[Editor’s Note: Today we present part five out of six in a series by microbiologist Donald L. Ewert. These posts are responding to the BioLogos Foundation’s blog where Kathryn Applegate argued that “random” processes that generate antibodies illustrate the creative power of Darwinian evolution. Previous installments of Dr. Ewert’s rebuttal can be found at the following links: Part One, Part Two, Part Three, and Part Four.]
Kathryn Applegate’s main point is that if “natural” processes — which she characterizes as “random” and “blind” — can be used to generate antibodies, the same mechanisms presumably could be used to “create life over long periods of time.”
The question addressed here is: Do the terms “random” and “blind” accurately describe the mechanisms for generating diversity via V(D)J rearrangement and affinity maturation by SHM? Based on our current knowledge about antibody development, briefly described above, I contend that what may appear to be a random process is actually highly orchestrated at many different levels — organismal (developmental), tissue (lymphoid tissues), cellular (B cells, helper T cells, antigen presenting cells), protein (MHC, enzymes, transcription factors, cytokines) and genetic (C and G placement, chromosomal accessibility). The function and structure of these highly specialized components must be coordinated to produce a specific antibody in response to an antigenic challenge. Independent developmental programs of the cell lineages, tissues, and organs must be controlled to ensure that their location and structure permit the interactions required for development of the B cell and antibody production. Therefore the combined functional and developmental aspects of antibody production involve a hierarchal matrix of regulatory controls that orchestrate the entire process. Antibody development is certainly not a “blind” or “random” process. What on the surface may seem like a random process is in fact an elegantly designed and regulated process.

Applegate’s approach to these complex mechanisms is an example of a reductionism that has dominated the field of biology, including evolutionary biology, for over a century. By focusing on the narrow aspects of structure and function, the context that operates to control and integrate them in an organism is overlooked. When viewed as a system, the highly complex, integrated and regulated operation of the immune system bears little resemblance to the undirected, blind processes that are theorized to drive Darwinian evolution.
What is “natural”?
Applegate argues that the processes of G.O.D. and affinity maturation involve the same “natural” processes involved in Darwinian evolution, i.e., undirected random mutations resulting in variable phenotypes that are selected based on their survival advantage. On the surface her narrow comparison may seem reasonable, but from the vantage of systems biology the process is anything but “random.” The mutations in question are not randomly dispersed throughout the genome but directed to regions within the V gene segments. Moreover, the process of G.O.D. is regulated at every step during BCR development. The entire process is programmed to achieve the goal of antibody production, and to prevent B cell lymphoma and autoimmunity. Purportedly, Darwinian evolution has the ability to produce new biological features. But no new novel structures are ever produced in this process as evidenced by the fact that sequence analysis and computer modeling show that the binding site (V) regions of the immunoglobulin genes of humans are similar to the most evolutionary distant vertebrate species, sharks (Marchalonis et al.). Furthermore, the intricate systems that control the development of antibody diversity are just as “natural,” and can provide greater insights for research on how living systems are designed to adapt to change.
The processes involved in BCR development in fact are not analogous to the Darwinian evolutionary model but rather suggest the work of a programmer who developed a complex program to sustain and protect the biological integrity of each organism in a constantly changing environment.
Implications: Change has limits
Any scientist committed to the pursuit of truth must follow the evidence where it leads. Can the elegant processes that regulate antibody development provide insights for how living organisms may be designed to adapt to changes in the environment? Melvin Cohn recently commented in the affirmative: “In my view, it is by revealing the elements and principles of somatic evolution that comparative immunology will some day have its greatest impact on biological thinking.” (Cohn, 2006)
If we take the data from the immune system at face value, a principle emerges: biological change is orchestrated within limits. The ability to both anticipate (generation of Ig diversity) and adapt (affinity maturation) to changes in the environment while maintaining the integrity of the system is likely a designed feature of organisms. Such change is anticipated to be limited to strategic sites in the genome, allowing the organism to adapt to its environment while maintaining its integrity. A recent paper by Li et al. provides evidence that the mechanism of targeting mutations found in Ig V gene hypermutaion may be deployed more generally to affect adaptations in other biological systems:

One of the most striking findings in our present study is that not only in the antibody-combining site but in other protein-protein interfaces almost all of the affinity-enhancing mutations are located at the germline (mutation) hotspot sequences (RYYW or WA)… (Li, 2010)

Their findings indicate that protein-protein interfaces which are important in the regulation and establishment of macromolecular complexes and networks use the same basic strategy to target sites of plasticity. Thus the strategic placement of mutation hotspots may be a design feature of many functional and structural elements of biological systems that allow organisms to adapt to internal and environmental changes.
This concept of bounded change also predicts that the essential characteristics which distinguish higher taxa will remain stable and be evident in the comparison of extant species with organism in the fossil record. Stephen Jay Gould and Niles Eldredge reported in 1977 that stasis is a dominant feature of the history of most fossil species. More recently, L�nnig and Saedler, in a review article in Annual Reviews of Genetics, stated that “the richness and often extraordinary quality of the fossil record … leave no reasonable doubt in the minds of most qualified observers as to the existence of stasis.”
Ironically, the molecular mechanisms found in the regulation of BCR development, rather than supporting a theoretical model of unguided evolutionary change, as Applegate proposed, may provide insights into how stability is maintained on the level of higher taxa while allowing for adaptation and limited diversity within taxonomic limits.
References
Cohn M, 2006. “What are the commonalities governing the behavior of humoral immune recognitive repertories?” Developmental and Comparative Immunology 30: 19-42.
Fuxa M and Skok J. 2001, “Transcriptional regulation in early B cell development.” Current Opinion in Immunology. 19: 129-136.
Gould S and Eldridge N, 1977. “Puncturated Equilibria: the tempo and mode of evolution reconsidered.” Paleobiology 2:115-151.
Hansen, JD and McBlane, JF. 2000. “Recombination-Activating Genes, Transposition, and the Lymphoid-Specific Combinatorial Immune System: A Common Evolutionary Connection.” Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 111-135.
Li B, Zaho L, Wang C, Guo H, Wu L, Zhang X, Qian W, Wang H, and Guo Y. 2010. “The protein-protein interface evolution acts in a similar way to antibody affinity maturation.” J. Biological Chem. 285:3865-3871.
L�nnig W-E and Saedler H. 2002. “Chromosome Rearrangements and Transposable Elements.” Annu. Rev. Genet. 36: 389-410.
Marchalonis JJ, Jensen I, and Schluter SF. 2002. “Structural, antigenic and evolutionary analysis of immunoglobulins and T cell receptors.” J Mol Recognit. 15: 260-271.
McBride KM, Gazumyan A, Woo EM, Schwickert TA, Chait BT, and Nussenzweig MC. 2008. “Regulation of class switch recombination and somatic mutation by AID phosphorylation.” Journal of Experimental Medicine. 205:2585-2594.
Nutt S and Kee B. 2007. “The Transcriptional Regulation of B cell lineage commitment.” Immunity 26: 715-725.
Zheng N-Y, Wilson K, Matthew J, and Wilson P. 2005. “Intricate targeting of immunoglobulin somatic hypermutation maximizes the efficiency of affinity maturation.” J. Exp. Med. 201:1467-1478.