Donald L. Ewert

[Editor’s Note: This is the final post in a six-part a series from microbiologist Donald L. Ewert, where he argues that the processes used by our immune system to generate antibodies are anything but “random,” and do not serve as an example of Darwinian evolution. Other posts in this rebuttal can be found at: Part One, Part Two, Part Three, and Part Four, and Part Five. In the first five posts, Dr. Ewert responded to Kathryn Applegate of the BioLogos Foundation. In this sixth post, he responds to similar arguments from Edward Max at TalkOrgins that antibody generation is “evolution in miniature.”]

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 naíve reductionist view of affinity maturation to give false comfort for his philosophical perspective.

[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.

[Editor’s Note: This is part four of a six-part series from microbiologist Donald L. Ewert responding to Kathryn Applegate, of the BioLogos Foundation, in her arguments that the vertebrate adaptive immune system illustrates the claimed creative the Darwinian mechanism. Previous parts of Ewert’s response can be found at the following links: Part One, Part Two, Part Three.]

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 (T_H) and the interaction of Class II MHC proteins.

[Editor’s Note: This is part three of a six-part response from microbiologist Don Ewert to Kathryn Applegate’s arguments that the vertebrate adaptive immune system is an example of Darwinian evolution in action. Part one can be found here, and part two is here.]

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.

[Editor’s Note: This is part two of a response from microbiologist Don Ewert to arguments from BioLogos’s Kathryn Applegate that our immune system shows the creative power Darwinian evolution. Part one can be found here.]

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.

[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”?