Ian Musgrave posted Entry 210 on May 16, 2004 12:43 AM.
Trackback URL: http://www.pandasthumb.org/cgi-bin/mt/mt-tb.fcgi/209

Behe published his book “Darwins Black Box” in 1996. In it he stated the principle of “irreducible complexity” and claimed that, amongst other things, the clotting system and the eubacterial flagella were irreducibly complex, and were not evolvable. Since that time, researchers have uncovered significant evidence for the evolution of both the clotting system and the eubacterial flagella, what has Behe been researching while this has been going on? Well at a recent ID conference Behe has apparently produced a calculation that shows that the evolution of new binding sites between proteins and things such as other protein, DNA and small molecules is so unlikely as to be impossible.

Now, I’m a pharmacologist, and my stock in trade is binding sites, so I was very interested in this. Binding sites are ubiquitous in biological systems; proteins bind together to form complexes, such as the respiratory complex in the mitochondrion (the cells power house), proteins bind to DNA in cell replication, and small protein hormones such as insulin bind to larger receptor proteins to cause various important cellular effects. So in effect, Behe is saying that an enormous part of the cell’s biology is vanishingly unlikely to have evolved. This is a very strong claim.

I’m very suspicious of this claim for several reasons. One is the phenomenon of “non-specific binding”, which is the tendency, when you are trying to follow the binding of a specific hormone to a specific receptor, for your specific hormone to bind to everything under the sun. That is, proteins tend to stick together by default, and it is not to hard to imagine this generalized binding evolving into a more specific binding. Also, a lot of experimental work has been done on evolving binding sites, especially by Jack Szostak, so it seems a very strange claim in the face of experimental evidence that binding sites can evolve. Unfortunately we don’t have Behe’s text from the Biola talk, but we do have one from a recent talk where he briefly discusses these issues.

I’ll use the text of this talk to illustrate some of the issues involved, as he apparently has kept the core concepts intact in the Biola conference talk. In the 2002 talk Behe uses the example of the Bovine Pancreatic Trypsin Inhibitor (BPTI). I’ll use the same protein to show how wrong he is. All quotes come from Behe’s 2002 talk.

Drawings of the bacterial flagellum picture proteins as bland spheres or ovals, but each protein in the cell is actually itself very complex. This ribbon drawing of bovine pancreatic (trypsin) inhibitor gives a little taste of that complexity. Now proteins are polymers of amino acid residues and some structural features of proteins require the participation of multiple residues. For example, up here, I know it’s hard to see, but this yellow link is called a disulfide bond.

http://www.pandasthumb.org/archives/images/BPTI_s.jpg

In biochemistry people tend to refer to amino acids as “residues”, so when Behe talks of residues he means amino acids. In the absence of Behe’s picture I’m using my own ribbon diagram of the BPTI. In ribbon diagrams the messy amino acid structure is idealized as ribbons and strings. The exception being the amino acid cysteine, which is here shown as yellow sticks. Two cysteines close together interact to form a disulfide bond. This disulfide bond is relative weak compared to the bonds that form the actual protein, but they are strong enough to help the protein keep its finger-like shape, rather than having the chains flop around aimlessly.  In the case of BPTI, it has three disulfide bonds (i.e. 6 cysteines). Similar interactions can occur between other amino acids to help keep a protein in a particular shape, and these relatively weak interactions between amino acids are also involved in binding separate proteins together.

A disulfide bond requires two (cysteine) residues. Just one (cysteine) residue can’t form such a bond. Thus in order for a protein that did not have a disulfide bond to evolve one, several changes in the same gene have to occur. Thus in order for a protein that did not have a disulfide bond to evolve one, several changes in the same gene have to occur. Thus in a sense, the disulfide bond is irreducibly complex, although not really to the same degree of complexity as systems made of multiple proteins.

“Several changes”? Most proteins have at least one cysteine in them, all you would need is to have a second cysteine to be inserted near the first one. Here is a diagram of a mutant BPTI where two of the cysteines have been replaced. Note the overall similarity to the structure of the native BPTI. To get from this structure to BPTI we need exactly two mutations.

http://www.pandasthumb.org/archives/images/BPTI_mut_s.jpg

Thus in a sense, the disulfide bond is irreducibly complex, although not really to the same degree of complexity as systems made of multiple proteins. The problem of irreducibility, irreducibility in proteins is a general one. Whenever a protein interacts with another molecule as all proteins do, it does so through a binding site whose shape and chemical properties closely match the other molecule. Binding sites however, are composed of perhaps a dozen amino acid residues, and binding is generally lost if any of the positions are changed.

This is not true. One reason for this is that the amino acids that make up proteins come in general structural classes (acidic, basic, aromatic), so it is usually possible to substitute an amino acid of one structural class for another of the same structural class to get fairly similar function. Sometimes changing one amino acid will destroy binding, but most times reasonable binding remains. I’ll go into this shortly, first lets look at the interaction between BPTI and its binding site on trypsin..

http://www.pandasthumb.org/archives/images/BPTI_trypsin_s.jpg

Here I show the interaction between BPTI and bovine trypsin using a ribbon diagram. BPTI is the green ribbon (I’ve not shown the disulfide bonds for simplicity) and trypsin is the blue. Most people should have at least have heard of trypsin, it is an enzyme that helps us digest protein. There is a pocket in the structure of trypsin where the proteins it breaks down fit into, this is the binding site.

Part of BPTI is a loop that fits into this binding site on trypsin. You can see on the diagram where the loop fits in, partially obscured by the tyrpsin molecule itself.  7 amino acids in BPTI bind to amino acids in the pocket in trypsin, preventing it from binding to the proteins trypsin is supposed to break down (hence the name bovine pancreatic trypsin inhibitor). BPTI is part of family of proteins called Kunitz proteins. BPTI and similar proteins regulate the activity of enzymes like trypsin, other Kunitz proteins are toxins in snake venoms.

While 7 amino acids are involved in binding of BPTI to trypsin, the key determinant of BPTI binding is the amino acid at the very tip of the loop (called the P1 site) that penetrates into the heart of the binding pocket of trypsin. In my diagram I’ve shown in yellow an amino acid that occurs at this P1 site, but I’ve omitted the remainder of the amino acids on the loop that bind to trypsin for clarity.

The P1 site is responsible for over 50% of the interaction between the BPTI and tryspin. Normally this is the basic amino acid lysine. Substituting 10 different amino acids at this position resulted in a spectrum of binding (and trypsin inhibition) from weak to very strong (1). Basic arginine could substitute for basic lysine with little change in affinity. Even substituting an acid amino acid for the basic lysine still resulted in reasonable binding. There are two key messages here. One is that is that you do not need this critical residue to be a specific amino acid to get binding or functionality.  The second is that binding is not an all or nothing affair, and that we get a graded change in binding with changing amino acids.  Thus Behe’s claim “binding is generally lost if any of the positions are changed” is shown to be incorrect for his own example. A lysine to valine mutation at P1 converts the trypsin inhibitor into an inhibitor of human neutrophil elastase, so you can get new functionality quite easily without changing each and every amino acid in the binding loop.

Now, you might object that this is just one mutation, when all the others are in place, so Behe’s suggestion still has some validity. Remember that the P1 position accounts for over 50% of the interaction, so it is the key amino acid. Also, in another paper(2) they mutated 4 of the 7 amino acids, and were able to convert a trypsin specific BPTI to a porcine pancreatic elastase (PPE) inhibitor in single mutational steps. The wild type PBTI had no affinity for PPE, and went to a reasonably high affinity binding with just one mutation, which was refined to very high affinity binding with subsequent mutations. Again, using Behe’s own example, we can show his proposition is false.

One can then ask the question, how long would it take for two proteins that originally interact to evolve the ability to bind each other by random mutation and natural selection, if binding only occurs when all positions have the correct residue in place. Emphasis added by IFM

As we have seen, his argument comes apart here. Binding does not occur only with all residues in place. Let’s have a look at another BPTI, example (3). It has three disulfide bonds as we saw above. However, even versions with only one disulfide bond will bind and inhibit trypsin. Four of all 15 possible single disulfide variants bound reasonably well, including one non-native variant. What’s more, if the disulphide bonds were broken, the proteins still bound reasonable well (3). Thus, even with major structural changes, you can still get reasonable binding of the peptide to trypsin.

Although it would be difficult to experimentally investigate the question, the process can be simulated on a computer… .(mentions equation that does this, but gives no details IFM).. The yellow dot is the time expected to generate a new disulfide bond in a protein that did not have one if the population size is 100,000,000 organisms. The expected time is roughly a million generations. The red dot shows that the expected time needed to generate a new protein binding site would be 100 million generations.

As we have seen, it is not that difficult to experimentally investigate the question in Behe’s example, BPTI. There new functionality and binding was generated rapidly. Jack Szostak (4) has been evolving binding sites de-novo for some time now, and no such 100 million generation limit is apparent. Also, a recent mutation in humans has resulted in a new disulfide bond binding site in the protein apolipoprotein A, which provides increased functionality to the mutant protein.

Behe’s argument at Biola was essentially similar to the one given here, so Behe has spent over 6 years developing an equation that gives results that a simple literature search would have show are completely wrong.

This is a general problem for ID apologists, as many including Dembski have claimed that protein structures are inflexible and do not change readily, while in fact there is a wealth of research showing that protein function is very flexible, and that novel functions are rather readily evolveable(5). The recent claim that “..[over the past 10 years]intelligent design has laid the foundations for a general biology whose fundamental organizing principle is intelligent agency and not blind natural forces” rings hollow when the chief proponents aren’t even familiar with the enormous body research that contradicts their basic claims, and even for their chosen examples.

(1) Helland R, Otlewski J, Sundheim O, Dadlez M, Smalas AO. The crystal structures of the complexes between bovine beta-trypsin and ten P1 variants of BPTI. J Mol Biol. 1999 287:923-42. 
(2) Kiczak L, Kasztura M, Koscielska-Kasprzak K, Dadlez M, Otlewski J. Selection of potent chymotrypsin and elastase inhibitors from M13 phage library of basic pancreatic trypsin inhibitor (BPTI) Biochim Biophys Acta. 2001 1550:153-63. 
(3) Krokoszynska I, Dadlez M, Otlewski J.  Structure of single-disulfide variants of bovine pancreatic trypsin inhibitor (BPTI) as probed by their binding to bovine beta-trypsin. J Mol Biol. 1998 275:503-13.
(4) Huang Z, Szostak JW. Evolution of aptamers with a new specificity and new secondary structures from an ATP aptamer. RNA. 2003 9:1456-63.
(5) Gerlt JA, and Babbitt PC. Mechanistically diverse enzyme superfamilies: the importance of chemistry in the evolution of catalysis. Curr Opin Chem Biol 1998. 2:607-12.

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Comment #2283

Posted by cs on May 16, 2004 8:34 AM (e)

Nice post. I would say the more general flaw in Behe’s argument is that he imagines that a given biological function can only be performed by one specific protein structure. Even if it were true that it was unlikely to evolve a protein that works exactly like BPTI (same binding site, same affinity etc.), one could imagine numerous, maybe unlimited, other ways that a protein might bind to trypsin and inhibit it’s function.

Comment #2285

Posted by Frank J on May 16, 2004 9:33 AM (e)

Amazing. Even Behe’s “research” reduces to another argument-from-incredulity, replete with bogus “impossibility” calculations. This is especially ironic because he did put forth one legitimate hypothesis (regarding the origin of the first cell). To my knowledge, however, he has not bothered to test it at all in the 8 years since “Darwin’s Black Box.” Meanwhile, most of his fans, let alone the general public, are still almost completely unaware as to exactly what his origins model is (old-earth plus common descent - virtually identical to that of mainstream science), and exactly what his alternative hypothesis is. Even though he plainly states both in his book! All this “design-speak” from his supporters and critics only serves to divert attention to the main issue - Behe’s one truly scientific claim, and why he mostly ignores it.

Comment #2287

Posted by steve on May 16, 2004 10:21 AM (e)

The central notion of Irreducible Complexity requires that an ‘IC’ structure not have any simpler variant which can do anything under any circumstances in any environment. So it’s obviously wrong. But strongly held religious beliefs are capable of making men think black is white and up is down, so it’s sad, but not surprising.

Comment #2288

Posted by Ed on May 16, 2004 11:45 AM (e)

In my job as a techical writer, I consult with subject matter experts and attempt to produce an output accessible to a wider range of readers. If the reader misunderstands, it’s my fault and I must revise or start over. Now the advantage of the Irreducibly Complex is that it need never be explained, only promoted with some authority.

Comment #2293

Posted by Bob Maurus on May 16, 2004 2:31 PM (e)

When I originally read Darwin’s Black Box, I’m sure I came across a statement by Behe which, effectively, claimed that the new generation of electron microscopes enabled us to see deep enough down to make ironclad pronouncements of IC. That’s obviously a damned slender branch to climb out on, and it seems to have cracked and fallen several times since he made it.

One of the damning shortcomings - or momentary safe harbors - of ID is that they keep claiming IC for things “evolutionists” haven’t yet figured out. Here’s a different tack, but evidently Behe didn’t do his homework first? Seems like a major blunder.

Comment #2303

Posted by Ralph Jones on May 16, 2004 6:48 PM (e)

Frank J,

What is Behe’s one legitimate hypothesis?

Comment #2327

Posted by Frank J on May 17, 2004 3:17 AM (e)

Ralph,

The one about the first cell containing all the genetic material for its descendants. H. Allen Orr suggested in an early review that a human pseudogene for chlorophyll would provide evidence. Apparently we’re still waiting.

Comment #2330

Posted by Ralph Jones on May 17, 2004 4:38 AM (e)

Frak J,

Thanks for the elaboration. Has is not been shown that beneficial mutations have been retained in various genomes? Doesn’t this obviate Behe’s hypothesis?

Comment #2335

Posted by erik on May 17, 2004 9:52 AM (e)

OK, now I’m curious (but too lazy to research this for myself). What does he mean to suggest when he says that the first cell contained all the genetic material of its descendents?

Obviously one cell couldn’t contain all of the isoforms of all of the genes in modern living things. And I’m pretty sure he can’t mean that one primordial cell contained genes for proteins performing all of the functions of modern proteins? Can he? (Maybe it depends how loosely you define “protein function”.)

Comment #2356

Posted by Frank J on May 17, 2004 5:40 PM (e)

Ralph and Eric,

I guess if Behe meant “every genetic variant that ever existed,” but I have found so little written about it that I am unsure if that’s what he meant (and suspect otherwise). It’s bad enough for a scientist to write a book that is >99% argument from incredulity. But what scientist in his right mind would not want to devote most subsequent efforts to investigating the one potential alternative, however unlikely?

H. Allen Orr elaborates more on what Behe proposed, and how to test it:
http://bostonreview.net/BR21.6/orr.html

As I often say on Talk.Origins, I understand the need to expose Behe’s incredulity strategy, but I wish that critics would focus more on what he did propose. First, it will give no comfort to YECs. Second, even nonscientists will be suspicious as to why he spends so much time on “how it couldn’t have happened” and so little on his own proposal of “how it could have.”

Comment #2360

Posted by Ralph Jones on May 17, 2004 7:44 PM (e)

Frank J,

A great essay by Orr. Can the guy play hockey too? I skimmed Behe’s book and missed the ludicrous Primal Cell nuttiness. It is scary when smart, educated people add 2 and 2 and get 5. That is how holocausts happen.

Comment #2392

Posted by Tom Frank on May 18, 2004 2:55 PM (e)

Behe must have never heard of gene/genome duplication. All you need is an absolutely minimal starting point, plus a slightly error-prone replication system capable of occasional duplications and you can have every thing that has happened since.

I am extremely interested in the direction the RNA world hypothesis is going, BTW. The canonical explanation gets more appealing the simpler the starting organism is required to be.

Comment #2419

Posted by David on May 18, 2004 7:54 PM (e)

The ID people sometimes say or suggest things like the following: “The Bacterial flagellum could not have evolved, because it contains property P.”

But it is clear that bacterial flagellums could have evolved, because it is clear that they did evolve. It is like when people used to argue: “The human body will never run 100 meters under 10 seconds, because the human knee joint just won’t allow it.” Well, we know that the knee joint will allow it, because it has happened – some people have run that fast.

It is clear that bacterial flagella can evolve, because it is clear that they did evolve. The evidence that all organisms descended from one of, at most, a few single-celled microorganisms that lived about 3.8 billion years ago is overwhelmingly strong.

Also, sometimes the ID people suggest the following: “the hypothesis of common descent is no more plausible than not, because no person has physically witnessed ‘macro-evolution.’” For the sake of argument, let’s suppose that no person has witnessed “macro-evolution.” That does not enable us to determine that it is no more likely than not that all organisms descended from a common ancestor. Many events that no person has witnessed are known (or at least overwhelmingly likely) to have occurred. For example, no person has witnessed a living T-Rex, and it is clear that some T-Rexes ate things. No person has seen the core of Pluto, and I know it’s not made of cream-cheese. No person has seen an electron, and I’m sure they move around protons.

Finally, it seems like by “irreducibly complex” they sometimes mean “could not have evolved.” So when they say “X could not have evolved, because X is irreducibly complex,” the premise does not support the conclusion. It contains the same meaning as the conclusion.

Comment #2478

Posted by Margaret on May 20, 2004 4:34 AM (e)

I find arguments about improbability astoundingly disturbing because they are so meaningless and yet so many people seem to think that they are legitimate.

For a rather good elucidation on why these sorts of arguments are useless, I refer anyone interested to the following site:
http://www.csicop.org/si/9809/coincidence.html

It is also mentioned at one of the best sites I’ve seen for explanations of logical fallacies and other common mistakes one runs across in evolutionary theory-creationist debates, The
Skeptic’s Dictionary.

Comment #2561

Posted by Jack Shea on May 22, 2004 11:36 AM (e)

Tom:

All you need is an absolutely minimal starting point, plus a slightly error-prone replication system capable of occasional duplications and you can have every thing that has happened since. 

The minimal starting point is already fantastically complex as is the replication system. How do we get to this starting point?

Comment #2562

Posted by Jack Shea on May 22, 2004 11:45 AM (e)

David:

But it is clear that bacterial flagellums could have evolved, because it is clear that they did evolve. 

The existence of flagellae does not necessarily mean that evolution explains their existence. Evolution is one explanation, creation is another microbes from space another. Existence on its own proves none of them the correct explanation. Your argument assumes that evolution exists but the existence of evolution is the question for which the irreducible flagellum attempts to provide an answer. It is tautological. You are saying “The answer is evolution because evolution is the answer”.

Comment #2563

Posted by Pim van Meurs on May 22, 2004 12:20 PM (e)

Jack: The minimal starting point is already fantastically complex as is the replication system. How do we get to this starting point?

I disagree, a minimal starting point can involve a simple self replicating system. Interesting tidbit, the clay mineral which catalyzes the formation of self replicating RNA also catalyzes the formation of ‘cells’

Study suggests life sprang from clay

As far as the flagellum is concerned plausible evolutionary pathways and mechanisms have been proposed. Of course unless Jack can present a ‘creation’ explanation, we cannot really reject the idea of ‘creation’ since it falls outside the view of scientific inquiry

Comment #2643

Posted by David on May 23, 2004 8:00 PM (e)

According to Jack, “The existence of flagellae does not necessarily mean that evolution explains their existence. Evolution is one explanation, creation is another microbes from space another. Existence on its own proves none of them the correct explanation. Your argument assumes that evolution exists but the existence of evolution is the question for which the irreducible flagellum attempts to provide an answer. It is tautological. You are saying ‘The answer is evolution because evolution is the answer.’”

Jack, of course the existence of bacterial flagellum does not, by itself, enable us to determine that all organisms evolved from a common ancestor. But it is clear that all organisms to have lived on earth descended from one of, at most, a few single-celled microorganisms that lived about 3.8 billion years ago. I don’t have time to list the evidence. But maybe I can get into it a little if you want.

My point in my previous post is that whether bacterial flagellums have property P is irrelevant to whether we are justified in believing that they evolved. Because we already know (or at least it is incredibly likely) that they did evolve. The other relevant data is so strong. That is why I used the example of people running 100 meters under 10 seconds. We know that some people have. So, let’s say someone argues the following: “It is unlikely that anyone can run 100 meters under 10 seconds, because the knee joint has property P.” Well, obviously, the premise does not support the conclusion, because we know that some people have run 100 meters under 10 seconds.