Evolution of IC: Evolution of Hormone-Receptor Complexity

Posted 10 April 2006 by Ian Musgrave

Update: I've added some substantial comments 81029 and 81054 that might be lost in the comment roll, but add some important perspective to Behe's arguments. Michael Behe is known as the author of the concept of Irreducible Complexity (IC, but see [note 1]). However, he has given several different, not entirely consistent, definitions of IC. Everyone is familiar with the "multiple parts" definition, fewer will be familiar with the "neutral mutational steps" definition (1) and fewer still with the idea that amino acids interactions themselves are IC (2, see my critique of this). Indeed, Behe's recent paper with David Snoke (3) relied on a combination of the last two definitions (see our critique), and Behe also used the latter definition in the Dover trial (3). A paper just out in the journal Science has effectively refuted the claims of the Behe and Snoke paper (4) Behe has claimed that he will accept that a system is not IC if someone can give a mutation-by-mutation account, with selective coefficients for each mutation, for that system. Now in general, this is just not practical, because it is very difficult to reconstruct these systems even for bacterial antibiotic resistance, where we can keep a close eye on the mutations, and can readily measure the effect of the mutations. In fact, for resistance to cefotaxamine, 5 mutations are required, and there are 18 high probability pathways to this resistance (5), so we have little idea of the historical path the system took. Reconstructing the actual mutation-by-mutation path of any given feature, especially in organisms that are not as easy to grow or test as bacteria (and given that many intermediate organisms may be extinct), is a daunting task. By requesting a ludicrous amount of detail, Behe has tried to insulate himself from the evidence for evolution. In a magnificent paper, Bridgham, Carroll and Thornton (BCT, 4) have tackled the daunting task of reconstructing evolutionary pathways head on, reconstructing ancient proteins in the process. The article looks at one of Behe's key examples, protein-binding sites for small molecules. The ability of proteins to bind small molecules is critical for organisms to function, because enzymes bind small molecules as part of metabolism, receptors proteins bind small hormone molecules to initiate cell signaling and many small molecules bind to a variety of proteins to modify their functions. For example, in the Behe and Snoke paper (3), they examine the ability of the oxygen carrying protein haemoglobin to bind the organic phosphate molecule 2,3-diphosphoglycerate (DPG, which modifies the oxygen binding capacity of haemoglobin). The BCT paper looks at the binding site of the receptors for some steroid hormone receptors, those for mineralocorticoids (MR) and those for glucacorticoids (GR). Receptors are proteins whose amino acid chains fold in such a way as to produce a pocket where particular small molecules (hereafter called ligands) bind. These pockets can be incredibly selective, and the term "lock and key" is often used. The small molecule fits into the protein receptor like a key into a lock (this is an oversimplification, as the molecules are flexible, and are "floppy" keys and locks, and the electrostatic charge and lipid solubility of the molecule comes into play, but it helps visualization).

Lock and key binding illustrated with the molecule adrenaline (right) Now, modern tetrapods (amphibians, reptiles, birds and mammals) have separate receptors for the steroid hormones cortisol (GR, which modulates metabolism, inflammation and immunity) and aldosterone (MR, modulates salt balance amongst other things). Hagfish and Lampreys ("primitive" jawless fish with cartilaginous skeletons) have only one receptor, which is activated by both aldosterone and cortisol. Sharks and such have two receptors, both of which are activated by both aldosterone and cortisol. Finally, bony fish and tetrapods have two receptors, one which is activated by aldosterone, and one which is activated by cortisol (See [Note 3]). What were the molecular steps which brought this about?

The aldosterone receptor (as helix and strings) showing aldosterone (the white collection of balls) binding in the pocket. On the right is a close-up, with the amino acids that are mutated to make the GR receptor shown as balls as well. BCT approach this in a very elegant way. Using phylogenetic analysis of the existing sequences of GR and MR receptors they were able to reconstruct the sequence of the receptor ancestral to the GR and MR. They expressed this reconstructed gene in cells, and tested the sensitivity to aldosterone and cortisol. The ancestral receptor responded to both aldosterone and cortisol. By a combination of phylogenetic analysis and mutagenesis they isolated two mutations that converted the ancestral receptor into a GR (serine to proline at position 106 in the chain, and lysine to glutamine at position 111). By studying their properties, and comparing them to MR and GR receptors from hagfish, sharks, bony fish and tetrapods, they determined that the seriene to proline mutation came first, followed by the lysine to glutamate.

Click Image to enlarge Fig. 4. Evolution of specific aldosterone-MR signaling by molecular exploitation. (A) Synthesis pathway for corticosteroid hormones. Ligands for the ancestral CR and extant MRs are underlined; cortisol, the ligand for the tetrapod GR, is overlined. The terminal addition of aldosterone is in green. Asterisks, steps catalyzed by the cytochrome P-450 11ÃŸ-hydroxylase enzyme; only the tetrapod enzyme can catalyze the step marked with a green asterisk. (B) MR's aldosterone sensitivity preceded the emergence of the hormone. The vertebrate ancestor did not synthesize aldosterone (dotted circle), but it did produce other corticosteroids (filled circle); it had a single receptor with affinity for both classes of ligand. A gene duplication (blue) produced separate GR and MR. Two changes in GR's sequence (red) abolished aldosterone activation but maintained cortisol sensitivity [see (C)]. In tetrapods, synthesis of aldosterone emerged due to modification of cytochrome P-450 11ÃŸ-hydroxylase. mya, million years ago. (C) Mechanistic basis for loss of aldosterone sensitivity in the GRs. Phylogenetically diagnostic amino acid changes that occurred during GR evolution were introduced into AncCR-LBD by mutagenesis. Dose-response is shown for aldosterone (green), DOC (blue), and cortisol (red). The double mutant (bottom right) has a GR-like phenotype. Arrows shows evolutionary paths via a nonfunctional (red) or functional (green) intermediate. From Bridgham JT, Carroll SM, Thornton JW. Evolution of hormone-receptor complexity by molecular exploitation. Science. 2006 Apr 7;312(5770):97-101. under "Fair Use" and non-profit educational provisions.

Deriving the ancestral sequence, determining the mutations, their temporal sequence and their relative selectability is all in all a virtuoso performance. And it directly addresses the issue Behe raised with the evolution of the DPG binding site (3, see our critique). Behe and the Discovery Insitute have reacted quickly and negatively to this paper. But in doing so they display a curious amnesia. Behe says:

I certainly would not classify their system as IC. The IC systems I discussed in Darwin's Black Box contain multiple, active protein factors. Their "system", on the other hand, consists of just a single protein and its ligand."

Yet this "system" is precisely the thing that Behe uses in his exemplar for the Behe and Snoke paper, the binding of DPG to haemoglobin. And Behe has said in testimony to the Dover trial (3) that the Behe and Snoke paper on evolution of binding sites is about irreducible complexity. So if the evolution of the DPG binding site (where you only need two mutations to make a functioning DPG binding site) is an example of IC, then the evolution of the aldosterone binding site is also ([note 2]). As the BCT paper specifically cites the Behe and Snoke paper, you would expect they would look at the ideas contained in the paper, not "Darwins Black Box". Behe has had a long history of citing examples of molecular IC. He has even called disulfide bond "irreducibly complex" (2). So his disavowal of an example that directly addresses the Behe and Snoke paper (3) is particularly disingenuous. Stephen Meyer also argues on this line.

Contrary to what the authors assume receptor-hormone pairs do not constitute irreducibly complex systems. The receptor-hormone pair is only a small component of a signal transduction circuit that regulates other complex physiological processes. For such pairs to have any selective or functional advantage many other protein components have to be present, including the other components of a signal transduction circuit and the physiological processes that such circuits regulate. http://www.discovery.org/scripts/viewDB/index.php?command=view&id=3406

Yet, and I emphasise this again, Behe himself has argued in sworn testimony to the Dover trial that they do constitute IC systems (3). Don't the DI fellows follow each other's work? Once again we see that the Intelligent design promoters are willing to move the goal posts to avoid refutation of their ideas. Molecular IC is Behe's own invention, and he can't ignore his idea when it is disproved. Notes and references. [Note 1] Actually, evolutionary biologist H.J. Muller came up with irreducible complexity in 1918, as a prediction of Darwinian evolution. See H. J. Muller, "Reversibility in Evolution Considered from the Standpoint of Genetics," Biological Reviews 14 (1939): 261-80. In 1986 another evolutionary biologist, Cairns-Smith, also described IC systems produced by evolutionary processes. [Note 2] Technically, the GR receptor is an example of subfunctionalisation, where a generalist receptor becomes more selective. This is quite important in evolution. Behe's exemplar, binding DPG in haemoglobin, is a result of a reduction of specificty, the ATP binding site now binds DPG. When Meyer complains that the BCT paper does not generate a new protein fold family, well, neither does Behe's DPG example, which Behe claims demonstrates IC. (ironically, there is also a recent paper showing in more detail how protein fold familes evolve. Zeldovich KB, Berezovsky IN, Shakhnovich EI. Physical origins of protein superfamilies. J Mol Biol. 2006 Apr 7;357(4):1335-43.) [Note 3] added 11 April. Hagfish, Sharks and bony Fish don't actually have aldosterone, this is only found in tetrapods, but their receptors bind adlosterone and are activated by it. In non-tetrapod vertebrates, 11-deoxycorticosterone (DOC) plays the role of aldosterone. (1) "An irreducibly complex evolutionary pathway is one that contains one or more unselected steps (that is, one or more necessary-but-unselected mutations). The degree of irreducible complexity is the number of unselected steps in the pathway." http://www.arn.org/docs/behe/mb_indefenseofbloodclottingcascade.htm (2)

"Thus in a real sense the disulfide bond is irreducibly complex, although not nearly to the same degree of complexity as systems made of multiple proteins" "The problem of irreducibility in protein features 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."

http://www.discovery.org/scripts/viewDB/index.php?command=view&id=1205 (3) Behe MJ & Snoke DW (2004) Simulating evolution by gene duplication of protein features that require multiple amino acid residues. Protein Science.

There are none that use that phrase, but as I indicated in my direct testimony, that I regard my paper with Professor David Snoke as to be arguing for the irreducible complexity of things such as complex protein binding sites. Emphasis added IFM

http://www.talkorigins.org/faqs/dover/day11pm2.html#day11pm547

"So the point is that those little colored squares [amino acids] are enormously complex in themselves, and further the ability to get them to bind specifically to their correct partners also requires much more additional information. It is not a single step phenomenon. You have to have the surfaces of two proteins to match."

http://www.talkorigins.org/faqs/dover/day10pm2.html#day10pm371 (4) Bridgham JT, Carroll SM, Thornton JW. Evolution of hormone-receptor complexity by molecular exploitation. Science. 2006 Apr 7;312(5770):97-101. [PubMed ] [Abstract] [Full Text (subscribers only)] See also commentary Adami C. Evolution. Reducible complexity. Science. 2006 Apr 7;312(5770):61-3. [summary] [Full Text (subscribers)] (5) Weinreich DM, Delaney NF, Depristo MA, Hartl DL. Darwinian evolution can follow only very few mutational paths to fitter proteins. Science. 2006 Apr 7;312(5770):111-4. [PubMed] [Abstract] [Full text (subscribers only)] [I corrected a few typos -- Nick]

51 Comments

Mike Z · 10 April 2006

Last Friday, April 7th, the NY Times picked up on this story:
http://www.nytimes.com/2006/04/07/science/07evolve.html

Ever since the Dover decision, I have noticed a distinct change in the Times' coverage of these things. Before, they just stated the DI's propaganda next to the scientists' conclusions -- all in the interest of "unbiased reporting." Now the Times says things like, "This new finding shows why the ID proponents are wrong."

wamba · 10 April 2006

Michael Behe is known as the author of the concept of Irreducible Complexity (IC, but see [note 1]).

I think it would be more accurate to say that Behe came up with the phrase Irreducible Complexity. The concept has been around since the time of Anaxagoras. Behe himself has admitted that his argument is logically identical to Paley's watch.

wamba · 10 April 2006

Ever since the Dover decision, I have noticed a distinct change in the Times' coverage of these things. Before, they just stated the DI's propaganda next to the scientists' conclusions --- all in the interest of "unbiased reporting." Now the Times says things like, "This new finding shows why the ID proponents are wrong."

Yes, and I don't think this is specific to the NYTimes. It seems to apply to a fairly large chunk of the mainstream media.

SteveF · 10 April 2006

Out of interest, will you be addressing any of Behe's other claims in his response?

PvM · 10 April 2006

Let me repeat one of Ian's references since it indeed show the short term memory problem of Behe

For example, this yellow link is called a disulfide bond. 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 first have to occur. Thus in a real sense the disulfide bond is irreducibly complex, although not nearly to the same degree of complexity as systems made of multiple proteins
— Behe

A large contingent of ID activists including Behe, Meyer and Nelson have gathered to reject the Bridgham studies. Faced with an onslaught of evidence that IC systems can indeed evolve, they are now arguing that the study shows how science is taking IC and Intelligent Design seriously. Have they forgotten how Behe's own testimony at Dover and the ruling by Judge Jones shows that IC has nothing to do with ID but is merely a negative argument against the ability of variation and selection to explain a particular feature?

(2) the argument of irreducible complexity, central to ID, employs the same flawed and illogical contrived dualism that doomed creation science in the 1980's; and
— Judge Jones

And did these ID activists forget the admission by one of their own during the trial that IC is not proof of design (Minnich)?

As referenced, the concept of irreducible complexity is ID's alleged scientific centerpiece. Irreducible complexity is a negative argument against evolution, not proof of design, a point conceded by defense expert Professor Minnich. (2:15 (Miller); 38:82 (Minnich) (irreducible complexity "is not a test of intelligent design; it's a test of evolution").

In fact IC fails to make any scientific case for ID

Irreducible complexity additionally fails to make a positive scientific case for ID, as will be elaborated upon below.

The judge found what countless scientists have since long observed, ID is scientifically vacuous, and it is a purely negative argument against Darwinian pathways, not an argument FOR ID. For instance when Paul Nelson claims that:

Two days ago, I pointed out that it's a tad inconsistent to say there is no scientific controversy about ID, when one is participating in that very controversy (as Thornton and in fact a whole lot of other scientists and scholars are).
— Nelson

he conveniently has forgotten that IC has nothing to do with Intelligent Design. And people still deny that Intelligent Design is scientifically vacuous? Sigh...

Ginger Yellow · 10 April 2006

Even for a paper as wedded to the he said/she said paradigm as the New York Times, you can only be blatantly lied to so often before it affects your reporting. Even if you can stomach the personal insult as a journalist, repeating obvious lies without at least hinting that you realise they are lies just makes the paper look stupid and unreliable. Of course, this doesn't apply to the president, who can bring rather more powerful incentives to bear than most sources.

PvM · 10 April 2006

Behe's response includes the following 'arguments' which are laid to rest by Ian's excellent overview

1) This continues the venerable Darwinian tradition of making grandiose claims based on piddling results. There is nothing in the paper that an ID proponent would think was beyond random mutation and natural selection. In other words, it is a straw man.
— Behe

2) The authors (including Christoph Adami in his commentary) are conveniently defining "irreducible complexity" way, way down. I certainly would not classify their system as IC. The IC systems I discussed in Darwin's Black Box contain multiple, active protein factors. Their "system", on the other hand, consists of just a single protein and its ligand. Although in nature the receptor and ligand are part of a larger system that does have a biological function, the piece of that larger system they pick out does not do anything by itself. In other words, the isolated components they work on are not irreducibly complex.
— Behe

3) In the experiment just two amino acid residues were changed! No new components were added, no old components were taken away.
— Behe

4) Nothing new was produced in the experiment; rather, the pre-existing ability of the protein to bind several molecules was simply weakened. The workers begin their experiments with a protein that can strongly bind several, structurally-very-similar steroids, and they end with a protein that at best binds some of the steroids ten-fold more weakly. (Figure 4C)
— Behe

5) Such results are not different from the development of antibiotic resistance, where single amino acid changes can cause the binding of a toxin to a particular protein to decrease (for example, warfarin resistance in rats, and resistance to various AIDS drugs). Intelligent design proponents happily agree that such tiny changes can be accomplished by random mutation and natural selection.
— Behe

Just like in the Behe-Snoke paper... Interestingly enough Behe also makes the following statement

5) Such results are not different from the development of antibiotic resistance, where single amino acid changes can cause the binding of a toxin to a particular protein to decrease (for example, warfarin resistance in rats, and resistance to various AIDS drugs). Intelligent design proponents happily agree that such tiny changes can be accomplished by random mutation and natural selection.
— Behe

Really... and yet we have such ID activists as Dembski 'argue' Does Darwinian Evolution Explain Antibiotic Resistance?. Not to mention the comments by various "ID visionaries"... In Does gravity explain why basketballs fall down? Josh Rosenau helps ID activists understand science.

9) The fact that such very modest results are ballyhooed owes more, I strongly suspect, to the antipathy that many scientists feel toward ID than to the intrinsic value of the experiment itself.
— Behe

10) In conclusion, the results (and even the imagined-but-problematic scenario) are well within what an ID proponent already would think Darwinian processes could do, so they won't affect our evaluation of the science. But it's nice to know that Science magazine is thinking about us!
— Behe

W. Kevin Vicklund · 10 April 2006

Darwinian evolution can follow only very few mutational paths to fitter proteins.

Watch for the quote-miners of this article title. "Very few" was still 18 out of 120 possible paths, or 15% of the possible paths being fully selectable. That's about 1 in every 7 paths. Also, the abstract didn't mention how many of the remaining 102 paths were simply neutral for one or more steps, versus detrimental for one or more steps (though they may well address that in the paper itself). But the important part to take away from this is that there are 18 different ways that a microbe can use single point mutations and selection to develop a drug resistance 5 orders of magnitude higher than it started with, each step along the way being beneficial (to the microbe, that is). Scary, isn't it?

W. Kevin Vicklund · 10 April 2006

Let me clarify. By important, I meant from a health policy standpoint.

ivy privy · 10 April 2006

If anyone wants to pick the low-hanging fruit, you could make these points over at The Design Paradigm, the new blog of the folks at the IDEA Club at Cornell.

PvM · 10 April 2006

he conveniently has forgotten that IC has nothing to do with Intelligent Design.

Since ID itself is fully based on a negative argument based on the elimination of any and all known and unknown alternatives and not on any positive argument, it's more of a necessity than convenience to ignore these aspects and focus instead on the 'argument' that since science addresses some of the vacuous claims of ID, they are therefor taking ID seriously and there is indeed a controversy. I guess, given the response by the ID activists and the DI one can similarly conclude that the paper hits too close to home for comfort?

CJ O'Brien · 10 April 2006

TurboGoalposts v.3:16 is in full effect.

Nick (Matzke) · 10 April 2006

There are yet more variations on the definition of "irreducible complexity":

1. Is "evolvability" part of the definition, or not? See the "definitional complexity" page at EvoWiki:

Definitional Complexity
http://wiki.cotch.net/index.php/Definitional_Complexity

2. Are metabolic pathways "irreducibly complex"?

But it's just a metabolic pathway!
http://www.pandasthumb.org/archives/2005/11/coopting_coopti.html

3. Are macroscopic structures "irreducibly complex"? Behe claims they are not, but basically everyone else on his side has eagerly applied it at all levels. Behe himself applies irreducible complexity to macroscopic bicycles, mousetraps, jungle traps, etc.

RBH · 10 April 2006

Of course, all of this is irrelevant to Dembski, who recently redefined "irreducible complexity" in such a way that it cannot be determined if a given structure is or is not IC. Dembski accomplished that by adding two new criteria to the definition of IC. In addition to the knockout criterion (loss of the "basic" function due to loss of a part), Dembski now requires that (1) No simpler structure can perform the same function, and (2) that after a successful knockout, one cannot recover the "basic" function by "rearranging and adapting remaining parts" (p. 5). Thus on Dembski's redefinition, he tells us that a three-legged stool is not IC, since a solid block can perform the same "basic function" (keeping one's butt off the ground by means of a raised platform). One might also note that Behe's mousetrap is not IC under Dembski's redefinition.

Mark Perakh and I myself have shown that Dembski's addition of those criteria makes it impossible to determine whether a given structure is IC, and thus makes IC (even more) vacuous.

RBH

Unsympathetic reader · 10 April 2006

"Behe has claimed that he will accept that a system is not IC if someone can give a mutation-by-mutation account, with selective coefficients for each mutation, for that system."

That is about as far from the definition of IC laid out in Darwin's Black Box as you can get. His original definition of ICness can be assessed independently of any knowledge about the origin of a system. In this more recent claim he conflates unevolvability with ICness which is putting the cart before the horse.

What you see here is the main problem: Behe has muddied the waters by introducing multiple, non-identical definitions of ID. But the fact is, having published the original definition of IC in DBB, Behe no longer 'owns' the idea of what constitutes an IC system. He can swap between definitions as suits his fancy but most would recognize that it's a charade (much like Spetner's morphing definitions about what constitutes 'information' adn which transforms 'increase' or 'decrease' information). You can't change definitions 'mid-stream'.

Here's another problem: What is the simplest IC system out there? When confronted with the question of ICness and its relationship to evolvability, most working scientists would proceed to identify the simplest, most recently emerged IC system they could find. After all, the choice of model systems based on experimental tractability often determine whethers a hypothesis can be successfully tested. It is a reductionist strategy known and practiced by all good scientists. So, where are Behe's comments on this fundamental question which most biologists would consider as a first step in beginning such an investigation? We know Behe has written grant applications. This is the sort of question that reviewers consider first. If you were writing a research proposal, would you address it in the same manner that Behe has? I sure wouldn't.

Mike Lin · 10 April 2006

Of the claims in Behe's response, this seems to me to be the only one that has any direct relevance:

4) Nothing new was produced in the experiment; rather, the pre-existing ability of the protein to bind several molecules was simply weakened. The workers begin their experiments with a protein that can strongly bind several, structurally-very-similar steroids, and they end with a protein that at best binds some of the steroids ten-fold more weakly. (Figure 4C)

I think what he is trying to say (through some staggering terminology) is that "The study did not demonstrate how a binding interaction evolves from scratch, merely how existing binding interactions can be specialized by microevolution" -- fair enough. A few bonus points to the study because aldosterone was not actually produced in the ancestral organism -- but other similar corticosteroids were. So, the Science paper tells a beautiful story of functional specialization following gene duplication, giving rise to a more specific interaction. I think it is a fair point that the sense that you get from the pop science commentators that this is a thunderous refutation of everything IDers have ever said and done is over-reaching a bit -- the chicken-and-egg/micro-macro question is still there. But - showing that complex things arise gradually is the whole point; of course the mechanism seems unimpressive or "piddling" in retrospect.

Unsympathetic reader · 10 April 2006

Mike Line: "I think what he is trying to say (through some staggering terminology) is that "The study did not demonstrate how a binding interaction evolves from scratch, merely how existing binding interactions can be specialized by microevolution" --- fair enough."

And completely irrelevant to the question of whether or not a system is IC. Dembski and Behe have both provided arguments or markers of 'design' that purport to be effective even in the absence of historical knowledge of the systen. But when backed into a corner, they always resort to punting the question of historical origins deeper into the past. More unjustifiable conflation of terms...

Gary Hurd · 10 April 2006

The DI (DIngenuous) Creationists (or DICs), make a "big to do" about the Behe and Snoke paper (BS 2004) as exemplifying IDC's scientific bonafides. They repeated this in their recent pamphlet "Traipsing Into Evolution."

Congratulations Ian for an excellent review and exposition of this research relevant to IDC, and why the "science" of IDC still fails.

Joseph O'Donnell · 10 April 2006

Firstly, I'd like to point out that this paper provides interesting insights into how Toll-like receptors may have evolved as well. There are currently 10 different TLRs in humans and far more in other animals, with the research presented here providing insight into how we could look at the evolution of those TLRs. It would be very interesting to investigate what mutations would derive different TLRs to recognise different PAMPs (pathogen associated molecular patterns) from a Spaetzel like molecule.

Further, I'd like to link to the excellent commentary that Carl Zimmer has provided on this as well.

http://loom.corante.com/archives/2006/04/10/the_final_adventures_of_the_blind_locksmith.php

Bruce Thompson GQ · 10 April 2006

The DI (DIngenuous) Creationists (or DICs)

Burn

Behe and Snoke paper (BS 2004)

Double burn I vote a keg to Gary Hurd. Delta Pi Gamma (Scientia et Fermentum)

Joseph O'Donnell · 10 April 2006

Personally I think the biggest burn has come from Carl Zimmer:

Is it me, or is it strange that intelligent design advocates are telling biologists that they aren't working hard enough, that they are not getting enough results from their lab work? Remember, this is the same Michael Behe whose sole peer-reviewed paper in the past eight years was a computer model (and a pretty poor one, it turned out). Compare that to the work of Joe Thornton, the principal investigator on the new paper. In the past eight years he's published twenty papers on hormones and their evolution: he's been sequencing hormone receptor genes, working out how they respond to different hormones, determining how they're related to one another, and even resurrecting them after 450 million years of oblivion.

Now that is a major burn. The best part about it is it's 100% factual as well, which is what makes it so awesome.

wamba · 10 April 2006

Since Behe & Snoke 2004 has come up, I'll take the opportunity to mention the response by Michael Lynch: Simple evolutionary pathways to complex proteins this was discussed here on The Panda's Thumb in August 2005.

Before proceeding, a fundamental flaw in the argument of Behe and Snoke needs to be pointed out. Although the authors claim to be evaluating whether Darwinian processes are capable of yielding new multi-residue functions, the model that they present is non- Darwinian (King and Jukes 1969).
— Michael Lynch

Burn, baby burn.

steve s · 10 April 2006

And if anyone appreciates a good burn, it's us Church Burnin Ebola Boys.

a maine yankee · 10 April 2006

David Brin wrote:

"IDers produce little or no evidence to support their own position. ID promoters barely try to undermine evolution as a vast and sophisticated model of the world, supported by millions of tested and interlocking facts and by nearly a century and a half of rigorous review. At the level that they are fighting, none of that matters. Their target is the millions of American voters, for whom the battle is as emotional and symbolic as it ever was."

Do you feel like your in some surreal whack-a-mole game and your arm is tired?

Sorry if this was off thread, but to read how years of difficult lab work is dismissed as "piddling" sometimes just gets to one.

Sir_Toejam · 10 April 2006

Do you feel like your in some surreal whack-a-mole game and your arm is tired?

an apt analogy in more ways than one. It's similarly very hard to convince other rational beings that arguing with creationists isn't just a kid's game. that part is getting easier as the evidence of the damage these IDiots cause, even at the University level, is starting to "hit home" (pun intended). soon, I think, more and more scientists will be asking for a mallet.

ivy privy · 10 April 2006

soon, I think, more and more scientists will be asking for a mallet.

Sir! It's someone requesting a mallet, Sir! Course announcement

I am very pleased and excited to announce the following new course at Cornell: COURSE LISTING: BioEE 467/B&Soc 447/Hist 415/S&TS 447 Seminar in History of Biology SEMESTER: Cornell Six-Week Summer Session, 06/27/06 to 08/03/06 COURSE TITLE: Evolution and Design: Is There Purpose in Nature? COURSE INSTRUCTOR: Allen MacNeill, Senior Lecturer in Ecology & Evolutionary Biology, Cornell University

Sir_Toejam · 10 April 2006

the wonderful thing about a large club like a mallet is that they're cheap and easy to make.

No need for requisitions, just go and make one yourself.

a group of scientists concerned about creationists on campus can easily talk to the head of a dept. and the relevant Dean about their concerns.

a blunt instrument, perhaps, but still effective, and all too rarely used, based on my experiences.

Sir_Toejam · 10 April 2006

I would point out, that the course you mention does look to be an examination of the history of the ID movement, as opposed to an indoctrination in the theory, per sae.

If you look at the reading list (especially the optional one), it does look like the instructors aim is to show the differences between what ID is (a PR stunt) vs. real science.

hey, i could be wrong, but that's my impression.

I would highly recommend you discuss any potential concerns with the instructor first.

Elf Eye · 10 April 2006

Um, shouldn't that be DIsingenuous, as in "lacking in candor; giving a false appearance of simple frankness; calculating." Sorry. I'm an English professor.

Elf Eye · 10 April 2006

Of course, the ID advocates would still be DICs.

'Rev Dr' Lenny Flank · 10 April 2006

Ever since the Dover decision, I have noticed a distinct change in the Times' coverage of these things. Before, they just stated the DI's propaganda next to the scientists' conclusions --- all in the interest of "unbiased reporting." Now the Times says things like, "This new finding shows why the ID proponents are wrong."

Yes, and I don't think this is specific to the NYTimes. It seems to apply to a fairly large chunk of the mainstream media.

As I noted before, I think this process began before Dover, in Kansas. It was at the Kansas Kangaroo Kourt that the IDers were finally forced to put out the best they have, in the full glare of world attention --- and made public idiots of themselves. Lots of reporters covered the first day of the Kourt. The number then declines drastically, as each saw how utterly vacuous ID really is. At its conclusion, nearly every major paper in the US ran editorials against ID as science (the only major exception I can think of offhand being the Moonie Times). It was in the wake of Kansas that the press dropped its kid gloves.

Jason · 10 April 2006

1) This continues the venerable Darwinian tradition of making grandiose claims based on piddling results.

HA HA! As opposed to ID, which makes grandiose claims based on NO results! O lord!

Mike Z · 10 April 2006

Lenny--
Good point about the Kansas silliness (rather than Dover) finally showing the reporters what ID is really about. You are probably right about that.

Still, the formal courtroom (not kourtroom) procedure and the official legal decision in the Dover case can provide the reporters with good cover in case they are accused of bias. Unlike Kansas, it was a fair fight and ALL the facts were finally laid out for everyone to see. No room for the "darwinists were too afraid to show up" nonsense that we saw after Kansas.

Donald M · 10 April 2006

Whatever the ultimate significance of this paper, one thing is clear: IC as a concept of ID is both testable and potentially falsifiable and therefore completely scientific. You'll forgive me for not just accepting Ian's word that this has all soundly refuted IC...we'll need to see much more than just this one report. But, so much for all the bogus claims of ID not being scientific. Thanks for making that much perfectly clear.

Steviepinhead · 10 April 2006

What's been tested is evolution.

What's been refuted is the claim that IC even has a cognizable definition. Since it's just yet another camouflage for ID's moving goalposts gimmick, it remains scientifically vacuous and untestable.

RBH · 10 April 2006

Donald M wrote

Whatever the ultimate significance of this paper, one thing is clear: IC as a concept of ID is both testable and potentially falsifiable and therefore completely scientific. You'll forgive me for not just accepting Ian's word that this has all soundly refuted IC...we'll need to see much more than just this one report. But, so much for all the bogus claims of ID not being scientific. Thanks for making that much perfectly clear.

Since irreducible complexity does not derive from any theory of ID (there is no theory of ID), its status has no bearing on ID. Creationists have made fact claims about the world for centuries, and every such fact claim that's been tested has turned out to be false. The claim that there are structures too complicated to have evolved predates Behe by roughly 150 years -- Darwin famously anticipated it -- and that claim has been shown to be false numerous times, most recently by the Bridgham, et al. paper. RBH

Joseph O'Donnell · 10 April 2006

Donald

Whatever the ultimate significance of this paper, one thing is clear: IC as a concept of ID is both testable and potentially falsifiable and therefore completely scientific. You'll forgive me for not just accepting Ian's word that this has all soundly refuted IC...we'll need to see much more than just this one report. But, so much for all the bogus claims of ID not being scientific. Thanks for making that much perfectly clear.

Funny, if this is a testable aspect of IC then surely this completely falsifies it? Or have you failed to notice that the 'responses' from Behe et al, have been to redefine IC so this experiment can't falsify it in any manner? What other pet hypothesis needs to be redefined to avoid falsification on a regular basis as IC has? Also, you mistake the fact Douglas that the claims of several ID advocates are able to be shown to be false, while their central claim about their designer among other things are inherently unfalsifiable. That's part of what makes ID pseudoscience, you can disprove their claims (IC, CSI, the law that isn't a law and such forth) but their inherent claim of there being a designer is unfalsifiable.

'Rev Dr' Lenny Flank · 10 April 2006

IC as a concept of ID is both testable and potentially falsifiable and therefore completely scientific.

Blah blah blah. Tell it to the judge. Oh, wait . . . you already DID. (shrug) But now that you're back for another drive-by, Donald, let me repeat my questions for you once more -- just in case you missed them the first dozen times: What, again, did you say the scientific theory of ID is? How, again, did you say this scientific theory of ID explains these problems? What, again, did you say the designer did? What mechanisms, again, did you say it used to do whatever the heck you think it did? Where, again, did you say we can see the designer using these mechanisms to do ... well . . anything? Or is "POOF!! God --- uh, I mean, The Unknown Intelligent Designer --- dunnit!!!!" the extent of your, uh, scientific theory of ID .... ? How does "evolution can't explain X Y or Z, therefore goddidit" differ from plain old ordinary run-of-the-mill "god of the gaps? Here's *another* question for you to not answer, Donald: Suppose in ten years, we DO come up with a specific mutation by mutation explanation for how X Y or Z appeared. What then? Does that mean (1) the designer USED to produce those things, but stopped all of a sudden when we came up with another mechanisms? or (2) the designer was using that mechanism the entire time, or (3) there never was any designer there to begin with. Which is it, Donald? 1, 2 or 3? Oh, and if ID isn't about religion, Donald, then why do you spend so much time bitching and moaning about "philosophical materialism"? (sound of crickets chirping) You are a liar, Donald. A bare, bald-faced, deceptive, deceitful, deliberate liar, with malice aforethought. Still.

Ian Musgrave · 10 April 2006

In Message 95843

Out of interest, will you be addressing any of Behe's other claims in his response?
— Steve F

Not really, they are either covered by the post itself, or by other commenters (ah, the joys of posting from a different time zone) or by Carl Zimmer's excellent article. Basically, Behe brings in large numbers of red herrings to avoid the fact that the kinds of structures that he claims are IC in Behe and Snoke (3) are eminently evolvable. For example:

In the experiment just two amino acid residues were changed! No new components were added, no old components were taken away.
— Behe

Just like the DPG binding site that Behe uses as an exemplar in Behe and Snoke (3), the paper that Behe claims demonstrates IC. Don't knock one or two amino acid substitutions, they can add completely new reaction chemistry to an enzyme, or give it a novel substrate, or give it a new binding site (I'm working on a long post on this). However, the main point is that Behe uses the DPG binding site, which shows the same changes as the evolved GR receptor (indeed throughout the Behe and Snoke paper, none of the discussion mentions adding or removing components). Why these changes are IC for Behe and not for BCT is left unexplained by Behe. .

Nothing new was produced in the experiment; rather, the pre-existing ability of the protein to bind several molecules was simply weakened. The workers begin their experiments with a protein that can strongly bind several, structurally-very-similar steroids, and they end with a protein that at best binds some of the steroids ten-fold more weakly. (Figure 4C)
— Behe

This is called producing an increase in selectivity. Producing selective receptors is rather important from an organisms point of view[1]. This is something that fellow ID travellers like Lee Spetner says can't happen (yet it does, see my critique of Spetner's arguments for more information about the evolution of binding sites). Rather than being activated by multiple steroids, the receptor is now more effectively activated by cortisol than aldosterone (just like the modern receptor, lets not forget that these mutations produce a receptor with the sensitivity and selectivity of the modern receptor). The evolved receptor has a thousand fold less affinity for aldosterone than the ancestral one, while only 10 fold less affinity for cortisol. The evolved receptor is 100 times more selective for cortisol than aldosterone (whereas the ancestral one was 30 fold more selective for aldosterone). Behe obscures this important point by citing only the 10 fold change. Furthermore, the evolved receptor is sensitive enough to cortisol that it will be effectively activated by the plasma cortisol levels found in teleosts and tetrapods; neither so sensitive that is permanently jammed on by these levels, but can respond to stress-induced changes, nor so insensitive that it will not be activated (and basically has the same sensitivity as the modern GR). These are important points, although not actually relevant to IC, that Behe either ignores or doesn't understand in his attempt to minimise the importance of the BCT paper. It is also important to remember that vast majority of evolution of protein structures, even of the binding sites that Behe dearly wishes to see as IC, are modifications of things that already exist (again, I have a much longer post on this in the pipeline, so please be patient a while). Proteins already have in their structure loops and pockets that will bind ligands with only minor modification. In trypsin, only a single amino acid replacement is needed to generate a sodium-regulated enzyme. (Dang QD, Di Cera E Residue 225 determines the Na(+)-induced allosteric regulation of catalytic activity in serine proteases. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10653-6.). Protein-protein interactions are relatively easy to produce (in my line of work, stopping protein-protein interactions is important, so wide spread are they), so Behe trying to hang IC on protein-protein interactions is somewhat astonishing. I could go on at length about Behe's misunderstanding of biology, but mostly it is one or other variants of the issues raised in the main post, Carl Zimmers post and the other commenters. [1] Although not always. As an example using enzymes, some metabolic enzymes are very, very specific, while others, especially those that degrade toxins, can handle very many substrates; this "lack of specificity" is also very important to the organism.

Pete Dunkelberg · 10 April 2006

IC as a concept of ID is both testable and potentially falsifiable and therefore completely scientific.

Creationists are quite able to make false claims. By some definitions of IC, including Behe's classic "All parts required" defn, one can test whether something is IC. Disco claims that if it's IC, then the Disco Designer * must have * done it. This is false.

Mark Perakh · 10 April 2006

Re: comment 95970 by Donald M.

Whereas a concept has to be falsifiable in order to be scientific, the opposite is not true: falsifiability is a necessary but not a sufficient condition for a concept to be scientific. There are any number of falsifiable notions which have nothing to do with science. If I tell you that my neighbor is so strong that he can lift a 1000 pounds stone and throw it onto my lot over the fence, this is a falsifiable assertion which does not have anything to do with science. In particular, certain elements of Behe's IC concept are falsifiable but still beyond science because of their utter inconsistency and uncertain meaning. Moreover, IC has been shown to be false from various standpoints, biological, probabilistic, informational, etc., and the paper by Bridgham et al is just a latest nail in the coffin of IC.

Even if IC is falsifiable in certain respects, it does not make ID falsifiable. ID is a very general conjecture enabling one to "explain" anything as resulting from design. In fact IC does not logically segue into ID. As I argued in my essay in Skeptical Inquirer (its text is available online - see here),
if a system is IC according to Behe's original definition, it points either to bad or to malevolent design (beyond the trivial suboptimality) or to the absence of design. Behe never responded.

The most plausible interpretation of IC is that it is an arbitrary concoction with no empirical support whatsoever, logically deficient, and contrary to factual data, and Behe is delusional (he believes he performed admirably at the Dover trial while the observers saw in fact a humiliating debacle of that former scientist). Of course the ID advocates will never accept the critique of IC because it is one of their last remaining arguments which, they hope, may have an appearance of being scientific.

Ian Musgrave · 10 April 2006

In Message 95979

This is called producing an increase in selectivity. Producing selective receptors is rather important from an organisms point of view[1].
— Ian Musgrave

I forgot to point out that the DPG binding site Behe uses as an exemplar goes from being an ATP binding site to a DPG/ATP binding site. This is a loss of specificity. Behe's complaints are ironic in this regard.

PvM · 10 April 2006

IC as a concept of ID is both testable and potentially falsifiable and therefore completely scientific.
— Donald M

IC has no relevance to ID it's just a negative argument against Darwinian evolution jeez. While ID activists are hardly upfront about this, it is self evident and even exposed when under oath in court. Conflation of terms, so commonly found in ID activists' writings, hides the scientific vacuity.

Ian Musgrave · 11 April 2006

In Message 81029

Out of interest, will you be addressing any of Behe's other claims in his response?
— Ian Musgrave
Not really, they are either covered by the post itself, or by other commenters (ah, the joys of posting from a different time zone) or by Carl Zimmer's excellent article.

However, I do want to highlight one other issue, which I have commented on (in a somewhat different version) over on Carl Zimmer's blog that throws light on Behe's understanding of biology.

"In the 'most promising' intermediate protein (the one that has just the S106P alteration) the protein has lost about 99% of its ability to bind DOC and cortisol, and lost about 99.9% of its ability to bind aldosterone."
— Behe

Talking about the effect of the S106P mutation in this way conceals what actually happens. The S106P receptor is less sensitive for the various hormones, it is a 100 times less sensitive to DOC, about 100 times less sensitive to cortisol and 1000 time less sensitive to aldosterone (so it's in the process of becoming more cortisol selective). But the S106P receptor still responds to the hormones, is activated more strongly (40 fold vs 20 fold for the maximally effective concentration of DOC). The significance of this is apparent when we look at the plasma concentrations of these hormones. In fish, typical DOC plasma concentrations range from 6 nM to 10 nM (and higher under stimulation), which would be more than adequate to stimulate the S106P receptors to the levels seen in the ancestral receptor (10 nM DOC produces a 20 fold activation of the S106P receptor, which is the maximal activation of the ancestral receptor). Typical plasma cortisol levels (around 165 nM) would provide only half the stimulation in the ancestral receptors, but stress-induced levels (typically around 1000 nM) would activate the S106P receptor to the same extent as in the ancestral receptors receptors. So compared to the ancestral receptors, with the typical levels of steroid hormones found in fish, the S106 receptor will be functioning pretty much as the ancestral one.

"The authors do not test for that [that S106P would be weeded out by natural selection]; they simply assume it wouldn't be a problem, or that the problem could somehow be easily overcome. Nor do they test their speculation that DOC could somehow act as an intermediate ligand. In other words, in typical Darwinian fashion the authors pass over with their imaginations what in reality would very likely be serious biological difficulties."
— Behe

This shows the limitations of critiquing biology when you don't know too much about it. Now, Thornton at least, being a steroid receptor specialist (and most of his receptor specialist readers) would be aware of the plasma steroid hormone levels and hence know he was talking about effectively neutral mutations. Furthermore, if you look at figure 2B in the BCT paper, you will see that the standard Teleost glucocorticoid receptor has effectively the same cortisol sensitivity as the S106P receptor. In fact, the Teleost receptor is a bit less sensitive, and a fair bit less effective, than the S106P receptor, and fish do just fine. So for all intents and purposes, the S106P mutation is neutral. Behe is very unlikely to know what the plasma levels of these steroids are, but he should have had a look for them if he had any biological background, as the plasma levels of a hormone are critical for understanding how the receptor functions. Also, he should have looked a wee bit more closely at look closely at figure 2B, showing the very low Teleost sensitivity to cortisol (the significance of which, if you are not a receptor biologist like me, is not immediately apparent). Behe assumed BCT pulled neutrality out of a hat, but we know from the biology that the S106P mutation will be neutral (after all, fish function quite nicely with a "worse" receptor). BCT may have not tested DOC as an intermediate ligand in the sense Behe intended (whatever that is, showing that it activates all current and ancestral receptors and does so effectively at its plasma concentration in fish isn't a test? Sounds like a test to me.). But we know that it does act that way in modern fish (Sturm A, Bury N, Dengreville L, Fagart J, Flouriot G, Rafestin-Oblin ME, Prunet P. 11-deoxycorticosterone is a potent agonist of the rainbow trout (Oncorhynchus mykiss) mineralocorticoid receptor.Endocrinology. 2005 Jan;146(1):47-55. [PubMed].) So if DOC acts as an aldosterone intermediate in fish, then what more do you need? Again, Thornton and other steroid receptor specialists will know this, I found this out with a very simple pubmed search, why couldn't Behe (I specialize in biogenic amine receptors, {heck, who could be interested in something that doesn't stimulate trimeric G-proteins [that's a receptorologist joke folks]}, so I'm not instantly familiar with the fine details)? He could have asked a receptor specialist at the very least before sounding off, or perhaps read some of the references in the reference list, which cover most of the issues here. However, ignorance of the relevant biology has never stopped Behe commenting in the past, so I don't expect him to change soon, but he could have at least read the paper with a little more care, as all the relevant clues are within.

SteveF · 11 April 2006

Thanks Ian, explanations much appreciated. I spend most of my day looking at pollen for the purposes of palaeoecology so this is a little out of my field of expertise.

Joseph O'Donnell · 11 April 2006

However, ignorance of the relevant biology has never stopped Behe commenting in the past, so I don't expect him to change soon, but he could have at least read the paper with a little more care, as all the relevant clues are within.

This is well said Ian, bearing in mind that Behe doesn't think much of actual published research anyway. This is the same Michael Behe that when presented with a large number of papers on the immune system, conceded that he had never bothered reading the vast majority of them. Why would he feel the need to become familiar with the area of research he is criticising?

Ginger Yellow · 11 April 2006

Surely the biggest "burn" with regard to Behe and Snoke is that Behe admitted under oath that contrary to supporting his claims it in fact demonstrated the evolvability of supposedly IC systems in a remarkably short period of time even under extremely unfavourable conditions. In other words the only actual research by an IDer disproves his own argument for design, by his own sworn admission.

Aagcobb · 11 April 2006

Ian Musgrave wrote

However, ignorance of the relevant biology has never stopped Behe commenting in the past, so I don't expect him to change soon, but he could have at least read the paper with a little more care, as all the relevant clues are within.

He could, if he was really interested in scientific research, which he isn't. We know that from his testimony in Dover. The accuracy of his comments are irrelevant to him; all that matters is that he sound scientific enough to fool his target audience, fundamentalist christians, into believing that their faith is supported by science. That doesn't require that he make any effort to appear credible to scientists.

Reed A. Cartwright · 11 April 2006

Damn, Ian, I'm so glad you blogged this instead of me. I don't have any background in receptor biology.

Clark D. Hinderleider, M.D., Ph.D. · 12 April 2006

Published comment quoted:
Using new techniques for resurrecting ancient genes, scientists have for the first time reconstructed the Darwinian evolution of an apparently "irreducibly complex" molecular system. The research was led by Joe Thornton, assistant professor of biology at the University of Oregon's Center for Ecology and Evolutionary Biology, and published in the April 7 issue of SCIENCE. How natural selection can drive the evolution of complex molecular systems - those in which the function of each part depends on its interactions with the other parts--has been an unsolved issue in evolutionary biology. Advocates of Intelligent Design argue that such systems are "irreducibly complex" and thus incompatible with gradual evolution by natural selection.
"Our work demonstrates a fundamental error in the current challenges to Darwinism," said Thornton. "New techniques allowed us to see how ancient genes and their functions evolved hundreds of millions of years ago. We found that complexity evolved piecemeal through a process of Molecular Exploitation -- old genes, constrained by selection for entirely different functions, have been recruited by evolution to participate in new interactions and new functions."
The scientists used state-of-the-art statistical and molecular methods to unravel the evolution of an elegant example of molecular complexity - the specific partnership of the hormone aldosterone, which regulates behavior and kidney function, along with the receptor protein that allows the body's cells to respond to the hormone. They resurrected the ancestral receptor gene - which existed more than 450 million years ago, before the first animals with bones appeared on Earth - and characterized its molecular functions. The experiments showed that the receptor had the capacity to be activated by aldosterone long before the hormone actually evolved.
Thornton's group then showed that the ancestral receptor also responded to a far more ancient hormone with a similar structure; this made it "preadapated" to be recruited into a new functional partnership when aldosterone later evolved. By recapitulating the evolution of the receptor's DNA sequence, the scientists showed that only two mutations were required to evolve the receptor's present-day functions in humans.
"The stepwise process we were able to reconstruct is entirely consistent with Darwinian evolution," Thornton said. "So-called irreducible complexity was just a reflection of a limited ability to see how evolution works. By reaching back to the ancestral forms of genes, we were able to show just how this crucial hormone-receptor pair evolved."

Morgan-LynnLamberth · 14 April 2006

Behe won't acknowledge reality .Logic is the bane of all creationists[theists].