Behe and Irreducible Complexity: Failure to Engage the Evidence

Behe argues that three aspects of the immune system—clonal selection, antibody diversity, and the complement system—are irreducibly complex and pose “massive challenges to a putative step-by-step evolution” (138).

Because we have already examined how antibody diversity is generated, we will limit our discussion to the evidence for how this ingenious system might have arisen. Much more could be said about other aspects of the innate and adaptive immune responses.

Recall that the genome contains several clusters of gene segments (red and green in the figure below), each of which has tens to hundreds of members. In B cells, proteins encoded by two Recombination ActivatingGenes (RAGs; blue) join together one member from each of the clusters by excising the DNA between them. The genome of each B cell is thus irreversibly altered in a unique way, depending on which segments are joined, such that the recombined gene segments code for the antigen-binding site of that B cell’s antibody.

RAG1 and RAG2 can’t bind just anywhere on the DNA; they recognize special sequences called Recombination Signal Sequences (RSSs; orange and yellow). RSSs are found flanking each gene segment, similar to special cues we use in grammar like capitalized words at the start of sentences and punctuation marks at the end. The RAG proteins home in on two randomly-chosen RSSs, bring them physically close to one another, and cleave the double-stranded DNA at both gene-RSS junctions. DNA repair machinery then repairs the break, joining the two gene segments together and the two RSSs together. The closed loop of DNA containing the RSSs gets removed, while the recombined gene is now ready to code for an antibody..

Behe’s mistaken assumptions

Behe argues that a minimally functional antibody diversity system needs three components: the antibody genes themselves, start and stop signals (like RSSs), and machinery to cleave and rejoin the DNA at the signals (like RAG and the DNA repair proteins). He can’t imagine how a multi-component system could have arisen by a gradual process, because each component is dependent on the other two for the whole shebang to work.

From the start, Behe makes the faulty assumption that antibody receptors incapable of recombination would be useless. He writes:

A primitive system with only one or a few antibody molecules would be like the propeller turning at one revolution per day: not sufficient to make a difference… Because the likelihood is so small for the shape of one antibody being complementary to the shape of a threatening bacterium—perhaps one in a hundred thousand or so—an animal that spent energy making five or ten antibody genes would be wasting resources…” (130-1).

What Behe fails to recognize is that many, many receptors in the immune system do their jobs without gene arrangements. These receptors bind to molecules commonly found on the surface of harmful microbes. In fact, some 90% of animal species on the planet don’t even have adaptive immunity, so antibody production by a gene rearrangement mechanism cannot be imperative for life (though humans and other vertebrates are quite dependent on it now). Contrary to Behe’s assumption, the first antibody genes could easily have had useful functions without RSSs and RAGs.

A family of molecules called the Toll-like receptors (TLRs) demonstrates the utility of having an all-purpose microbe detector that does not require millions of randomly-generated variants. TLRs, located on the surface of special immune cells in the blood, recognize bacterial cell walls and virus-specific DNA sequences, causing an all-out attack by the body on the foreign invader. In the process, some of the host tissue gets destroyed, but this collateral damage is a necessary cost to slow down the infection.

This so-called innate immune response—the first line of defense—occurs immediately upon infection, while antibodies take several days to produce. Without innate immunity, the animal might die before antibodies even have a chance to work. The fact that virtually all multi-cellular organisms have TLRs indicates how critical they are to survival.

If innate immunity is so effective that 90% of animals live just fine without adaptive immunity, it’s natural to wonder why some animals do have it. A major advantage it provides is an immunological “memory” of past infections, making it easier to fight off similar pathogens in the future. (Vaccines work on this principle—by exposing the body to inactivated or dead viruses, we give B cells a “heads up” so they can make and store antibodies before the real thing hits.) Antibodies also enable targeted killing of the pathogen, preventing further damage to the host by the non-specific innate immune response.

There’s another way to ask why some animals have an adaptive immune response: rather than seek to explain what added function or advantage it serves, we can ask about the mechanism by which it came to be in the first place.

Recall from Part I that the antibody production system has three interdependent components, as shown in Figure 1: 1) clusters of gene segments that can be combined in different ways to code for antigen receptors (red and green), 2) start and stop signal sequences between these gene segments, called RSSs (orange and yellow), and 3) machinery to cut and rejoin the DNA at the RSSs (blue). ). (Also necessary are DNA repair proteins, which rejoin the severed DNA strands, but they are not specific to this process and are thus not included in the diagram.)

The RAG genes, which carry the instructions for how to make the RAG proteins, are critical for antibody gene recombination. Surprisingly, these genes are found in jawed vertebrates, but missing in jawless vertebrates and invertebrates. Thus, jawed vertebrates can make a vast array of antibodies, but the other 90% of species on the planet cannot. What could account for this seemingly arbitrary division? We have very good evidence that at least 450 million years ago, an ancestor for all jawed organisms acquired the RAG genes. Where might those genes have come from?

Transposons on the move

To answer that question, I need to first tell you about a strange and fascinating feature of bacterial DNA. Bacteria have short segments of DNA, called transposons, which can jump from one location to another in the genome (See Figure 2). By itself, DNA can’t do anything—it just provides the information the cell needs to make proteins. Proteins do all the mechanical work in the cell, including interpreting the instructions in DNA. Transposons jump around by carrying instructions like this:

CUTHEREMAKESCISSORSANDGLUECUTHERE

The cell’s protein machinery reads the message and promptly makes the “scissors and glue” proteins. The scissors break the DNA at the “cut here” sequences (blue regions), and the glue pastes them back into the genome somewhere else. Where the transposon gets pasted is indeterminate—it may land within a gene, disrupting its protein-making instructions, or between genes, as shown in Figure 2.

A possible stepwise route to an irreducibly complex system

How does this relate to antibody gene recombination? Well, the RAG genes, which do the cutting to make functional antibody genes, are believed to have come from a transposon. The working model for how jawed vertebrates came to have antibody genes capable of recombination is known as the “transposon hypothesis.”

According to the hypothesis, a RAG-containing transposon invaded the genome of an early jawed vertebrate, probably through a bacterial infection. Such an infection would have occurred around 450 million years ago, shortly after the jawed and jawless vertebrate lineages diverged from their common ancestor.1

Suppose the transposon became inserted within a pre-existing, non-rearranging antibody gene (see Figure 3, step 1). (At this point in history, both vertebrates and invertebrates already had perfectly useful antibody-like receptor proteins—they just didn’t rearrange.) The inserted transposon sequence would have the effect of splitting the gene into two segments.

When the cell began to read the host gene, the bacterial RAG genes were interpreted instead. The resulting RAG proteins snipped out the transposon and pasted it into a new location in the genome (step 2). Over time the RAG genes became immobilized in the genome, never to jump again. The RAG proteins still recognized the RSSs, though, and continued to excise the DNA between them. Now, instead of cutting out the transposon, they cut out the short stretch of DNA separating the two halves of the original antibody gene (step 3). Thus, the gene segments were reunited and voila! The antibody gene could make protein again.

Suppose that in a future generation, the gene segments duplicated. This would create more gene segments, allowing some limited recombination to take place. Suppose that later still, the whole set of gene segments underwent duplication. Successive rounds of duplication and divergence would lead to the diversity of gene segments we see today (step 4).

But is there any evidence it happened this way?

This sequence of events might sound like an evolutionary “just-so” story, but it actually rests on solid evidence. First, the RAG genes themselves bear striking resemblance to known bacterial transposons. Most immunologists think the similarity is too great to have occurred by coincidence. The RAG1 and RAG2 genes are also physically very close to each other in jawed vertebrates. This would be expected if they arrived together from an external source like a transposon. In addition, the signal sequences (RSSs) to which the RAG proteins bind are closely related to those found associated with bacterial transposons.

Perhaps most convincing: the RAG proteins can not only excise DNA, but insert one stretch of DNA into anotherin vitro (in a test tube). The RAG proteins don’t normally do this latter step in cells; there they are only used for DNA cleavage. In bacteria, transposon proteins do both, and in the test tube, the vertebrate RAGs can do both! How could the RAG proteins function just like those from a transposon, unless they had originally been part of one?

Irreducible complexity by a gradual route—God’s route

Behe argues that design can only be detected when no possible stepwise route to an irreducibly complex system exists. Here I have described such a route (and a well-supported one at that) by which the antibody diversity generating system—one of Behe’s best examples of irreducible complexity—could have developed gradually. We’ll examine his response to the data next time.

To me, the fact that the transposon hypothesis has passed though decades of scrutiny and experimental testing leads me not to question God’s design of the adaptive immune system, but to marvel at his ability to create it gradually through a long but ultimately fruitful process. Immunologist Ronald Plasterk reflected poignantly, “We may owe our existence to one transposition event that occurred 450 million years ago.” In my mind, while it may have occurred by entirely natural processes, the evolution of our immune system was no accident. The fact that we can use science to read this small story from God’s book of nature is a special gift indeed.