Assessing Applegate's Attack
by BilboIt's beginning to look like professor Michael Behe won't be responding to Dr. Kathryn Applegate's critique of his claim that the [adaptive] immune system did not evolve by strictly Darwinian means. So although I am not a biologist, I thought I would offer my reactions. First, let me make it clear that I like and respect the people at Biologos, including Dr. Applegate. They have a good spirit about them and I enjoy commenting there. So my rebuttal is offered in a respectful, friendly manner, and I hope it is taken that way.
In chapter 6 ("A Dangerous World") of his book Darwin's Black Box, Behe writes,
…I have looked at three features of the immune system — clonal selection, antibody diversity, and the complement system — and demonstrated that each individually poses massive challenges to a putative step-by-step evolution. But showing that the parts can't be built step by step only tells part of the story, because the parts interact with each other….an animal that has a clonal selection system won't get much benefit out of it if there is no way to generate antibody diversity. A large repertoire of antibodies won't do much good if there is no system to kill invaders. A system to kill invaders won't do much good if there's no way to identify them. At each step we are stopped not only by local system problems, but also by requirements of the integrated system. p.138
Dr. Applegate's offers a critique of Behe in three parts. In
Part 1, she writes,
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 , 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.
I think Applegate has scored a point, but it's not clear how big a point. Given that jawed vertebrates already had an innate immune system that produced a few antibodies, would producing a few more antibodies make enough of a difference to be selectively advantageous? I'll return to this when I discuss her part 3. Meanwhile, the rest of Behe's second thesis, that the clonal selection and complement systems seem to be interdependent remains intact. More importantly, Behe's first thesis, that the clonal selection, antibody diversity, and complement systems are irreducibly complex still hasn't been addressed.
It's in Part 2 that Dr. Applegate offers her hypothesis on how "the antibody diversity generating system—one of Behe’s best examples of irreducible complexity—could have developed gradually."
Applegate agrees with Behe that
…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).
Applegate then presents the transposon hypothesis, that a section of a bacterial genome including RAGs and RSSs jumped to the genome of a jawed vertebrate. There appears to be strong evidence for the similarity between the RAGs of bacteria and vertebrates, so such a hypothesis sounds initially plausible. Once it jumped,
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; see Part I.) 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).
First, it's important to realize that Applegate only discusses one of the three systems that Behe has presented: the antibody diversity system. So even if her argument is sound, Behe's arguments that the clonal selection and complement systems are irreducibly complex remain completely intact.
Second, I think one could argue that what we have is one irreducibly complex system — RAGs + RSSs — becoming another — RAGs + RSSs + antibody genes. This is not a direct Darwinian pathway. No two parts of the system create antibody diversity. It takes all three. So we would have an indirect Darwinian pathway. Behe has admitted that such systems can arise. He just thinks the probability for such systems diminishes the more parts that are needed in order to achieve selective advantage. Are there reasons to think that Applegate's hypothesis is improbable? Perhaps. Here are my thoughts:
If the RAG was inserted randomly into a genome of a jawed vertebrate, would it likely have some selective advantage or become fixed in the population by genetic drift? The fact that RAGs do not show up anywhere in the genomes of jawed vertebrates, except in genes for the immune system suggests that neither was the case.
In that case, the hypothesis seems to depend upon the very lucky occurence of the transposon first landing in the genes for the immune system. What are the odds of that happening?
But now given that amazing scenario, what would be the selective advantage? How many different antibodies would need to be produced to confer selective advantage?
In Wikipedia's article on the adaptive immune system, we are told,
A very small proportion (less than 0.01%) of the total lymphocytes are able to bind to a particular antigen, which suggests that only a few cells will respond to each antigen
So for an immune system (such as ours) that produced a trillion different antibodies, it would take one hundred million different antibodies in order to make sure that some antibody binds to a particular antigen.
So there seem to be some reasons to be doubtful that the transposon hypothesis will result in an immediate selective advantage. If there was no immediate selective advantage, what are the odds that the mutation would have survived long enough to achieve such an advantage?
And there may be other problems that I have not even thought of.
In Part 3, Applegate takes Behe to task for supposedly ignoring the vast body of scientific literature that deals with the transposon hypothesis. But it's not at all clear that Behe has ignored it. What seems more likely, as Behe remarked in his letter to Science, is that he recognizes (as apparently Applegate does not) that "speculation is not data, let alone an experimental result. Students are poorly served when they are not taught to distinguish among them."
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July 17th, 2010 at 9:38 pm
"speculation is not data"
Behe's absolutely right. That's why evolution is not science. It's based on speculation, assumptions, and wishful thinking.
Comment by nobody — July 17, 2010 @ 9:38 pm
July 17th, 2010 at 10:00 pm
Hi Nobody,
Let's make a distinction between common descent, for which Behe (and I) think there is very good evidence, and evolution by random mutation and natural selection or genetic drift, for which Behe (and I) think there is very little or weak evidence.
For example, I think it is very likely that RAGs are descended from bacteria, but unlikely that it all happened via random mutations.
Comment by Bilbo — July 17, 2010 @ 10:00 pm
July 18th, 2010 at 1:15 pm
Hi Bilbo,
If the RAG was inserted randomly into a genome of a jawed vertebrate, would it likely have some selective advantage or become fixed in the population by genetic drift? The fact that RAGs do not show up anywhere in the genomes of jawed vertebrates, except in genes for the immune system suggests that neither was the case.
I'm not sure about that. As Applegate notes:
The RAG genes, which carry the instructions for how to make the RAG proteins, are critical for antibody gene recombination
Increased capacity for recombination greatly increases the genetic variance. And as RA Fisher demonstrated in The Genetical Theory of Natural Selection, the rate of fitness increase in a population is proportional to its genetic variance. So it's possible the insertion of the RAG genes had a significant positive selective effect.
Comment by KC — July 18, 2010 @ 1:15 pm
July 18th, 2010 at 8:04 pm
Random points you'd have to understand to even begin to talk sense about this topic, which you are definitely not doing at the moment.
1. The ancestor of RAG was a transposon. Transposons are common in many genomes, including humans. They don't have to benefit the organism to persist, because they replicate themselves like viruses. A big chunk of your genome, right now, it composed of transposons and their remnants — probably more of your genome than codes for the standard protein-coding genes!
2. There is ubiquitous evidence that receptor diversity is selectively beneficial. First, there's the logic: bacteria etc mutate quickly. The more diverse defense receptor proteins you have, the more likely that one of them will detect the intruder. Second, there is the widespread fact that organisms that don't have rearranging receptors instead have big collections of non-rearranging receptors, and these are under strong diversifying selection (as are our receptors, e.g. MHC — they are the classic case of diversifying selection!). Third, many different groups have developed different ways to have somatic enhancement of receptor diversity — the vertebrate RAG system is just one of these.
4. This evidence came in only in 2006, but there is actual direct evidence that the transposon-derived ancestors of the RAG genes were in deuterostome genomes *before* they were used to generate receptor diversity. E.g. the genes are found in sea urchins and other non-vertebrate deuterostome genomes. So the thing which you think is most unlikely, the sudden incorporation of the transposon from a bacterium, right into the right spot in the right receptor in some early fish genome, didn't have to happen all in one step, indeed we now have evidence that it did not.
5. And, yet again, you totally fail to mention, let alone rebut, the variety of experimental work that has come in since 1996 that was provoked by, and which confirmed, the transposon hypothesis for the origin of RAG. Most impressive was the prediction that a free-living transposon homologous to RAG would exist. There was no reason to expect this, except for the transposon hypothesis. And this prediction was confirmed. This would be a huge point in favor of RAG for anyone who cared to be thorough and fair about the evidence.
6. The IC argument fails if any of Behe's examples of a multiple-parts-required system is shown to be evolvable through standard variation/selection mechanisms. It's not necessary for Applegate or anyone else to address every sub-system to refute Behe. The RAG system is the sexiest and most impressive part of the immune system, which is the sexiest and most impressive of Behe's IC systems (the immune system is definitely the most complex). You show Behe's wrong there, his whole argument that multiple-parts-required means unevolvable collapses in all the other cases.
7. I explained all of this years ago, so it is distressing that even the basic points (e.g. the known advantages of, and distribution of, receptor diversity) haven't sunk in at all. This does not reflect well on Behe's defenders.
http://ncse.com/creationism/le...
Comment by nickmatzke — July 18, 2010 @ 8:04 pm
July 19th, 2010 at 9:07 am
That is incorrect.
You have to show the IC system with the greatest number of IC core componets can arise via blind, undirected chemical processes.
And as for your "explanation", it lacks evidentiary support.
Comment by ID guy — July 19, 2010 @ 9:07 am
July 19th, 2010 at 9:08 am
Recombination is evidence for Intelligent Design…
Comment by ID guy — July 19, 2010 @ 9:08 am
July 19th, 2010 at 9:15 am
The debate is not whether or not the immune system can/ did evolve.
The debate is about whether or not blind, undirected chemical processes can build such a thing from scratch.
Fill in the blanks:
"If immune systems evolved via blind, undirected chemical processes I would expect to see ______________."
"This is because we have evidence of blind, undirected chemical processes producing ______________." (present that evidence)
Comment by ID guy — July 19, 2010 @ 9:15 am
July 19th, 2010 at 10:13 pm
Stop getting hung up on "blind, undirected chemical processes", which you get from a mutated and extremified version of what popularizers like Richard Dawkins have written. Evolution is not a chemical process, and evolution by natural selection is neither blind nor undirected. NS is not blind — or if it is blind, then it's blind in the same what a creature would be blind: lacking in long-distance sensory capability, but perfectly able to react to events and objects within the range of physical contact. And evolution is not undirected: NS provides direction.
A reasonable question would be: provide evidence that known sorts of mutational events produced the adaptive immune system. And that evidence is everywhere, e.g. the evidence of transposon insertion, the evidence of copying and rearranging of the RSS sequences and flanking Ig gene parts, etc.
Comment by Nick Matzke — July 19, 2010 @ 10:13 pm
July 19th, 2010 at 10:16 pm
Tell it to Nature and Science and the other journals we've cited which have published hundreds of articles on the evolutionary origin of the immune system over the years.
Comment by Nick Matzke — July 19, 2010 @ 10:16 pm
July 20th, 2010 at 2:09 am
Nick writes:
I don't think it can be said that this is due to standard variation/selection. Choanoflagellates have immunoglobin domains without having an immune system. There is also evidence that V domains likely already had a sequence-diversification function in the immune system.
Mobile elements in general are quite obviously major players in genome evolution, and there are many questions about them that are not answered by classic population genetics. As an aside, it's interesting that insertions can create new introns or nudge alternative splicing into action that can create new transcripts.
Comment by Guts — July 20, 2010 @ 2:09 am
July 20th, 2010 at 2:38 pm
Hi Nick,
First, let me say I had a strong touch of nostalgia when I read your post. It reminded me of old times at ARN, when almost all we ever did was debate IC. It brought a tear to my eye.
OK, but are there remnants of RAGs in the genomes of jawed vertebrates? Or do they only show up in the antibody genes? If they're only in the antibody genes, would this be strong evidence that the transposon entered the antibody genes first?
OK, but the question still remains: If there is no antibody for an antigen, then it can't be selected for. If we have a system that only makes 100 different antibodies, and none of them match the 1000 antigens, then that system won't be selected for.
So what function do RAGs have in sea urchins? Did they have that function in early jawed vertebrates? If so, shouldn't there at least be remnants of that function?
I agree that it's very strong evidence for the transposon hypothesis. What I would challenge is the idea that the RAG transposon was inserted randomly. BTW, I'm curious what inspired the transposon hypothesis. Would you know?
I disagree. The RAG system is not the "sexiest" part. I think the clonal and complement systems are sexier. And I also disagree that refuting one refutes the others. In the case of the RAG system, we seem to already have an IC system before it's inserted into the antibody genes, RAG + RSSs, which gives us the system: "Begin-cutting-stop." All that is needed is the right something to cut. It may turn out that you are right, that even a small amount of diversity in the antibodies is selectable. But the real question is how did we get RAG + RSS? From bacteria? But where did they get it from?
Sorry for distressing you, Nick. You know I wouldn't if I could help it. It's just that I don't keep up with what the ncse has on its website. Sorry.
Comment by Bilbo — July 20, 2010 @ 2:38 pm
July 20th, 2010 at 4:21 pm
And which paper shows that blind, undirected processes can produce an immune system?
That is what this whole debate is about Nick.
Also it is more than Dawkins saying that:
blind, undirected chemical processes
DNA is a chemical molecule- everything in living organisms are chemicals.
NS is a result Nick.
If surivival is a direction.
Only if you want to misrepresent the debate.
And you seem to be OK with doing that.
It seems that misrepresentation is all you can do…
Comment by ID guy — July 20, 2010 @ 4:21 pm
July 20th, 2010 at 8:58 pm
[...] Assessing Applegate's Attack – Telic Thoughts [...]
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July 20th, 2010 at 9:53 pm
Aw…
I doubt it. If other RAG remnants were produced, they would only be preserved for 500 million+ years if they had a function. Long after 500 mya we had huge invasions of LINEs, SINEs, etc. in the genome.
Matching isn't an all-or-nothing thing. A more realistic scenario is:
* critter with several hundred non-rearranging receptors with broad specificity hard-coded into the genome (many such critters exist today). Gene duplication means that many of them exist in multiple copies. If a cell detects an invader with its (one, non-rearranging receptor), it starts signalling and/or replicating
* the bacteria & viruses are suppressed by these receptors, but regularly escape via mutation, leading to increased mortality, limits on size and lifespan, etc.
* now a transposon invades one of the receptors (perhaps a duplicate). Everything works like it did before, except one of the receptors is now variable, producing a population of immune cells with different receptors. Now it is more likely that new invaders will be recognized, and less likely that old invaders will be able to escape by mutation.
That's basically how it could start.
I don't think anyone knows yet. They aren't necessarily even "RAGs" in sea urchins — they might just be transposons that are maintaining themselves through self-replication.
The fact that we know how tranposition works and that location of insertion is pretty much random (AFAIK) is evidence that it was random. What is leading you astray is the idea that there was only one insertion event. There could have been thousands of insertion events as this transposon bounced around in genomes over millions of years. But the only insertion events that would be preserved over hundreds of millions years would be those few that were selectively beneficial.
So: insertion was random, but preservation was not.
Re: origin of the idea — it goes back to Sakano et al.'s paper (1979 I think? check the Bottaro, Inlay, Matzke review). They noticed similarities between the RAG process and bacterial transposon processes.
Probably. (Although like I said, the lateral transfer event to eukaryotes might have happened millions of years before the insertion into the immune gene.)
Who cares? Transposons are ubquitous, and, like viruses, they probably go all the way back to the early RNA-protein world. It's a different question, and it's moving the goalposts to say that the origin of adaptive immunity is an open question because we don't have all the answers on the origin of life. We've reduced adaptive immunity to something simpler. Behe 0, science 1.
Well, this stuff has been posted regularly ever since it came out in 2006. But interesting questions…you just need to do more of your own research, and not make us do it for you.
Comment by Nick Matzke — July 20, 2010 @ 9:53 pm
July 21st, 2010 at 9:32 am
Nick,
ID is not anti-evolution.
ID says that (most) mutations are directed- ie not random with respect to anything.
The only thing that sez mutations are "randon" is our ignorance.
It is as if a first grader was asked to analyze a complex computer program just by watching the output- what the program does- on a monitor.
That first grader wouldn't have any knowledge of the command statements that are directing the flow of the program.
Transposons carry the coding for the enzymes necessary to allow it to be cut out and then spliced back.
The problem, Nick, is you are argiung against some strawman you have made up and you don't seem to care.
It does not matter how many times your strawman is exposed you are just going to keep presenting it because that is just the type of person you are.
Also the origin is very important because that is also what the debate is about.
That you choose to hand-wave that away says quite a bit about your agenda.
Comment by ID guy — July 21, 2010 @ 9:32 am
July 22nd, 2010 at 3:37 pm
I agree that it is more likely that new invaders will be recognized, etc. But the question is, how more much likely? Enough to make selection probable? I think we're at the point where experiments could be performed to determine the answer.
If there were thousands of insertions of this transposon, then I agree that insertion was probably random. Do we have a way of knowing how often it probably happened?
My argument is that the core of the antibody diversity system — RAGS + RSSs — is IC. Cutting without start and stop signals is rather useless, and vice versa. And once we have that, all we need is something to cut that reaches a level of selectivity.
What do you think I pay you for?
Comment by Bilbo — July 22, 2010 @ 3:37 pm
July 22nd, 2010 at 9:17 pm
I thought about it some more, Nick, and I guess I have to admit to moving the goalposts. But only a little. Behe claims that there had to be additional design events besides the origin of life. If it was demonstrated that the antibody diversity system could have come about by using features of ancient life and without additional design, this would weaken his claim. But we're still left with the clonal selection and complement systems. Let's say for the sake of argument that those could also be explained without additional design. And the same with Behe's other examples. Then I think the most plausible form of ID would be Mike Gene's FLE.
Comment by Bilbo — July 22, 2010 @ 9:17 pm
July 27th, 2010 at 5:56 pm
Well Nick your strawman version of ID has be explained to you so it is distressing that even the basic points haven't sunk in at all.
This does not reflect well on Darwin's defenders.
Comment by ID guy — July 27, 2010 @ 5:56 pm
May 2nd, 2011 at 3:10 pm
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