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The Evolutionary Origins of Irreducible Complexity, Part 5

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June 14, 2012 Tags: Genetics
The Evolutionary Origins of Irreducible Complexity, Part 5

Today's entry was written by Dennis Venema. You can read more about what we believe here.

Note: One of the challenges for discussing evolution within evangelical Christian circles is that there is widespread confusion about how evolution actually works. In this (intermittent) series, I discuss aspects of evolution that are commonly misunderstood in the Christian community. In this post, we continue to examine evidence that proteins in irreducibly complex (IC) systems can form and refine new interactions through gradual mechanisms.

In the last post in this series, we introduced an elegant experiment on virus evolution done by the Lenski group, and suggested that, despite Behe’s claim to the contrary, this work poses some significant challenges to Behe’s arguments. We now turn to those arguments in detail.

Has Behe found the Edge of evolution?

Behe lays out his detailed case for what evolution can and cannot do in his 2007 book The Edge of Evolution. In a chapter called “The two binding-sites rule”, Behe lays out his argument for defining the “edge”– the limit of what random mutation and selection can do to create new protein-protein binding sites:

So one way to get a new binding site would be to change just five or six amino acids in a coherent patch in the right way. This very rough estimation fits nicely with studies that have been done on protein structure. Five or six amino acids might not sound like very much at first, since proteins are often made of hundreds of amino acids. But five or six amino acid substitutions means that reaching the goal requires five or six coherent mutational steps – just to get two proteins to bind to each other. As we saw in the last chapter, even one missing step makes the job much tougher for Darwin than when steps are continuous. If multiple steps are missing, the job becomes exponentially more difficult. (p. 134)

Then after an aside where Behe considers the possibility that some of the mutations might be neutral (and thus not be required to happen simultaneously), he settles on an estimate of three or four simultaneous mutations to effect a new protein-protein binding site:

So let’s suppose that of the five or six changes that have to happen to a protein to make a new binding site, a third of them are neutral. They could occur before the other key mutations, as a separate step, without harm. Although finding the right neutral changes would itself be an improbable step, we’ll again err on the conservative side and discount the average number of neutral mutations from the average number of total necessary changes. That leaves three or four amino acid changes that might cause trouble if they occur singly. For the Darwinian step in question, they must occur together. Three or four simultaneous mutations is like skipping two or three steps on an evolutionary staircase. (p. 134)

Note well: Behe’s model is based on an assumption that new protein-protein binding sites require multiple, simultaneous amino acid substitutions. Behe continues the argument:

Although two or three missing steps doesn’t sound like much, that’s one or two more Darwinian jumps than were required to get chloroquine resistance in malaria. In chapter 3 I dubbed that level a “CCC”, a “chloroquine complexity cluster,” and showed that its odds were 1 in 1020 births… Now suppose that, in order to acquire some new, useful property, not just one but two new protein-binding sites had to develop. A CCC requires, on average, 1020, a hundred billion billion, organisms – more than the number of mammals that has ever existed on earth. So if other things were equal, the likelihood of getting two new binding sites would be what we called in Chapter 3 a “double CCC”- the square of a CCC, or one in ten to the fortieth power. Since that’s more cells than likely have ever existed on earth, such an event would not be expected to have happened by Darwinian processes in the history of the world. (pp. 134-135)

Again, note well: in his estimation of the probability of generating two new protein-protein binding sites that perform a specific function, Behe calculates it as the square of the probability of getting one. This means that Behe is assuming that the two probabilities are independent, and thus all the non-neutral mutations (for both new binding sites) occur simultaneously. From this calculation, he concludes:

Admittedly, statistics are all about averages, so some freak event like this might happen – it’s not ruled out by force of logic. But it is not biologically reasonable to expect it, or less likely events that occurred in the common descent of life on earth. In short, complexes of just three or more different proteins are beyond the edge of evolution… And the great majority of proteins in the cell work in complexes of six or more. Far beyond that edge. (p. 135)

Indeed, mutations that simultaneously changed six to eight amino acids to instantaneously bring about two new protein-protein binding sites would be a freak event. (Note: I am aware that the precise numbers Behe uses have been criticized, but I’ll assume them for the sake of argument). The real question, though, is whether new protein-protein binding sites require simultaneous mutations. If they do, then Behe might have a case. But if new binding sites can arise one amino acid substitution at a time, however, then Behe’s case is based on a flawed assumption. In this case, protein complexes could add new binding partners one protein at a time, and build up systems of numerous proteins gradually, in a step-wise manner. Moreover, if one new binding site can arise gradually, then it is reasonable to expect that multiple binding sites could also arise without requiring simultaneous mutations.

Adding new protein binding partners, one amino acid substitution at a time

This is where the experiment done by the Lenski group on λ phage evolution (that we introduced in the last post in this series) becomes a key test of Behe’s hypothesis that simultaneous mutations are required for new protein-protein binding sites. (Readers may wish to refresh their memory of this experiment before continuing). The key points are as follows:

  1. For protein J of λ phage to bind to the new partner, OmpF, at least four amino acid substitutions were required before the new binding ability arose. Only with the fourth substitution did the new binding take place.
  2. The probability of these four mutation events happening simultaneously is pretty much zero (approximately one in a thousand trillion trillion). This is well beyond the probability “edge” that Behe claims.
  3. In repeated experiments, the λ phage managed to “find” these mutations over and over again without much trouble.
  4. Subsequent analysis showed that the amino acid substitutions happened sequentially, not simultaneously.

Over the edge, with ease

As we have seen, Behe’s argument for defining the edge of what evolution can do is based on his assumption that multiple mutations producing certain amino acid substitutions must occur at the same time in order for new protein-protein binding sites to arise. What the Lenski experiments on λ phage demonstrate, however, is that new protein–protein binding sites can arise just fine by accumulating random amino acid substitutions one at a time, even if numerous mutations are needed to achieve the new binding properties. Moreover, they can arise just fine by many different routes, and not always with the exact same mutations present, and this result can be repeated in the lab over and over.

In short, the fundamental assumption of Behe’s model has not stood up to experimental scrutiny. If new protein-protein binding sites can (and do) arise in this way, Behe’s assertion that several mutations must occur at the same time falls apart, and with it his proposed “edge” of what evolution can do. Behe has drawn a line in the sand, but we’ve watched evolution stroll right over it as if it wasn’t there—one amino acid substitution at a time.

In the next post in this series, we’ll return to looking at the p24-2 and Éclair genes of Drosophila melanogaster, and consider Behe’s response to the evidence that these proteins have developed new functions and interactions within the last three million years.

For further reading:

Behe, M.J. Darwin’s Black Box: the Biochemical Challenge to Evolution. Free Press, New York, 1996.
Behe, M.J. The Edge of Evolution: the Search for the Limits of Darwinism. Free Press, New York, 2007.
Meyer, J.R., Dobias, D.T., Weitz, J.S., Barrick, J.E., Quick, R.T., and Lenski, R.E. (2012). Repeatability and contingency in the evolution of a key innovation in phage lambda. Science 335; 428-432. http://www.sciencemag.org/content/335/6067/428.abstract

Dennis Venema is professor of biology at Trinity Western University in Langley, British Columbia. He holds a B.Sc. (with Honors) from the University of British Columbia (1996), and received his Ph.D. from the University of British Columbia in 2003. His research is focused on the genetics of pattern formation and signaling using the common fruit fly Drosophila melanogaster as a model organism. Dennis is a gifted thinker and writer on matters of science and faith, but also an award-winning biology teacher—he won the 2008 College Biology Teaching Award from the National Association of Biology Teachers. He and his family enjoy numerous outdoor activities that the Canadian Pacific coast region has to offer. Dennis writes regularly for the BioLogos Forum about the biological evidence for evolution.

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George Bernard Murphy - #70452

June 14th 2012

This is an interesting but totally irrelevant controversy which assumes evolution is the alternative of creation by God.

 Instead of Rube Goldberg schemes about proteins, he should be considering the question of “Where did the atoms come from?”

From Quarks, you say.Then where did the quarks come from?

“Where did the fundamental forces come from?.... like gravity”

 This question  about protein formation is an insignificant minor detail.

 Why do we alwys get fixated on it?

Mohammad Nur Syamsu - #70454

June 14th 2012

it is very clear that the criticism of intelligent design theory is ideological. To suggest that freedom is not irrellevant in the universe, that sophisticated ways of deciding may occur, is entirely reasonable. like any theory it warrants scrutiny, but the criticism of intelligent design is way over the top, and indicates deep philisophical problems with free will and spiritual issues on the part of the critics. 

Bilbo - #70455

June 14th 2012

Hi Dennis,

A couple of points:

1.  Behe’s discussion in EoE referred to amino acid substitutions that were non-selective.  In the case of J undergoing amino acid substitutions, Behe claims (I haven’t read the original paper that he’s responding to) that the first three substitutions provide J with stronger binding ability to LamB.  So each of the substitutions has selectivity.  It is the fourth substitution that allows it to bind to OmpF.  So assuming that Behe is correct that the first three substitutions were selective, then we do not have a case that violates Behe’s edge.

2.  More interestingly (and to me still difficult to understand) is Behe’s claim that the new ability of J to bind to OmpF is not a GoF (I think that’s the correct abbreviation), but merely a modification of function.  I’ll have to re-read Behe’s peer-reviewed paper to try to get a handle on the point he tries to make on his blog.  I’m wondering if you’ve read that paper.

Dennis Venema - #70458

June 14th 2012

Hi Bilbo, 

Thanks for the questions. I also wanted to say that I’ve appreciated your work to hold the feet of certain ID folks to the fire over at UD.

Here are my thoughts:

1. EoE is actually based on the assumption that adaptive paths to new protein-protein interactions don’t exist. If new interactions can be built piece by piece, with adaptive benefit along the way, then it makes no sense to claim that new protein-protein binding sites can be used to demarcate an edge of evolution since multiple mutations have to arise at once. This line of thinking is also what permeates the recent paper in BioComplexity by Gauger and Axe.   In Behe’s response to the Lenski paper you’ll notice that he does not deal with this issue at all. Yet this shows that his reasoning in EoE doesn’t stand up to experimentation. So, instead we see equivocation on the idea that it’s not really a big change, not a gain of function, etc. Behe needs to say why, if new protein-protein binding sites can be observed to form in the lab without all the mutations happening at once, why this does not invalidate his argument (when it is so clear that it does). 

2. In the review paper Behe defines a “gain-of-FCT” mutation as a “gain of a Functional Coded elemenT” event - i.e. when a new gene arises. He then flips back and forth between using this narrow definition and talking about “gain of function” mutations in general. This leads to the odd situation where he will call the gain of the ability of J to bind OmpF, without any loss of its ability to bind the original receptor (and for that matter an improved ability to bind it!) “not a gain of function.” Behe’s definition is non-standard, and I don’t know anyone else who uses it. It’s a gain of funciton mutation, plain and simple. Protein J has a new ability, and it hasn’t lost any ability (and even the original ability is enhanced!), but somehow that’s not a gain of function? If that strikes you as odd, it should.

Hope all is well with you, and thanks again for the excellent questions. 


Bilbo - #70456

June 14th 2012

Hi George,

Behe is a biochemist, not a physicist nor a philosopher.  He is merely interested in the question of whether features at the biochemical level of life should best be explained by intelligent design.

HornSpiel - #70462

June 15th 2012

For me the interesting point is that the Lenski group found that evolutionary processes took an unexpected though, in hindsight, perfectly reasonable route to make an organism better fit with its environment.

Why Behe’s analysis is not convincing to me is that he claims to know exactly what path or paths an evolutionary process must take to reach a particular end. The experiment above shows that biological processes are too complex to be limited by our preconceptions. Moreover, all sorts of evidence exists and dovetails together that points conclusively to common decent of organisms with progressive small modifications of the geanome as the means by which that happened. If that is not evolution, what do you call it?

Is it realistic to demand that science know all the mechanisms or pathways that evolution took to result in our current biological diversity? That is what ID does, and then says our ignorace is evidence for God (oops sorry) a Designer.

Dennis could have written:

Behe has dug a gap in the sand, but we’ve watched evolution stroll right over it as if it wasn’t there

Mohammad Nur Syamsu - #70505

June 17th 2012

Only theories about origin based on a logic of freedom can be exhaustive explanations for origins, because with freedom you get the new information in the universe of which way the choice turned out. Thats true origin, new information. I am descendent from my parents, but its not an exhaustive explanation for me. The decisionmaking in freedom, by which I was created is the true origin. And agency of any decision is categorically a subjective issue. What decides in freedom, can only be identified in a free way, and not forced by evidence. There is no evidence for me as the owner of my choices. 

Bilbo - #70465

June 15th 2012

Hi Dennis,

You wrote:

1. EoE is actually based on the assumption that adaptive paths to new protein-protein interactions don’t exist.

I would say his assumption is that adaptive paths to new protein-protein interactions either don’t exist or are very rare. 

As to your second point, it did strike me as odd.  But since his definition of gain of function was accepted in a peer-reviewed paper, I hesitate to reject it without at least making sure I understand it.  I still need to re-read his paper. 

As to UD, yes I try to hold their feet to the fire.  But I try to extend that courtesy to the folks here, as well.  (I would put a smiley face here, but the format doesn’t seem to work.)

Bilbo - #70466

June 15th 2012


I just read Thomas Cudworth’s repsonse to your remark to me.  At this point it sounds as if he just wants you to clarify your views, first, before he proves what a heretic you are.  I think I’ll just stand on the sidelies and watch for a while.  Hopefully the flames around the stake won’t get to hot before somebody puts them out.

PanIN - #70467

June 15th 2012

Hi, Dennis

I should have asked my question/comment in the previous post, but I’ll post here to get your response. Regards to the lethality of p24-2 knockdown by siRNA in Drosophila, I wondered  how they specifically knockdowned p24-2 over highly similar other paralogs, as you mentioned there are nine p24 protein genes and p24-2 differs only five AA.

When I searched the siRNA clone to knockdown p24-2 gene in the supplementary method of that Science paper and the RNAi library of Vienna Drosophila RNAi Center (VDRC), I found they used GD5843 clone. Surprisingly it is predicted to knockdown three members (CG31332, CG33104 and CG33105).

CG31332 is Unc-115b,

CG33104 is Eclair

and CG33105 is p24-2.

Lethality from GD8543 siRNA seems to be due to abrogation of Unc-115b, Eclair and p24-2 not p24-2 alone. 

In general, highthroughput analysis requires further confirmations with other methods. Other examples (HP6, CG12842 and spn2), (lethality has been confirmed by other methods) would be better examples for your argument.

Dennis Venema - #70468

June 15th 2012

Hi Pan, 

It’s a good point - but don’t forget there is other evidence that p24-2 isn’t merely a redundant copy of Eclair: the various RNAi lines have distinct phenotypes, the two transcripts have distict expression patterns, and there is the amino acid sequence divergence. Have a look at some of the other papers I reference in addition to the Chen paper, the data is in there. 

The reason why Unc-115b is included as a possible off-target is because p24-2 is nested within Unc115b, but this gene isn’t one of the p24 - like proteins, IIRC. 

The broader point is not necessarily to show that p24-2 is a full-fledged new IC system, but rather to examine the process early on, after duplication. Early after duplication we would expect some inter-dependence among the duplicates. Lethality alone isn’t the issue either, but rather that p24-2 has picked up functions of some sort - which the evidence points towards. 

In future posts I might look at some of the other genes identified, which are older, to compare with this example.  

Thanks for the comment. 

Bilbo - #70472

June 15th 2012

In reading Behe’s review it’s difficult for me to tell if any of the virus or phage examples that he cites are similar to the example being discussed by Dennis here.  By similar, I mean a case where the same binding site has been modified so it both retains it’s ability to bind to the first protein and also to a similar second protein.  If so, then Behe would have a peer-reviewed paper where the reviewers didn’t seem to have a problem with Behe calling this a “modification of function,” instead of a “gain of function.”

But let’s say Behe was mistaken, and that we should call the present example a “gain of function.”  Is it reasonable to think that this example is typical for how most new biochemical complexes and systems have originated?  Perhaps if I knew more biology I might say yes.  But I’m having trouble accepting an extrapolation from a bacteriophage modifying it’s binding site so it can attach to a similar protein on bacteria to the same process resulting in new biochemical complexes.

Am I just being obtuse?  I don’t think so.

Bilbo - #70479

June 16th 2012

Hi Dennis,

Since it was your comment here about UD and me that initiated Cudworth’s latest post at UD, I thought I would post part of his response to my question and my answer:

Thomas: “I prefer plain, simple English. If their position is “God did nothing in evolution except sustain the laws of nature, and random mutations and natural selection took care of all the rest” — then that’s what I’d like them to say, straight out, with no pussyfooting around. And yes, I would find that specific enough.”

[me]: “From what I’ve read at BioLogos, that would seem to be their position.”

“And after they have said that, I want them to explain how that model of evolution can guarantee any results, which it must be able to guarantee if God’s providence is not to be thwarted.”

[me]: “They argue that neo-Darwinian evolution is able to provide a large probability that human-like creatures would result (which is usually what everyone is worried about when they talk about God’s providence). And if it is a large probability, then by simply making the probable resources large enough, this in effect “guarantees” the results.

If they are mistaken, then I think it is an empirical mistake. Not a theological one.”

If you think I have misrepresented your views, let me know.

Darrel Falk - #70521

June 18th 2012

For my own personal views on the matter please see: http://biologos.org/blog/southern-baptist-voices-a-biologos-response-to-william-dembski-part-i

For a great series please see this and then check the side bar for remaining articles in the series: http://biologos.org/blog/addressing-christian-concerns-on-the-implications-of-biologos-science-1

Bilbo and Thomas have not accurately summarized our position.  

Bilbo - #70540

June 19th 2012

Hi Darrel,

I apologize if I haven’t accurately summarized your position.  Thomas seemed interested in knowing what BioLogos’ position was regarding the freedom of Nature.  I would understand your position to be that God’s natural activity refers to God’s sustaining Nature (everything that exists in our universe)  in existence and the (quantum) laws of nature, which means that subatomic particles are individually indeterminate but statistically predictable.  It is this indeterminacy that gives Nature a degree of “freedom.”  The question would then become how does God remain sovereign over Nature?  And the answer would seem to be the same way that God remains sovereign over humanity, while still allowing us freedom.  If this is an inaccurate summary of your position, I’m willing to be corrected. 

Darrel Falk - #70552

June 20th 2012

Bilbo, providing an adequate answer to this question would be an interesting grant project, don’t you think?  

Bilbo - #70556

June 20th 2012

Interesting, but well above my pay grade.

Darrel Falk - #70551

June 20th 2012

To clarify further:  Here is what I said in the above post.

Given the many examples of supernatural activity in Scripture, we human beings tend to expect that for something as special as creation of stars or new species, supernatural activity would have been required. But we cannot derive this from the scriptural account and, therefore, it is wise not to second-guess how God might have worked based on the Scriptures.

In Part II of my response to Dembksi, I said this:

I see no scripturally-based rationale for determining the expected ratio of natural vs. supernatural divine activity in creation.  Scripture is silent on the issue and so far at least, science is as well—other than demonstrating that many biological features and mechanisms previously thought by some to be evidence of supernatural action can now be explained via God’s regular activity—that associated with his natural laws.  For the present, I think it is best to withhold judgment about the extent to which God suspends his ongoing regular activity in favor of miraculous supernatural activity in the history of the creating life’s diversity.


So since Scripture, as I see it leaves the matter open, and science doesn’t provide a clear answer either, I think it is pointless to speculate further.  I don’t think I am dancing around the issues.  I am simply saying “I don’t know,” because the two ways by which I would know (God Written Word and the scientific investigation of God’s World) do not provide the answer for me.   As I have stressed in each of the above two blog posts it all happens through God’s activity and I have to leave it at that for now.   But what a place to leave it….http://www.youtube.com/watch?v=MHIfRLNYUGw

Bilbo - #70555

June 20th 2012

Hi Darrel,

Perhaps I don’t remember as clearly as I ought, but there seems to be a subtle shift in your position from earlier at BioLogos to the present:

1)  I believe that probably God did not use His supernatural activity in natural history


2)  I don’t know if God used His supernatural activity in natural history or not.

I think either position is theologically acceptable and defensible.  However, (1) allowed for a theodicy against natural evil, by claiming that God was allowing nature to be free.  (2) doesn’t give up that theodicy, but it’s getting close to giving it up.

Darrel Falk - #70558

June 20th 2012

Hi Bilbo,

I don’t think I ever have held position #1, above.   See “Coming to Peace with Science,” (IVP, 2004) for example.


Darrel Falk - #70554

June 20th 2012

One more thing (sorry):

I would also encourage readers to see Part III of my response to Bill Dembski. There I wrote:

Dembski also suggests that it would be best for me to withhold judgment on whether God’s natural activity was sufficient to account for all of creation: “What is the evidence that purely natural forces are capable of doing all the creative work required for nature to produce a profligate living world that includes hawks, hippos, and humans?” he asks. I agree completely. That is why I do withhold judgment. 


I appreciate the attention that this is receiving at Uncommon Descent.  Thomas, if you are in San Diego, I’d love to go out for coffee with you, or alternatively maybe I’ll get to visit with you in your home city one of these days.  I hope so.

Dennis Venema - #70483

June 16th 2012

Hi Bilbo,

This is just a quick note to say I appreciate your efforts, but life is far too busy right now for me to engage this conversation in any depth. Often I am accused of avoidance when the more boring truth is that I have a lot on my plate that requires my attention, and comments on UD usually need to rank lower than many other, more pressing needs.

I will say that (a) I do see the issues that Cudworth is concerned about as very much a free will / predestination type of question, and (b) I don’t cross my fingers when I say the creeds. I doubt that will suffice for Mr. Cudworth (I do wish he would be willing to sign his real name to his comments, but be that as it may) but it is the truth. 

Gregory seems to be making some good points as well. Between the two of you I think you’ve raised many good points for him to consider. Has he given an answer to how free will does not undermine the soverignty of God? I think that would be a good conversation to have vis a vis this one. 

I’m also happy to note that I am *not* a theologian - so I’m an amateur on these issues. I try to stick to my areas of expertise. 



Bilbo - #70484

June 16th 2012

Hi Dennis,

It’s difficult to understand how anything (even one’s family) could be more important than the demands of UD [Insert smiley face]  But just a quick question.  When you say it is a free will/ predestination issue, the free will you are referring to is the indeterminacy that quantum mechanics suggests exists?  That is how I’ve understood the BioLogos position, but I thought I should double check.

Bilbo - #70485

June 16th 2012

One quick question, Dennis.  When you suggest that it is a free will/ predestination issue, the free will (of Nature) you are referring to is the indeterminacy that quantum mechanics suggests exists?

Bilbo - #70486

June 16th 2012

Oh, I didn’t realize my first attempt at asking the question was going to be published.  Sorry about that.

Dennis Venema - #70489

June 16th 2012

Hi Bilbo,

Yes, to my mind quantum mechanics is good evidence that we don’t live in an absolutely predetermined universe. I think human free will is another reason. The ability of humans to exert their free fill and alter their natural surroundings is another. I think God has granted humans and nature some freedom by not predetermining everything from the beginning. He has also set bounds for how that freedom works out, so the freedom is not limitless.

Imagine if I were to play chess with a grand master (note - even my nine-year old can beat me at chess). I would be free to make any move I wanted within the rules of the game, but the outcome would never be in doubt. My complete freedom might change the precise details of how the game would play out, but would have no impact on the outcome. 

Cudworth seems to be working from a notion of evolution that emphasizes its contingent nature to the exclusion of its convergent nature. Like the chess game, the details will be contingent, but in broad outcome evolution produces remarkably convergent outcomes, time and again. Maybe Cudworth should read Simon Conway Morris’ book. Nick’s point on the UD thread was a good one. 



Dennis Venema - #70490

June 16th 2012

gah. that should be *free will* above, of course, not “free fill.” I note too that I’ve misspelled “sovereignty” in a previous comment. Perhaps this amateur theologian should stick to genetics (insert smiley face here). 

Bilbo - #70491

June 16th 2012

That sounds like a good answer to this amateur theologian, Dennis.  Thanks.

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