in Christian Perspective
The Origin of Antibody Diversity
Gordon C. Mills*
One Fleet Landing Blvd.
Atlantic Beach, FL 32233
From: Perspectives on Science and Christian Faith 51.4 (December 1999): 254-256.
A recent article in Science News began with the following statement: "Immunologists have wrestled with the origin of GOD for several decades."1 The author of the article went on to explain that: "This spiritual-sounding acronym stands for Űgeneration of diversityÝ and emerged in the jargon of scientists after their realization in the 1970s that the human immune system manufactures tens of millions of distinct antibodies." The above quotations, the articleÝs title, "The Accidental Immune System," and its subtitle "Long ago, a wandering piece of DNAˇ perhaps from a microbeˇcreated a key strategy," suggested to me that the process of antibody formation merited further examination from a theistic viewpoint.
In a 1995 PSCF paper proposing a theory of theistic evolution as an alternative to the naturalistic theory, I chose not to include antibody formation in my theory.2 I noted: "Our understanding of this fascinating process is not sufficiently complete for me to suggest which genes, or portions of genes, might involve new genetic information."3 Now I believe my understanding of this process, too, may be readily incorporated into my design theory of theistic evolution. As proposed in 1995, this theory is as follows:
Í in the history of the origin and development of living organisms, at various levels of organization, there has been a continuing provision of new genetic information by an intelligent cause.4
In a 1998 PSCF paper, I considered the possible role of protein modules in a theory of theistic evolution.5 As defined in that paper, protein modules are usually 80˝250 amino acids long, contiguous in sequence, and used as building blocks in functionally diverse protein molecules. The diversity of antibodies is a consequence of the building up of antibody genes in mature lymphocytes from smaller gene segments. Hence antibody gene formation is a special case of modular transfer of gene segments. A major difference in modular transfer for antibody formation is that this process is occurring whenever the immune system is challenged by a foreign substance. The modular transfer discussed in my earlier paper would occur only rarely over extended periods of geologic time. The two modular processes, i.e., modular transfer in the building of new protein molecules and modular transfer in formation of antibodies, appear to have many similarities in regard to necessary recognition factors and enzymes.
Mechanisms of Antibody Formation
In order to evaluate possible roles of chance and design, let us consider in more detail what occurs in antibody formation, and how the tremendous diversity of antibodies is achieved.6 The cells responsible for production of antibodies are the lymphocytes, a particular type of white blood cell. They produce protein antibodies in response to foreign substances (antigens) taken into the body. A unique aspect of this process is that the organism does not need prior exposure to the antigen to produce an antibody that will combine with it. A million different synthetic chemical compounds may serve as antigens and cause the production of antibodies. Since the genetic information for protein production resides in the genes, it might appear that a corresponding number of genes would be required to produce a million different antibodies. By using modular gene segments, however, antibody diversity may be achieved with a much smaller gene pool.
The antibodies all fall into a group of plasma proteins known as immunoglobulins, of which there are five major classes (IgG, IgA, IgM, IgD, and IgE). Of these, I will consider only IgG in some detail. Each IgG molecule is a tetramer and consists of two heavy (H) and two light (L) chains. The L chains are of two types (designated by Greek letters k and l), each 214 amino acid residues in length. Of these amino acids, 108 at the N-terminus are variable and the remaining 106 are constant. By variable, we mean that if L chains of a particular type were isolated from a pool of lymphocytes and sequenced from the N-terminus, we would find variations in amino acids at a given position for the first 108 amino acids of the molecule, with no variation in the remaining portion. The two IgG H chains are of the t type, with 446 amino acid residues; of these, 108 at the N-terminus are variable and the remainder are constant. Other immunoglobulins may have other types of H chains, designated as a, m, d, or e.
The finding of variable amino acids in the L and H chains of immunoglobulins is unique among protein molecules. This variability can now be explained in the following manner. Each mature lymphocyte contains three different types of gene segments coding for the variable portion of the H chain, a V (for variable), a D (for diversity), and a J (for joining). In the lymphocyte stem cell, however, there are several hundred different gene segments for the V portion of the H chain; about fifteen different gene segments for the D portion; and about five different gene segments for the J portion. During the maturation of the lymphocyte, only one of each type is selected. In different lymphocyte cells, however, the single, V, D, and J gene segment retained after cell maturation appears to be randomly selected. Hence, any pool of mature lymphocytes would contain some with each of the original V gene segments, some with each of the original D gene segments, and some with each of the original J gene segments. Further, in the process of lymphocyte maturation, these three different types of gene segments are joined (V-D-J) to complete the variable portion of the H chain gene. This principle of joining gene segments is illustrated in Fig. 1. The constant portion of this gene is formed from three additional gene segments (CH1, CH2, and CH3) plus a small hinge gene segment. The L chain gene formation differs slightly from that of the H chain since no D gene segments are included, but the principle remains the same: i.e., translocation of different gene segments to form the complete gene.
Two other factors further increase the possible gene diversity of H and L chains. These are (1) V and J gene segments may be spliced in several different joining frames, and (2) a terminal deoxyribo- nucleotidyl transferase may insert extra nucleotides between the V and D gene segments of the H chain gene. Altogether, the different joining possibilities for the various portions of the L and H chains of the five classes of immunoglobulins, together with the variable joining frames and chain lengthening, give the genes for the five different immunoglobulins the possibility of producing something like 108 different antibodies. This is clearly enough to account for the 106 postulated different antibodies.
An additional aspect of antibody formation, critical for the successful production of antibodies, is recognition of an antigen by a particular lymphocyte immunoglobulin. For this recognition, each lymphocyte has a surface receptor made up of the variable portion of an immunoglobulin molecule that spans the lymphocyte membrane. The matching of this receptor with a foreign substance (antigen) triggers production of additional antibody molecules to meet the requirement for inactivation of the foreign substance.
Chance or Design?
Although certain aspects of this fascinating process of antibody formation may be due to random chance events (e.g., the selection for each cell of the one active V gene segment, the one active D gene segment, and the one active J gene segment), many other aspects clearly require genetic information. A few of these are: (a) only gene segments belonging to the V, D, and J types are joined together. Other sequences are rejected. There is a clear requirement for specific recognition sites adjacent to the V, D, and J segments for the cleavage and joining reactions to occur. These recognition sites range from 7 to 23 nucleotides in length. (b) There is a requirement for genetic information in the nucleotide sequences of the many different V, D, and J gene segments found in the lymphocyte stem cell. (c) There is surely a genetic requirement for the various controlling factors that permit the cleavage and joining events to occur in a synchronous manner; and (d) there is the genetic information requirement in the nucleotide sequences for the many different specific enzymes involved in these processes. These would include the nucleases carrying out the initial cleavage of the stem cell immunoglobulin gene to free the V, D, and J gene segments, as well as the ligases or nucleotidyl transferases required for the final rejoining of the single V, D, and J gene segments. Recent studies have identified two specific proteins, RAG1 and RAG2, that play a role in the splitting and joining of the V, D, and J gene segments.7 The information requirement would also include other enzymes participating in the activation of precursor molecules and cofactors.
Did this whole process come about suddenly in the jawed vertebrates 300 million years ago as a consequence of incorporation of a "wandering trans- posase" from an unknown virus or bacterium into a vertebrate geneˇas suggested in the Science News article?8 That seems unlikely. The author notes that there is only the slightest resemblance between the RAG proteins and known bacterial transposases; translocation of a transposase by itself would not produce antibodies.
I have tried to demonstrate that the system of antibody formation is much too complex to be accounted for by a simple transposase gene transfer from a virus or bacterium to a vertebrate organism. I believe that the system of antibody formation clearly qualifies as "irreducibly complex" as defined by Behe: i.e., "a simple system composed of several well-matched interacting parts that contribute to the basic function wherein the removal of any one of the parts causes the system to effectively cease functioning."9 The interacting parts in this case would be the many immunoglobulin gene segments, the recognition factors, and the enzymes required for translocation of the different gene segments. In addition, they would necessarily include mechanisms for formation of the immunoglobulin surface receptor, which is critical to the production of adequate amounts of antibodies.
1J. Travis, "The Accidental Immune System," Science News 154 (1998): 302˝3.
2G. C. Mills, "A Theory of Theistic Evolution as an Alternative to the Naturalistic Theory," Perspectives on Science and Christian Faith 47 (1995): 112˝22; also see ____, "Theistic Evolution: A Design Theory Utilizing Genetic Information," Christian ScholarÝs Review XXIV (1995): 444˝58.
5G. C. Mills, "Possible Role of Protein Modules in a Theory of Theistic Evolution," Perspectives on Science and Christian Faith 50 (1998): 136˝9.
6The primary source for this discussion is: L. Stryer, Biochemistry, 3d edition (New York: W. H. Freeman & Co., 1988), 897˝911.
7A. Agrawal, Q. M. Eastman, and D. G. Schatz, "Transposition Mediated by RAG1 and RAG2 and its Implication for the Evolution of the Immune System," Nature 394 (1998): 744˝51.
8Travis, "The Accidental Immune System," 303.
9M. Behe, DarwinÝs Black Box: The Biochemical Challenge to Evolution (New York: Free Press, 1996), 39.