atypical autobiography (p. 213), which now included the one cell–one antibody requirement.

  23. Burnet, F.M. The Clonal Selection Theory of Acquired Immunity p. 59 (Cambridge University Press, Cambridge, 1959).

    Google Scholar 

  24. A “Landsteiner-size repertoire” refers to the ability of the host to make an antibody to almost any chemical structure that may be attached as a hapten to a carrier protein, that is, an extremely large one.

  25. Burnet, F.M. Aust. J. Sci. 20, 67–69 (1957), see p. 68.

    Google Scholar 

  26. Lederberg, J. Science 129, 1649–1653 (1959).

    Article  CAS  Google Scholar 

  27. See, for example, M. Cohn's discussion in Progr. Immunol. 2, 261–284 (1974).

  28. See, for example, Dreyer, W.J. & Bennett, J.C. Proc. Natl. Acad. Sci. USA 54, 864–869 (1965); Hood, L. & Talmage, D.W. Science 168, 325–334 (1970). See also Cunningham, A.J. (ed.) The Generation of Antibody Diversity (Academic Press, New York, 1976).

    Google Scholar 

  29. Talmage, D.W. Science 129, 1643–1648 (1959).

    Article  CAS  Google Scholar 

  30. See Kindt, T.J. & Capra, J.D. The Antibody Enigma (Plenum, New York, 1984).

    Book  Google Scholar 

  31. Lederberg, J. Science 129, 1649–1653 (1959), see p. 1651.

    Article  CAS  Google Scholar 

  32. Burnet, F.M. Aust. J. Sci. 20, 67–69 (1957), see p. 54.

    Google Scholar 

  33. Lederberg, J. Science 129, 1649–1653 (1959), see p. 1652.

    Article  CAS  Google Scholar 

  34. Billingham, R.E., Brent, L. & Medawar, P.B. Nature 172, 603–606 (1953).

    Article  CAS  Google Scholar 

  35. Burnet, F.M. Science 133, 307–311 (1961); Burnet, F.M. The Integrity of the Body, (Harvard University Press, Cambridge, 1962); Burnet, F.M. Self and Not-Self (Cambridge University Press, Cambridge, 1969).

    Google Scholar 

  36. Wilson D. The Science of Self: A report of the new immunology (Longman, Essex, 1971); Klein, J. Immunology: The science of self-nonself discrimination (Wiley, New York, 1982).

    Google Scholar 

  37. Burnet, F.M. Self and Not-Self p. 30 (Cambridge University Press, Cambridge, 1969).

    Google Scholar 

  38. Burnet, F.M. in Conceptual Advances in Immunology and Oncology pp. 7–21 (Hoeber-Harper, New York, 1963). See also Szenberg, A. et al. Brit. J. Exp. Pathol. 43, 129–136 (1962).

    Google Scholar 

  39. See Nossal, G.J.V. & Mäkelä, O. Annu. Rev. Microbiol. 16, 53–74 (1962). See also Melvin Cohn's retrospective review of this debate in Annu. Rev. Immunol. 12, 1–62 (1994) p. 16ff and Kindt, T.J. & Capra, J.D. The Antibody Enigma (Plenum, New York, 1984).

    Google Scholar 

  40. Szenberg, A. et al. Brit. J. Exp. Pathol. 43, 129–136 (1962).

    Google Scholar 

  41. Trentin, J. & Fahlberg, W.J. in Conceptual Advances in Immunology and Oncology pp. 66–74 (Hoeber-Harper, New York, 1963). Burnet would say (p. 72), “This blows out the original clonal selection theory. I've said before that I don't believe the original clonal selection theory ...”.

    Google Scholar 

  42. Zinkernagel, R.M. & Doherty, P.C. Adv. Immunol. 27, 1–177 (1979).

    Article  Google Scholar 

  43. Bretscher, P.M. & Cohn, M. Science 169, 1042–1049 (1970); Langman, R.E. & Cohn, M. Scand. J. Immunol. 44, 544–548 (1996). See also Langman, R. The Immune System (Academic Press, San Diego, 1989).

    Google Scholar 

  44. Cohn, M., Langman, R. & Geckeler, W. Prog. Immunol. 4, 153–201 (1980).

    Google Scholar 

  45. Janeway, C.A. Immunol. Today 13, 11–16 (1992); Janeway Jr., C.A., Goodnow, C.C. & Medzhitov, R. Curr. Biol. 6, 519–522 (1996).

    Article  CAS  PubMed Central  Google Scholar 

  46. Matzinger, P. Semin. Immunol. 10, 399–415 (1998) and .

    Article  CAS  PubMed Central  Google Scholar 

  47. Jerne, N.K. Ann. Inst. Pasteur Immunologie C 125, 373–389 (1974).

    CAS  Google Scholar 

  48. Coutinho, A. et al. Immunol. Rev. 79, 151–168 (1984); Coutinho, A., Kazatchkine, M.D. & Avrameas, S. Curr. Opin. Immunol. 7, 812–818 (1995).

    Article  CAS  PubMed Central  Google Scholar 

  49. Lederberg, J., Science 129, 1649–1653 (1959), see p. 1649.

    Article  CAS  Google Scholar 

  50. These positions by Silverstein, A.M. & Rose, N.R, Grossman, Z. & Paul, W.E., Coutinho, A. & Cohen, I.R. are elaborated in Semin. Immunol. 12, 159–344 (2000). See also Silverstein, M. & Rose, N.R. Immunol. Rev. 159, 197–206 (1997).

    Article  Google Scholar 

Download references

Acknowledgements

I thank K. Schaffner for his helpful discussion of the structure of scientific theories and N. Rose for useful suggestions.

Author information

Authors and Affiliations

  1. Institute of the History of Medicine, Johns Hopkins School of Medicine, 1900 East Monument St, Baltimore, 21205, MD, USA

    Arthur M. Silverstein

Authors
  1. Arthur M. Silverstein
    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

Silverstein, A. The Clonal Selection Theory: what it really is and why modern challenges are misplaced. Nat Immunol 3, 793–796 (2002). https://doi.org/10.1038/ni0902-793

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni0902-793

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