Adaptive Immunity: Chance or Necessity? - Evolution News & Views

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Adaptive Immunity: Chance or Necessity?

[Editor's Note: Earlier this year, in a series of posts on the BioLogos website ("Adaptive Immunity: How Randomness Comes to the Rescue" and "Evolution and Immunity: Same Story"), Kathryn Applegate argued that the "random" processes of the vertebrate adaptive immune system serve as an example of how Darwinian mechanisms can generate biological complexity. Today, Discovery Institute presents part one of a response to Dr. Applegate 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 Ph.D. 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, National Science Foundation, and Department of Agriculture grants, has involved the immune system, viruses, and cellular biology.]

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.

[This article will be continued on Evolution News & Views in a series of subsequent posts.]