In his essay (2011) on the history of Darwinian (or evolutionary) medicine, Jonathan Fuller describes potentially relevant interests and insights that preceded the famous paper by Nesse and Williams (1991) that is widely regarded as having catalyzed the resurgence of interest in applying evolutionary concepts and principles to medicine.  For example, the author describes aspects of Aristotle’s biological thinking as well as elements of the medical concepts of Hippocrates that anticipated some features of evolutionary medicine while possibly also impeding full acceptance of the evolutionary perspective on medical phenomena.  Fuller also mentions the writings of individuals such as A. C. Allison and Paul Ewald relating to infectious disease as relevant examples of pre-1991 applications of evolutionary thinking to medically-relevant problems.

There is, however, another medical field with a relatively long history (going back at least a century) of applying evolutionary principles and concepts to understanding phenomena of interest, immunology (Silverstein, 2003), which Fuller mentions only in passing.  Over 55 years ago, the Danish immunologist Niels Jerne put forth a new explanatory framework (1955) for antibody generation that explicitly referenced the central evolutionary concept of natural selection, although the precise mechanisms advocated truned out to be incorrect.  Two years later, MacFarlane Burnet (1957) and David Talmage (1957) explicitly used the notions of variation and selection with respect to antigen receptor-bearing cells to account for many features of antibody responses, which are of  significance in a wide array of diseases and conditions through involvement in pathogenesis, diagnostic tests, or therapies.

Both authors elaborated on their ideas in publications that arrived after an interval of another two years.  Burnet’s seminal book (1959) introduced the clonal selection theory of immune responses to a wide audience.  The debt to Darwin’s ideas was clearly evident in Burnet’s notion that antigen conferred on the lymphocytes with the best-matched receptors a reproductive advantage.  In his review in Science (1959), Talmage sought to explain the specificity of anti-sera for almost any foreign substance by reference to varying collections of antibodies each of which reacted, with meaningful affinities, with a range of antigens on the basis of chance.  Although Talmage’s ideas were extraordinarily similar to Burnet’s, and may have preceded them, Burnet received the preponderance of credit for the notions underlying the clonal selection theory (Forsdyke, 1995).  Individuals interested in the history of the development of these ideas and their even earlier precursors can consult such additional sources as the commentary by Silverstein (2002) on the concept of clonal selection and the reminiscences of imunologists active in the era of Burnet and Talmage (Cohn et al., 2007).

There is however an interesting twist on the notion that the ideas of individuals such as Jerne, Talmage, Burnet, Lederberg, Cohn and others placed the key phenomena of immunology into an explicitly evolutionary context.  Subsequent decades of research have both confirmed key elements of the clonal selection concept as applied to B-cell and T-cell immune responses but at the same time revealed the limitations of the original conception of immune responses as controlled solely by the presence and amount of antigen.  It is now abundantly evident that B and T lymphocytes integrate information from many receptors in addition to that provided by the antigen-specific receptors.  This additional complexity is entirely consistent with an evolutionary perspective which would support the idea that the immune system and immune system cells would use all relevant information in determining what and what magnitude of response to mount.  A successful evolutionary strategy necessarily entails both limiting the unproductive expenditure of energy available to an organism under threat as well as assuring an adequate expenditure of resources to respond to microbial threats and achieving this balance is made more likely by the utilization of the fullest range of pertinent signals.

In recent years, it has become increasingly apparent that the notion of an immune system as an entity clearly separable from the rest of the body is problematic.  Lymphocytes are functionally influenced not only by other lymphocytes and their soluble products but also by neurotransmitters, hormones, metabolic products from multiple sources, and mediators (e.g. cytokines and chemokines) produced by parenchymal cells.  For example, a recent commentary by Matzinger and Kamala (2011) cites numerous sources of evidence supporting the notion that the parenchymal cells of tissues contribute to determining the types (in terms of which serum antibody isotypes or T cell subsets and secreted cytokines predominate) of immune responses that are generated in those tissues, consistent with the evolutionary imperative that all physiological ‘systems’ be fully integrated. 


Fuller, J. Darwinian medicine: the past and present state of medicine’s unifying science. University of Toronto Medical Journal 2011 88(3):209-214.

Williams GC, Nesse RM. The dawn of Darwinian medicine. Q Rev Biol. 1991 Mar;66(1):1-22. Review. PubMed PMID: 2052670.

Silverstein AM. Darwinism and immunology: from Metchnikoff to Burnet. Nat Immunol. 2003 Jan;4(1):3-6. Review. PubMed PMID: 12496967. 

Jerne NK. The natural-selection theory of antibody formation. Proc Natl Acad Sci U S A. 1955 Nov 15;41(11):849-57. PubMed PMID: 16589759; PubMed Central PMCID: PMC534292. 

Burnet FM A modification of Jerne’s theory of antibody production using the concept of clonal selection. Aust. J. Sci. 1957;20: 67–69. 

Talmage DW. Allergy and immunology. Annu Rev Med. 1957;8:239-56. PubMed PMID: 13425332.

Burnet, F. M. The Clonal Selection Theory of Acquired Immunity (Cambridge Univ. Press, Cambridge, 1959).

Talmage DW. Immunological specificity, unique combinations of selected natural globulins provide an alternative to the classical concept. Science. 1959 Jun 19;129(3364):1643-8. PubMed PMID: 13668511.

Forsdyke DR. The origins of the clonal selection theory of immunity as a case study for evaluation in science. FASEB J. 1995 Feb;9(2):164-6. Review. PubMed PMID: 7781918. 

Silverstein AM. The Clonal Selection Theory: what it really is and why modern challenges are misplaced. Nat Immunol. 2002 Sep;3(9):793-6. PubMed PMID: 12205463.

Cohn M, Mitchison NA, Paul WE, Silverstein AM, Talmage DW, Weigert M. Reflections on the clonal-selection theory. Nat Rev Immunol. 2007 Oct;7(10):823-30. Review. PubMed PMID: 17893695.

Matzinger P, Kamala T. Tissue-based class control: the other side of tolerance. Nat Rev Immunol. 2011 Mar;11(3):221-30. PubMed PMID: 21350581.