Currently, I am on vacation near the beach in South Carolina.  Consequently, I have opted for a topic that is bit different than the majority of my monthly commentaries in that it focuses not on a recent original report but instead on a conceptual point made in a book over thirty years ago.  Nevertheless, after a somewhat less strictly scientific diversion I will come to the central idea at issue, which is arguably the premier exemplar of the relevance of evolutionary principles to the operation of the immune system on short time scales, by which I refer to the concept of clonal selection.  But first, we make a foray into the world of magazine publishing and the niche within that domain focusing on the arguably more intellectual readers.

Earlier this year, Prospect magazine (2013) sponsored a poll to identify the leading thinkers in the world.  After input from more than 10,000 voters in more than 100 countries, Richard Dawkins, the famous evolutionary biologist and implacable foe of organized religion, was named as the world’s number one thinker, whatever that may mean.  To my knowledge, the magazine editors did not query the voters to find out how many had read any of Dawkins’s books or academic papers, or understood evolutionary theory at more than a superficial level. 

What the preceding has to do with our subject today relates to Richard Dawkins’s book, “The Extended Phenotype: The Long Reach of the Gene,” a mostly rigorous exploration of the notion that genes can influence phenotypes that extend out into the world well beyond the accepted physical boundaries of the organism within which the genes reside.  This idea, although implicit in the more usual conceptions of gene action, requires considerable effort to be rendered explicit and comprehensible and may challenge the preconceptions of some.  In any case, it is of substantial interest to me.  I was reading this book because of specific, possibly novel, examples of extended phenotype that I hope to explore in future work and wanted to have a first-hand exposure to what I take to be the first thorough exploration of the notion that a gene can be associated with a phenotype of an arguably inanimate object constructed by the organism in which the gene is transcribed and translated or even a phenotype associated with another organism with which the former interacts.

On page 170 of my paperback edition of “The Extended Phenotype”, in the midst of a discussion of the ideas of E. J. Steele, on putative inheritance of a sort of an acquired immunological phenotype, Dawkins has cause to discuss the clonal selection theory of the Australian immunologist, virologist, and Nobel Laureate, Sir Frank Macfarlane Burnet.  This theory was enunciated at length in Burnet’s book of 1959 (“The Clonal Selection Theory of Acquired Immunity”).  Unfortunately, Dawkins seriously mischaracterizes the claims of the theory as articulated by Burnet (see http://evomed.org/?p=724 for my thoughts on the history of the idea of clonal selection).  Sadly, I cannot say that I am surprised despite my recognition that Dawkins is in general a careful, rigorous, and subtle thinker who might therefore be expected to grasp the beautiful logic of clonal selection of lymphoid cells in immune responses.  My lack of surprise stems from repeated encounters with evolutionists of considerable eminence who appear to struggle with penetrating the admittedly terminologically and conceptually challenging domain of immune phenomena.

Here is the key and somewhat extended passage on Burnet’s notion of immunological clonal selection, as interpreted by Dawkins, from “The Extended Phenotype” quoted verbatim:

“The problem is this.  The qualities that make for success in clonal selection would necessarily be those that give cells an advantage over rival cells in the same body.  These qualities need have no connection with what is good for the body as a whole, and our discussion of outlaws suggests that they might well actively conflict with what is good for the body as a whole.  Indeed, to me a slightly unsatisfactory aspect of the Burnet theory itself is that the selection process at its heart is contrived ad hoc.   It is assumed that those cells whose antibodies neutralize invading antigens will propagate at the expense of other cells.  But this propagation is not due to any intrinsic cellular advantage: on the contrary, cells that did not risk their lives smothering antigens but selfishly left the task to their colleagues should, on the face of it, have a built-in advantage.  …  Unadulterated clonal selection should favour selfish cells whose behavior conflicts with the best interests of the body as a whole.”

The errors contained in the above passage are several-fold and are delineated point-by-point below.

1)   It is not the case as alleged by Dawkins that there is in general a lack of connection between what is good for the body and what is good for the immune cells selected in the course of an immune response by antigen, the substance, generally foreign, that can directly pose a threat or is at least produced by a microbe that directly poses a threat to the body in question.  Clonal selection as currently understood applies primarily to two main classes of white blood cells known respectively as B and T lymphocytes.  For the purposes of this discussion and in the interests of relative brevity, I will confine my comments below to clonal selection involving B lymphocytes, the process that was recognized first, has been studied in enormous molecular detail, and was specifically what Burnet was referring to in his original enunciation of his theory.  What we now call T lymphocytes were not yet discovered as such in 1959.

2)   Contrary to the claim that the selection process in Burnet’s theory is contrived ad hoc, the selection process is well established to reside in measurable differences in affinity (strength of binding) of antigen-specific receptors displayed on the surfaces of B lymphocytes (for details at an introductory level, consult an immunology textbook).  Essentially, the B cells that express the receptors best able to bind to antigen are the ones that gain a survival and reproductive advantage directly by virtue of that superior recognition and the signal transduction processes enabled thereby.

3)   Propagation of B lymphocytes is not related directly to the ability of cells to “smother” antigens, or as immunologists might prefer to phrase it, neutralize (i.e., functionally inactivate), destroy, or hasten the clearance of antigen.  In the case of B lymphocytes, the cells themselves are not generally responsible for such mediation of immunity.  Instead, immunity is mediated by secreted forms of those antigen-specific cell surface receptors that are responsible for initial interaction of the B cell with antigen leading to cellular activation, differentiation, and proliferation. These secreted molecules are glycoproteins known as immunoglobulins or antibodies and they circulate in the blood.  Antibodies actually mediate immunity, generally at a comfortable distance from the B cells in which they were synthesized by the standard processes of gene transcription and translation, by neutralizing functions of parasite-encoded molecules or by engaging with one of a limited number of antigen-nonspecific effector mechanisms (that can sequester or destroy exogenous material) involving either other plasma proteins or other immune cells (i.e., not B cells).

The affinities of B lymphocyte cell surface antigen receptors and the corresponding antibodies for antigen do not correlate perfectly with effectiveness in mediating immunity due to the influence of other variables, such as which pathogen molecules are bound and precisely where they are bound by the antibodies.  However, if a set of distinguishable antibodies binds a relevant pathogen molecule at a propitious location, from the host’s point of view, there can be a clear relationship between affinity and the effectiveness of immunity to the pathogen, such that higher affinity antibodies are usually more effective, but more complex relationships between affinity and immunity are also possible.   

4)   The B lymphocytes with better adapted receptors do not “risk their lives” but instead gain a survival and proliferative advantage over other B lymphocytes expressing receptors that bind to antigen less effectively.  Perhaps Professor Dawkins was confusing B lymphocytes with neutrophils, which are white blood cells of the granulocyte subset as opposed to the   lymphocyte subset, that upon ingesting bacterial or other pathogens frequently undergo a form of cell death and thus seemingly sacrifice themselves for the good of their sister cells, including the B cells.  Antibodies collaborate with neutrophils in mediating immunity to many species of bacterial pathogens and other types of pathogens.  In any case, clonal selection does not apply directly to neutrophils, which do not express clonally-distributed antigen-specific receptors like B and T lymphocytes.

5)   Thus, clonal selection of B lymphocytes as originally delineated by Burnet and as currently understood more than fifty years later does not favor cells whose behavior typically conflicts with the best interests of the body as a whole.  There are, as is almost always the case in biology, exceptions where an advantage in clonal proliferation does not benefit the host but results in disease (such as an autoimmune disease like lupus or a B lymphocyte cancer like acute B lymphocytic leukemia), sometimes life-threatening.

6)   On the contrary, genes favoring B lymphocyte clonal selection on the basis of preferential binding of antigen by surface receptors clearly, on average, favor survival of the body as whole.  The weakness that Dawkins presumed he had found in the theory of clonal selection is actually a weakness of his understanding of the theory in spite of what I found on initial reading approximately forty years ago to be a clear and readily grasped exposition.

Therefore, as Professor Dawkins would no doubt agree in principle, in science and beyond it is always fair to bring a measure of skepticism and a questioning attitude to the claims of even the most eminent of expositors, even the recently anointed and celebrated number one thinker in the world, whatever that title may mean.  In this presumably isolated instance, the long-ago thoughts of the putative present-day number one world thinker are not of his usual quality, reliability, or accuracy.  Or, in the terminology popularized by Dawkins himself, this meme or set of memes deserves an unsentimental and permanent demise as an unfit entity unworthy of propagation, unlike those B lymphocytes expressing receptors with relatively high affinity for encroaching and potentially threatening antigen.

References

https://www.prospectmagzine.co.uk/magazine/world-thinkers-2013/#.UhkinH-wcwo  (last accessed on 8/24/13)

Dawkins, Richard. The Extended Phenotype. Oxford University Press, Oxford, 1982, 1989, p. 170.

Burnet, F. M. The Clonal Selection Theory of Acquired Immunity . Cambridge University Press, Cambridge, 1959.