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Adaptive Immunity: Chance or Necessity?
By: Donald L. Ewert
Discovery Institute
November 24, 2010


[Editor’s Note: In a series of posts on the BioLogos website, Kathryn Applegate has attempted to use the immune system as an alleged illustration of how the unguided and undirected processes of Darwinian evolution work. Her first two posts, “Adaptive Immunity: How Randomness Comes to the Rescue” and “Evolution and Immunity: Same Story,” appeared on May 13 and May 28, 2010, respectively. In these two posts, she points to two stages in the life of a B lymphocyte that appear to involve random changes in genetic information that allow the development of receptors (antibodies) that can detect specific pathogens, as evidence of a Darwinian process. Her argument is that if chance (random genetic changes) and selection (of antibodies with the best fit to a pathogen) can operate at the level of a cell, why can’t they produce complex biological systems at the organismal level, as Darwin proposed? Or in her words: “the adaptive immune system harnesses the power of randomness to protect the body from assaults it has never seen before” and antibody “production requires randomness at multiple levels.” This response to Applegate’s first set of arguments is from Donald L. Ewert, a research immunologist/virologist who spent much of his career studying the molecular and cell biology of the immune system as well as theories about its evolution. Dr. Ewert received his PhD from the University of Georgia in 1976. As a microbiologist, he operated a research laboratory at the Wistar Institute in Philadelphia for almost twenty years. The Wistar Institute is one of the world’s leading centers for biomedical research. His research, supported by National Institute of Health (NIH), National Science Foundation (NSF), and Department of Agriculture grants, has involved the immune system, viruses, and cellular biology. While Applegate’s arguments frame this issue in theological terms, Dr. Ewert’s response focuses on the scientific questions alone.]

Introduction

In her articles on the BioLogos website, Kathryn Applegate attempts to show how the mechanisms used by the adaptive immune system to generate a diversity of antigen receptors are an example of Darwinian evolution. She focuses on aspects of these mechanisms that she characterizes as "blind" and "random," stating, "Antibody production and evolution both involve mutation and selection." She further claims that "the adaptive immune system harnesses the power of randomness to protect the body from assaults it has never seen before" and antibody "production requires randomness at multiple levels." Applegate, however, frames her argument in theological terms, arguing that if "God uses natural processes -- indeed, even a 'blind' system for generating massive amounts of diversity," why could he not use the same mechanisms to "create life over long periods of time"?

I too believe that God can and does use natural processes to accomplish His will. But this debate is not about what God can or could do, but about having an accurate understanding of natural processes before drawing conclusions about their implications for the origin of life. It is essentially a scientific question and not religious. My goal in this response is not to address the question of how these complex mechanisms for B cell development originated. Rather, I will assess whether or not the mechanisms themselves resemble the processes posited by neo-Darwinian synthesis as the basis for "creating life over long periods of time" as Dr. Applegate claims.

When the "natural" mechanisms that generate antibody diversity are examined as an integrated system, it becomes apparent that, unlike Darwinian evolution, they are not "blind" or "random," but rather are highly regulated both temporally and physically to achieve specific purposes while maintaining the integrity of the surrounding genome. If these processes tell us anything, it is that the immune system leaves very little to blind chance, but instead is designed to allow organisms to adapt to changing environmental conditions without altering the integrity of their genome.

Yet Applegate is not alone in finding similarity between antigen receptor development and the mechanisms of Darwinian evolution. In 2001, Edward Max, a practicing physician and immunologist who comprehends the complexity of the immune system, posted an article on the Talk Origins website titled "The Evolution of Improved Fitness." He concludes that somatic mutation and selection of antibody genes "provide an unambiguous biological example of the power of random mutations and selection." I have commented on his assertions in an addendum* since the body of this article provides the basis for those comments, and because Max, unlike Applegate, does not invoke God as the agent of evolution.

A Brief Overview of Antibody Development

The vertebrate immune system is probably the most studied complex biological system in nature. It is essential for maintaining the integrity of organisms by detecting and destroying potential pathogens in a constantly changing environment.

One of the characteristics of the adaptive immune system of jawed vertebrates is the vast repertoire of antibodies with distinct antigen combining site specificities that are generated to detect all the thousands of antigens an individual may encounter in a lifetime. This is accomplished by one of the most amazing feats of molecular biology: relatively few (several hundred) germ-line genes produce millions of receptors, each with an ability to recognize different pathogen-associated antigens. In human beings, receptors are expressed on the surface of B and T lymphocytes, referred to as B cell receptors (BCR) and T cell receptors (TCR), giving them the capacity to detect virtually all pathogens an individual may encounter during their lifetime. To ensure this capacity, during their development both T and B lymphocytes undergo a complex process of receptor gene diversification and selection. Only antigen receptor development for B cells and the subsequent production of high affinity antibodies will be discussed here. T cell development and TCR repertoire selection that occurs in the thymus is beyond the scope of this essay, however general arguments regarding the nature of receptor diversification and selection, as observed in the jawed vertebrate species, remains applicable for both cell types. The process of generation of diversity (G.O.D.) of antigen receptors takes place at the earliest stage of lymphocyte development. Receptor diversity is generated by random combinations of three gene segments, the variable (V), diversity (D), and joining (J) segments, and by removal and addition of nucleotides at the V-J or V-D-J junctions. Both mechanisms maximize the diversity in the antigen binding region establishing a pool of B cells, each with distinct cell surface antigen receptors with sufficient diversity to recognize any antigen a human may encounter.

The second stage of receptor development occurs when a mature B lymphocyte detects a pathogen via its cell surface receptor and begins to proliferate. At this stage the antigen combining site of the BCR is fine-tuned to improve its ability to bind a specific antigen by an elegant process of somatic hypermutation (SHM) which inserts point mutations in the genes that encode the antigen-combining site. SHM alters the affinity of the combining site, and subsequent positive selection ensures that only cells with high-affinity receptors are allowed to live, and produce plasma cells which secrete the high-affinity antibodies, and to produce memory B cells that are retained for the next encounter with the pathogen.

Both of these stages of antigen receptor diversification involve non-templated changes in the DNA that generate new combinations of gene segments and amino acids in the antigen combining site. The question is whether the processes involved in antibody diversification are analogous to the process of random and unguided mutations that are the cornerstone of the neo-Darwinian model of evolution. I argue that they do not.

In the following sections, the processes of G.O.D. and SHM are described in the context of their molecular and cellular components. I will first briefly outline the processes that are programmed to allow changes in the variable region of the antigen receptor. This is not an open-ended process like evolution, but precisely controlled to prevent changes that would alter the hard-wired design of the immune system that is essential for its function. These apparently "random" processes are essential for the immune system to prepare receptors that anticipate and adapt to challenges from pathogens but are fundamentally different from Darwinian evolution.

Generation of Antibody Diversity is Unlike Darwinian Evolution

The intricate mechanism for generating antibody diversity from very few germline (existing) genes was discovered over thirty years ago. It involves shuffling gene segments and then fusing them to produce new combining sites for the antibody receptor displayed on individual B cells. How much of this process is pre-programmed and how much is random? Is this an example of the use of a "'blind' system to sustain and preserve life," as Kathryn Applegate suggests? The evidence from decades of research reveals a complex network of highly regulated processes of gene expression that leave very little to chance, but permit the generation of receptor diversity without damaging the function of the immunoglobulin protein or doing damage to other sites in the genome.

The most remarkable aspect of antibody production is the mechanisms that generate the binding site of the antigen receptor. The antigen receptor of B cells are proteins called immunoglobulins. They have an antigen combining site at one end that binds to foreign proteins (variable or V region) and a tail, or constant region (C region), at the other end that controls the interaction with other components of the immune system that are responsible for eliminating the foreign invader. The variable end of the BCR heavy chain is generated by the shuffling and joining of gene segments from separate pools of V (45), D (23), and J (6) segments per cell and the random deletion and insertion of nucleotides at the joining sites. This process is duplicated on the second (light) chain of the immunoglobulin gene. The combined diversity generated by recombination which is limited by the number of gene segments and by nucleotide exchanges, which are unlimited, produces a potential repertoire of about 1011 different receptor specificities. This process occurs during transcription of the DNA and involves a set of coordinated enzymatic reactions. The total number of available receptor specificities is limited by the number of B and T lymphocytes.

The joining of the V, D, and J segments is orchestrated by a set of enzymes, RAG-1 and RAG-2, which cleave the DNA at specific markers called recombination signal sequences (RSS), which flank each V, D, or J gene segment. The RAG-1/2 complex brings the segments together and the segments are joined using the general DNA repair mechanisms of the cell. The shuffling of the V, D, and J gene segments alone has limited ability to generate the necessary diversity of required receptor specificities. The unique feature of this recombinatorial process is the imprecise joining and inclusion of non-templated nucleotides at the junctions of the rearranged V, D, and J gene fragments. During the process, gaps in the joined DNA are filled using repair enzymes (polymerases) that insert nucleotides. These changes generate thousands of new ways of folding the proteins in the V region.

Confining RAG
The RAG proteins belong to a family of proteins called transposases. As the name implies, these proteins are able to cut and paste segments of DNA in the genome, which would otherwise be highly disruptive of normal operations, if not lethal to the organism. Thus, the transposon components of RAG have to be tightly controlled. To be precise, their physical and temporal deployment and function are tightly regulated and highly specific. Remarkably, they function only in jawed vertebrates to rearrange the V(D)J segments and only in the immature B cells (and T cell), while maintaining the integrity of other parts of the genome:

Expression of the Rag proteins is regulated at both the transcriptional and post-transcriptional levels, and co-expression of RAG 1 and RAG 2 is limited to lymphoid committed cells. In order to guarantee that the V(D)J recombinase acts only within the B and T lymphocyte lineage, the reaction is tightly regulated at multiple stages, including expression of the RAG genes themselves as well as controlled access of the recombinatorial machinery to its substrates within chromatin. (Hanasen, J.D. and McBlane, J.F)

B cell development: Irreducibly complex?

The RAG genes do not operate in isolation from the rest of the organism, but are part of a complex gene regulatory network which controls each stage of B cell development. The development of B cells from hematopoietic stem cells is a highly regulated multistep process. Each stage of development can be described on the basis of a constellation of gene expression patterns. Over 100 genes have been identified that are regulated to guide a multipotent hematopeitic stem cell down a pathway that leads to a functional B cell. Some of these are transcription factors which regulate gene expression while others actively suppress genes that are not appropriate for B cell function (Fuxa and Skok). In another recent review Nutt and Lee conclude:

instead of a simple transcriptional hierarchy, efficient B cell commitment and differentiation require the combinatorial activity of multiple transcription factors in a complex gene regulatory network....[T]he transcriptional network controlling B cell specification and commitment is not a simple linear cascade but involves multiple combinatorial inputs and feedback loops. [T]his process involves hierarchical forward steps and feedback loops, with this handful of factors being used in multiple contexts and distinct combinations. It has also demonstrated the surprising requirement for continual reinforcement of the commitment process throughout the life of a B cell.

The irreducible nature of this network has been demonstrated using knockout mice in which individual factors are eliminated (Fuxa and Skok). For example, RAG knockout mice are immuodeficient due to a lack of T or B lymphocytes. Thus failure to rearrange the receptors leads to cell death which has practical implications for survival. Similarly, removal of any of the factors that lead to Ig rearrangement or repress expression of lineage-inappropriate genes will affect B cell survival. Furthermore, this network of regulatory factors is critical for controlling processes that have the potential for causing harm to the genome and cellular function. As noted by Nutt and Kee, B cell transcriptional regulators are targets of mutation or deletion in mouse and human acute lymphoblastic leukemia:

These findings demonstrate that the function of these essential B cell transcription factors needs to be carefully controlled to avoid unwanted outcomes such as malignancy. (Nutt S and Kee B)

Rules of Recombination:

The process of V(D)J joining is also highly regulated to ensure the production of functional antibodies and to avoid distal chromosomal damage. The recombination of the V(D)J loci takes place only between gene segments flanked by RSSs with the additional requirement that space lengths of either 12 or 23 bases separate the joining DNA regions. This "12/23" rule prevents non-productive rearrangements by directing recombination of D to J, but not V to V or J to J. Also, recombination occurs sequentially with D to J recombination occurring prior to V to DJ on the heavy chain and heavy chain recombination preceding that of light chains. Each stage is controlled by specific transcription factors:

The transcription factors E2A and EBF control the initial DH-JH rearrangement step by activating expression of the RAG genes and promoting accessibility of the DH-JH region within the IgH locus. PAX, by contrast, induces large-scale contraction of the IgH locus; this is essential for the second stage of VH-DJH recombination. (Fuxa and Skok)

Additionally, recombination is restricted to the G0/G1 phase of the cell cycle in order to avoid chromosomal instability and associated lymphoid cancers.

In conclusion, the mechanism for generation of antibody diversity by V(D)J recombination is, unlike Darwinian evolution, highly regulated and carefully designed to permit expansion of receptor variability but within well defined limits. It is just the kind of system one would design for independent survival of an organism whose encounter with pathogens is not programmed.

Affinity Maturation and Somatic Cell Hypermutation: Intricately Controlled Processes that are Unlike Mutation and Selection

The second stage of B cell receptor development is initiated when a foreign protein enters our body and is detected by a circulating B cell using its cell surface antigen receptor (BCR). The BCRs that recognize these antigens improve their affinity (binding capacity) for the antigen by entering into a fine-tuning process called affinity maturation. This process ensures that highly effective antibody receptors are produced and released as cell-free antibodies into the circulation as the B cell completes its development. This increase in the strength of binding between a single antigenic determinant and an individual antibody combining site does not affect the specificity of the antibody, i.e. its ability to distinguish between small regions (epitopes) on the same antigen. Rather it allows for antibodies to remain bound to the foreign antigen for longer periods of time, thus giving the body a greater chance to clear the antigen-antibody complexes. The changes in the affinity of the receptor for an antigen results from the accumulation of nucleotide replacements that change the attractive and repulsive forces, mainly electrostatic forces, of the antigen combining site. The molecular mechanism for improving the affinity of the BCR is called somatic cell hypermutation (SHM), since the changes that are introduced in the DNA of the B cell (a somatic cell) cannot be passed on to the offspring of the animal.

Once the B cell begins to proliferate, each of the progeny cells undergoes a process which introduces mutations in the variable (V) (antigen binding) region of the immunoglobulin gene at a rate that is six orders of magnitude greater than the average spontaneous mutation rate. These mutations are designed to produce slight changes in the regions of the antigen combining site of the antibody, called the complementarity-determining region (CDR). As a result, the clonal progeny of the activated B cells each have slightly different affinity for the antigen. Each of the clonally derived B cells then pass through a gauntlet of cells presenting the antigen in the lymph nodes and spleen. B cells with receptors that bind weakly or not at all are programmed to die by apoptosis, and those that can bind will continue to proliferate antigen.

As the level of antigen decreases during the immune response, B cells with high affinity receptors are able to out-compete low-affinity receptor B cells for the scarce antigen and will continue to proliferate and differentiate to become plasma cells that secrete high affinity circulating antibodies, and also to become memory B cells that stay around waiting for another encounter with the antigen. This process of positive selection ensures that the most effective antibody and the cells that produce them (memory cells) are retained, such that the second encounter with the pathogen will be met rapidly with "tailored bullets" specific to the foreign invader.

On the surface, affinity maturation may appear to resemble a neo-Darwinian mechanism: random mutations produce an altered phenotype that causes the more "fit" to survive and the less fit to die. But that is where the similarity ends. Research during the past decade has revealed that SHM is an intricately controlled process that targets genetic changes to specific sites within the variable region of the rearranged immunoglobulin gene while protecting the rest of the genome. It is anything but an undirected process like Darwinian evolution.

Not By Chance: Controlling Affinity Maturation

Pathogen-directed activation of the immune response

The initiation of an immune response is designed so that the cellular and molecular components that are best equipped to deal with a pathogen are engaged. There are basically three response pathways. Non-protein antigens that have repeating carbohydrate units on their surface, such as are found on bacteria, can directly activate B cells. These B cell do not go through affinity maturation or class switch since multiple binding sites on the antigen make a strong bond with the B cell and the IgM class of antibody that is produced which has five receptors per molecule.

Responses to protein antigens fall into two classes, depending on whether the pathogen is intracellular or extracellular. Since intracellular antigens such as viruses are not accessible to circulating antibody, they activate cytotoxic T lymphocytes that are best equipped to kill them. This activation is directed by the Class I MHC antigen that is attached to the antigens as they are processed in cells. Extracellular proteins, which are best dealt with by circulating antibody, activate B cells to begin the process of affinity maturation and class switch that leads to the production of a monomeric IgG class of antibody. This latter pathway requires the assistance of a class of T lymphocytes called T helper cells (TH) and the interaction of Class II MHC proteins.

The collaboration with the TH cells at this stage of B cell development is critical to insuring that the antigen it has detected is indeed foreign and not one of the host organism's proteins. The B cell obtains confirmation to proceed by packaging or "presenting" a part of the antigen it recognized in a Class II MHC molecule for the T lymphocyte to "look" at. If the antigen receptor of the T lymphocyte, the TCR (which was also generated by V(D)J recombination), recognizes this antigen-MHC complex on the surface of the B cell, it in turn signals back to the B cell telling it to further differentiate into a plasma cell which produces the antibody protein, i.e., the cell-free form of the BCR. This double-key confirmation process prevents false starts, conserves energy, and reduces the risk that antibodies will be made against "self" antigens.

Subsets of TH cells are able to direct the production of specific classes of antibodies by B cells depending on the type of antigen. TH1 cells direct the production IgG antibodies that promote the ingestion and killing of microbes whereas TH2 cells direct the production of the IgE class of antibodies to pathogens such as helminthic parasites which are too large to be ingested by macrophages. The IgE coats the helminthes for destruction by eosinophils. This specialization of the adaptive immune response is not a random process and involves a matrix of intracellular and extracellular proteins that communicate information between the cells.

How do cells and pathogens find each other?

At the cellular level, as noted above, the process is initiated by the independent recognition of an antigen by two different classes of lymphocytes, a B cell and a T cell, each of which has an independent history of development that prepares them to cooperate with each other and regulate the immune response. This ensures that any potential B cell antigen (at least for T cell-dependent antigens) is confirmed by at least two antigen receptors before the immune system commits to producing high affinity class-switched antibodies. It is thus essential that these two lymphoctes, both of which have bound to the same pathogen, are able to find each other. With several million B and T cells distributed throughout the body, this is no simple task . While the chances of two cells encountering the same antigen and then coming together are very small, the activated B and T cells are programmed to release specialized proteins (chemokines) that attract one another within the confines of particular compartments found within lymphoid organs (lymph nodes and spleen). If these encounters were left to chance alone, the adaptive immune system could not mount a response in time to defend the host against a proliferating pathogen.

Controlling the destructive effects of AID

At the molecular level, SHM utilizes highly dangerous enzymes to make un-templated changes at very precise regions of the DNA. SHM is initiated by an enzyme, activation-induced cytidine deaminase (AID), which deaminates cytidine residues in single-stranded DNA that are exposed during Ig gene transcription. The resulting mutations (uridine/guanine mismatches) are then processed by mismatch repair enzymes and error-prone polymerases that normally correct errors in the DNA. In this case, however, they cause point mutations and substitutions to increase. The latter effect is the result of a pre-programmed subversion of a natural repair process, as will be discussed below.

Due to AID's potential to alter the information contained in the genome, its expression is highly regulated and targeted to specific regions in the antigen-combining site of the immunoglobulin gene called the complementarity-determining region (CDR). A recent paper by McBride et al. identified several levels of AID regulation, concluding:

Thus, AID appears to be controlled by multiple potentially overlapping mechanisms. We speculate that this type of combinatorial regulation facilitates fine control of AID level, which is required because small imbalances in its expression can result in catastrophic effects on genomic stability.

Control of AID activity is important for the following reasons:

First, it is essential to cause only subtle changes that alter the affinity the BCR for the antigen, but not the specificity of the antigen-combining site. AID induced changes are targeted to sites in the CDRs of the V region that form the antigen-combining site, when the protein is folded. These changes slightly alter the amino acid composition of the receptor, changing its affinity for the antigen. Other regions of the V gene that form the scaffolding for the V region, called framework regions (FWR), have a low mutation rate. Mutations in the FWR would damage the structure of the antibody and cause the B cell to initiate a program of cell suicide called apoptosis.

Second, the V region which contains the CDR genes is adjacent to the constant region gene segments, which are the business end of the immunoglobulin gene. The constant region of the antibody must reliably interact with other components of the immune system (Fc receptors) to execute destruction and removal of a pathogenic agent. Therefore, this region must be spared from genetic changes to preserve the ability of the antibody-activated effector mechanisms that destroy a pathogen.

Third, enzymes like AID that alter the genetic code have the potential to wreak havoc on the information contained in the genome. Therefore, their activity must be regulated to preserve the integrity of the organism. It is remarkable that mutations can occur at an exceptionally high rate to effect a positive improvement in a specific region of the antibody but be controlled so as not to damage the B cell's ability to survive and proliferate.

Enhancing mutations by subversion of DNA repair enzymes

The molecular mechanisms involved in SHM have only recently been discovered. The targeting of the hypermutation mechanism involves two steps that determine the location and frequency of preserved mutations. The initial step targets the AID to specific sites (called mutation hotspots) that support formation of mutations in CDRs while minimizing mutations in the FWRs. This is not a random process. The next step, following the introduction of AID mutations, is the activation of DNA repair enzymes (DNA polymerases) that normally repair the damaged (deaminated) nucleotides. However, due the intricate positioning of the C and G nucleotides in the V region, the enzymes' repair activity is subverted, making the changes permanent in the CDRs and leading to an increase in the number of mutations (Zheng et al).

The intricate nature of the regulatory control of this process is presented in a paper by Zheng et al. in which they identify nine special features of IgV genes that "precisely regulate SHM while retaining a functional amino acid sequence."

Evidence is presented that IgVH genes have evolved to support the initiation of SHM by AID, but to minimize the occurrence of C-to-T-induced amino acid replacements through intricate positioning of coding strand Cs. The complexity of these evolved biases in codon use are compounded by the precise concomitant hotspot/cold-spot targeting of both AID activity and the errors typical of Polh to maximize the accumulation of mutation in the CDRs and minimize mutations in FWRs. (Zheng et al., emphasis added. Note that the gratuitous use of the adjective "evolved" was not supported in this or any other referenced research report.)

Adaptive Immunity: Darwinism in Miniature or High-Tech Tinkering with Stasis?

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, Lönnig 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.

Lönnig 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.

Postscript: Response to Edward Max on TalkOrigins Immunity Article

One of the goals of Edwards Max's post at TalkOrigins is to refute a narrow claim of "creationists" that "random mutations are detrimental." But he goes further and, like Applegate, asserts that "clearly what we observe in the antibody response is evolution in miniature." Max believes that because affinity maturation of antibodies is an established biological process, it therefore carries more weight than the computerized model of evolution used by Richard Dawkins to demonstrate that "without the intervention of any intelligent designer...successive rounds of mutation and selection could be unambiguously shown to lead to increased fitness within living organisms." Like Applegate, Max draws inspiration from a naïve reductionist view of affinity maturation to give false comfort for his philosophical perspective.

I would agree that somatic hypermutation (SHM) is a good model for the efficacy of random mutation and selection in promoting "increased fitness." However, it is not a model for how Darwinian evolution works. In contrast to neo-Darwinism, the process of introducing un-programmed changes in the DNA during SHM is tightly regulated. Unless one is willing to accept that the entire process of evolution was pre-programmed (orthogenesis), as Applegate may, there is no room for teleology in modern evolutionary theory. The fallacy of the argument is that both the computer in Dawkins's scenario and the process of hypermutation show evidence of a design which permits the mutations to achieve a defined objective. Chance is bounded by the limits of the system in which it operates.

Furthermore no significant new information is being generated by SHM. The nucleotide changes are limited to replacing amino acids that alter the electric forces between two proteins. The specificity of the antigen receptor must remain unaltered or the B cell would be destroyed by cell-suicide or apoptosis.

As noted above, when the entire system of enzymes, cells, and regulatory networks is viewed as a whole, the hallmarks of design are apparent. Therefore, I find Max's concluding remarks astounding. After outlining the process of affinity maturation, he states: "And, to people who can appreciate the amazing complexity of life as a thing of wonder, the story of the generation of antibody diversity reveals in the immune system another example of an undesigned but beautifully functioning system." This view amounts to an article of faith, not science. Unlike Applegate, Max has ruled out, a priori, a designer, so all he has left is blind chance and a process, natural selection, that has never been shown to create anything but the simplest levels of complexity.

The question is not simply whether the immune system is designed, but whether there is any objective evidence in the universe of comparable design that did not have an intelligent "first cause." Max notes that "evolutionists believe that this resemblance is misleading (that complex mechanisms resemble mechanisms designed by intelligent humans); they hypothesize that astounding complex adaptations can arise from simple organisms by evolutionary mechanisms." The literature of comparative immunology provides no empirical evidence to support the latter hypothesis. However, there is ample evidence that complex programmed biological mechanisms like SHM resemble hierarchical computer-based systems. Tomorrow we may discover a self-evolving program emerging from a pool of carbon compounds, but until then, all complex programs I know of originated from an intelligent source.



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