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Author
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Topic: No False Positives and the Lust for Certainty
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William A. Dembski
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Member # 7
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posted 06. November 2002 12:45
On another thread, the concern was raised that ID allows no tentativeness in inferring design because of the claim (in fact my claim) that specified complexity admits no false positives. Please have a look at my paper http://www.designinference.com/documents/2002.10.logicalunderpinningsofID.pdf, which clarifies what's at stake.
Briefly, the claim that specified complexity is a reliable marker of design means that if an item genuinely instantiates specified complexity, then it was designed. As I argue and continue to maintain, no counterexamples to this claim are known.
But how do we know that something is complex and specified? It's here that we need to move from specified complexity as we can best assess it on the basis of available evidence to specified complexity as a fact about some item in nature. The issue, then, as I argue in the paper cited above is not with reliability but with assertibility, namely, our epistemic justification for asserting that some item instantiates specified complexity. Such assertions can be wrong, so varying degrees tentativeness attach to design inferences as to all scientific claims.
The logic of design therefore moves from assessing the assertibility of specified complexity in specific circumstances to specified complexity as a reliable marker of design to design itself.
My readers, it appears, have been thrown by the reliability issue. There's a definite fact of the matter connected with specified complexity (things genuinely instantiate specified complexity or they don't). Moreover, that fact of the matter is a different fact from an item's causal history and design. The reliability claim connects the two, but says nothing about whether we can know or be justified in asserting that something instantiates specified complexity in the first place.
I argue that we are justified asserting specified complexity (and therefore design) once we have eliminated all known material mechanisms. It means that some unknown mechanism might eventually pop up and overturn a given design inference. But it also means that we have prima facie evidence of design and that we are justified in holding to this claim in the absence of such mechanisms being found. I also note that there can be cases where all material mechanisms (known and unknown) can be precluded decisively. Have a look at the paper cited above.
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charlie d.
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Member # 159
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posted 06. November 2002 14:42
I have no qualifications to review the theoretical/philosophical aspects of this paper, but I would like to briefly correct what I think is a substantial biological error, that I have seen made repeatedly on this board and elsewhere.
In his paper Bill Dembski discusses the implications of Doug Axe's JMB paper on the effects of TEM-1 mutations on beta-lactamase enzymatic activity; unfortunately, this discussion highlights a deep and unfortunate misinterpretation (again, apparently common among ID theorists) of this work.
Dembski says: quote:
But there is now mounting evidence of biological systems for which any slight modification does not merely destroy the system's existing function, but also destroys the possibility of any fucntion of the system whatsoever (Axe, 2000). For such systems, neither direct nor indirect Darwinian pathways could account for them.
The truth is, however, that in his paper Axe only tested the function of mutant TEM-1 beta-lactamase variants against 2 antibiotics, penicillin and ampicillin, which are known TEM-1 targets. No other potential function of TEM-1 was tested, leaving the theoretical possibility of indirect Darwinian pathways, in fact, wide open, contrarily to ID interpretation.
Interestingly, that this can be exactly the case was confirmed empirically, just recently, by Wang and coworkers, in the following JMB paper: quote:
J Mol Biol 2002 Jun 28;320(1):85-95
Evolution of an antibiotic resistance enzyme constrained by stability and activity trade-offs.
Wang X, Minasov G, Shoichet BK.
Pressured by antibiotic use, resistance enzymes have been evolving new activities. Does such evolution have a cost? To investigate this question at the molecular level, clinically isolated mutants of the beta-lactamase TEM-1 were studied. When purified, mutant enzymes had increased activity against cephalosporin antibiotics but lost both thermodynamic stability and kinetic activity against their ancestral targets, penicillins. The X-ray crystallographic structures of three mutant enzymes were determined. These structures suggest that activity gain and stability loss is related to an enlarged active site cavity in the mutant enzymes. In several clinically isolated mutant enzymes, a secondary substitution is observed far from the active site (Met182-->Thr). This substitution had little effect on enzyme activity but restored stability lost by substitutions near the active site. This regained stability conferred an advantage in vivo. This pattern of stability loss and restoration may be common in the evolution of new enzyme activity. (c) 2002 Elsevier Science Ltd.
That is, TEM-1 variants that had lost stability and ability to confer penicillin resistance (thus, mutants of the inactive kind described by Axe), were found to be active against a different class of antibiotics, cephalosporins.
As this pathway could obviously be run "in reverse", these findings clearly show how an ampicillin/penicillin-active enzyme can be derived by point mutation of a closely related enzyme with different, non-overlapping specificity (which would qualify as the supposedly evanescent "indirect Darwinian pathway" to beta-lactamase activity).
Most importantly, this shows how selective pressures acting on biological organisms, in the form of bacteria under lethal cephalosporin selection, have a way to come up with unpredicatble solutions that even good, intelligent molecular biologists like Axe cannot foresee.
Hopefully, this very basic mistake will now cease to find its way into ID literature.
[ 06. November 2002, 17:00: Message edited by: charlie d. ]
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Janitor@MIT
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posted 06. November 2002 15:28
?
For nature, necessity, and chance are thought to be causes, and also reason and everything that depends on man.—Aristotle (Nichomachean Ethics III: 3)
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William A. Dembski
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Member # 7
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posted 06. November 2002 15:51
Charlie:
Your refutation doesn't seem quite as knock-down as you suggest. In the experiment you cite, how many amino acid changes were made? I don't have the paper in front of me, but I would guess it's less than the number of changes Axe needs to get global degradation. Also, how do we individuate the functions? We're talking some sort of antibiotic/penicillin resistance in both cases. So depending on how we individuate function, it seems that you may well lose the evolvability you're after.
I'll see if I can get Doug Axe to respond to your post.
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charlie d.
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Member # 159
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posted 06. November 2002 16:15
I'd have to check the Wang paper again to find out how many aminoacids were mutated in the variants they identified (btw these were natural variants from clinical samples, not artificially generated ones *), but this is irrelevant to the fundamental point. The authors show that an unstable and penicillin-inactive enzyme can have detectable activity vis-a-vis another substrate, and be selected for this function. The same, theoretically, could hold true for one or more (or all) of Axe's mutants, as far as anybody knows (but it would be good if he commented on this directly, this is not my field).
Quite obviously, and unfortunately, we cannot check all inactive mutants against all the possible ranges of biological activities such mutants may have. Thus, it is impossible to assert with any reasonable degree of certainty that a mutant protein cannot have any function whatsoever, as claimed by you and others for TEM-1 mutants. The ability of evolution to co-opt the most unlikely candidates for the most disparate functions (enzymes for crystallins, or anti-freeze peptides, etc) should give anybody pause in this respect.
Nobody disputes Axe's conclusion that TEM-1 beta-lactamase function is strictly dependent on a large number of structural constraints that are not prima facie evident when looking at the protein. Indeed, that such structural constraints may be more common than expected is the real, important message of Axe's work, and if confirmed and expanded to a larger number of proteins, it could have have implications for evolutionary biology. However, that such constraints preclude indirect Darwinian pathways seems an untenable conclusion, first of all on theoretical grounds, and, in light of Wang's data, possibly empirically as well.
[*Edit: actually, IIRC, they were artifical re-creation of natural variants, that is, the sequence of natural variants found in the literature was introduced by mutagenesis into wild-type TEM-1]
[ 06. November 2002, 16:57: Message edited by: charlie d. ]
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William A. Dembski
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Member # 7
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posted 06. November 2002 16:25
Charlie,
The point I raise is not irrelevant since the number of amino acid substitutions was important in Axe's work, where after a certain number of such substitutions there was no folding. So have a look at the paper you cite and answer the question. If the number of substitutions they consider is considerably less than the number Axe determined for total degradation of function, then your refutation fails.
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charlie d.
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Member # 159
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posted 06. November 2002 16:55
But Bill (if I can call you that), I am sure you do appreciate that, logically, even if you show that X mutations in a protein A cause a loss of one specific function f, this tells you very little about whether the same X mutations will inactivate the unrelated function f' of protein A', a single-aminoacid variant of A (even assuming that Wang's is a single aminoacid variant). It is indeed well possible that function f is more sensitive than function f' to the cumulative effect of X mutations.
So, as long as you can get to A' by a smooth, direct darwinian pathway, from there you can get to A through the back door, so to speak. In fact, you can even imagine a series of successive, related A', A", A(n) mutants, with functions f'-f(n), all connected to each other by single substitutions. I am sure you get the picture. You simply cannot a priori exclude that an indirect pathway through another selectable function exists, simply because cumulative mutations kill the one or two activities you know about and/or can test in the lab.
Wang's paper just shows that such a back-door might be open for TEM-1 through its mutants with cephalosporin resistance activity.
[PS: Incidentally, I am not even sure Axe ever made any point about his mutations killing "any function whatsoever", and about direct/indirect darwinian pathways to a function. It seems to me his much more specific argument was that within the beta-lactamase gene family, evolution by neutral mutation and drift was unlikely, because cumulative mutations appear to kill the intermediate proteins, hence their ability to confer penicillin/ampicillin antibiotic resistance. Of course, this also is strictly dependent on identifying the relevant functions under selection, any alternative functions that may be involved, and the conditions in which such selective pressures occurred.]
[ 06. November 2002, 18:18: Message edited by: charlie d. ]
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rafe gutman
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Member # 134
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posted 06. November 2002 20:50
quote:
dembski:
But there is now mounting evidence of biological systems for which any slight modification does not merely destroy the system's existing function, but also destroys the possibility of any fucntion of the system whatsoever (Axe, 2000). For such systems, neither direct nor indirect Darwinian pathways could account for them.
dr. dembski, don't you think you're exaggerating the results of the axe paper? for example, axe creates groups of mutations of the beta-lactamase gene TEM. each of the mutant groups by themselves result in a functional protein, yet you write that "any slight modification" destroys function. also, you describe the mutations as "slight". however, there are 10 amino acid substitutions per group. those are hardly "slight" modifications.
as charlie already pointed out, axe never tested for any alternative function, so you cannot conclude that no function exists. in fact, the wang paper demonstrates otherwise. in light of the evidence in the wang paper, would say the following is true or false?
any slight modification of TEM-1 destroys any possible function of the system whatsoever
it should also be pointed out that the massive number of mutations that axe created were done in a single round without selection. this is not be representitive of evolution. a better experiment would be to amplify the gene via PCR with an error-prone polymerase, reintroduce it into bacteria, then select for function. after several rounds of this you might start to see some drift. i don't think the purpose of axe's experiments was to test darwinian evolution, but rather to see whether mutations that were stable individually would be unstable when grouped together. i'm not sure how you concluded from his article that, "For such systems, neither direct nor indirect Darwinian pathways could account for them". could you explain this?
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William A. Dembski
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posted 06. November 2002 21:57
Rafe,
I met with Douglas Axe at the recent RAPID conference and I've had a preview of where his research is going for some time (at least since the summer of 2000), so in reading his JMB paper, I'm anticipating where's he's going. I agree that the JMB paper does not resolve the issues we are debating. That's why I put it in terms of "preliminary indications."
I'd still like to know how many amino acid substitutions we were talking about in the Wang paper. Also, I would like to get this thread back on track -- namely, the issues of reliability and assertibility in relation to specified complexity, which are logically separable and whose conflation has caused some of my critics difficulty.
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charlie d.
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posted 06. November 2002 22:24
Hi rafe:
Thanks for pitching in. I think your analysis is largely correct. I realize now this thread did not develop well, in large part because my initial post sounded excessively confrontational, which led Dembski to turn defensive. My fault.
For the sake of clarity, let me recapitulate briefly what I see Axe’s claims to be, what Wang’s paper adds to them, and what the current ID interpretation is (as epitomized by Dembski in his article).
Axe’s paper
As I remember it (I don’t have access to a copy right now), the central point of Axe’s paper was the existence of constraints posed by apparently “neutral” substitutions to protein evolution by genetic drift. That is, he challenged the probably somehow simplistic view that proteins are largely made up of “stuffer” sequences, with great tolerance for aa substitutions, that can freely mutate and “wander around” without much effect on protein function, which is restricted to a small subset of aa. Thus, he took TEM-1 and (IIRC) barnase, and replaced a number of residues that on the basis of phylogenetic analysis were expected to be selectively neutral. He found that combining more than a certain number of such supposedly neutral mutations effectively killed protein function. Therefore, he concluded, proteins cannot just perform easy random walks at their non-essential positions during drift. Indeed, he said those two proteins appeared to exist in largely isolated peaks, each corresponding to the protein in a certain organism, and that transition form one peak to another, maintaining function intact, appeared highly unfavored.
Again, this is an interesting finding regarding neutral evolution of related proteins within a functional family, with the caveats mentioned above of understanding what the function under selection really is at any given transitional stage, of the progressive nature of evolution (vs the single-shot alteration Axe made), and of course the potential extension of these findings to other proteins.
Wang’s paper
The Wang paper addresses a different point. It shows that new functions (in this case, a substrate specificity change) can evolve from an existing protein, at the expense of other functions, if the selection pressures are appropriate. They also showed that to a certain extent adaptive “valleys” can be crossed in the transition from one peak to another (in their case, certain mutations allowed some level of cephalosporin resistance by sacrificing both penicillin resistance and protein stability, but that the latter could be regained by a successive mutation found in some highly resistant variants).
Therefore, Wang’s paper speaks more directly to the issue of direct vs indirect Darwinian evolution, co-option, functional shifts and so on. This paper of course does not stand in opposition to Axe’s results. Both findings are compatible.
ID interpretation
To paraphase Dembski, Axe’s data supposedly show that certain proteins are so functionally isolated, that evolutionary pathways in any direction, whether direct or indirect, are precluded. These proteins cannot evolve new functions, nor can they be the evolutionary product of functional shifts in other proteins. In a sense, they are monomeric IC complexes (I guess one can almost construe each mutation-sensitive aa residue as a necessary element in the multimer).
To me, this conclusion is clearly erroneous, and is based on
a) a major misunderstanding of Axe’s paper, which did not address protein evolutionary origin or shifts in function, by whatever pathway (Darwinian or neutral, direct or indirect), at all. Axe’s “evolutionary isolation” only referred to the potential for neutral evolution within a functional family.
b) lack of appreciation of the objective impossibility to predict and experimentally address all the potential alternative functions of any protein, and of the remarkable flexibility of proteins as far as functional diversification. As empirically shown by Wang, loss of anti-penicillin activity, and even of protein stability (which would appear as objectively counterselected properties) in fact may be selectively favored when a different and more significant selective pressure (cephalosporins) is applied. Thus, any claim of complete evolutionary isolation of a protein is theoretically pretty much unsustainable.
I realize this topic is only tangential to the original post (although in a sense it bears on the issue of drawing "false positive" inferencces based on incomplete knowledge). However, since I had heard this claim made in several occasions, I thought it was important to straighten it out vis-ā-vis what’s actually in the published literature. If Axe shows up, I’d love to hear his take. As far as where Axe’s research is going, I’d love to hear that too (although until it’s published I bet he is going to be cautious spelling it out), but of course any public claim based on whatever unpublished research is purported to show should be accompanied by the necessary clarifications and an obvious amount of due caution.
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Frances
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Member # 169
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posted 07. November 2002 00:28
I would like to revisit the thread's original thesis about false positives.
So far the confusion remains, does the EF have false positives or not? That a very limited sample of examples which seem to be mainly involving chance versus ID scenarios seem to work is not surprising, after all criminology, archaeology all have been able to infer 'ID'. BUT there is a major problem, these ID inferences all posessed _independent_ evidence to help forumulating the thesis. Lets call these example of design regular Intelligent design. But then there is something which has been refered to as 'rarefied design' by Elsberry and Wilkins. Rarefied design cannot be distinguished from ignorance since rarefied design does not allow for inductive generalizations.
I argue that in absence of any independent evidence, rarefied design cannot be separated from ignorance and thus we should refrain from jumping to conclusions of design.
After all it is hardly self evident that CSI cannot be generated by chance or regularity. Given the major problems with the design inference, probabilistic modus tollens arguments and recent findings that seem to argue that the NFL theorems may not even apply to biological evolutionary algorithms and we come to the conclusion that unless we have some supporting evidence, we should not find the defendent 'guilty'. In fact, more than enough reasonable doubt exists to chalk one up to our ignorance until additional data shows otherwise.
Why is ID different from scientific hypotheses? ID does not propose any hypotheses so while science can propose hypothetical pathways to escape from ignorance, ID is bound tightly to ignorance until it can shake the rarefied adjective.
Thus my call for exploring possible predictions of ID as explained in the thread 'the future of ID'. Bill seems upset about the AAAS recent comments on ID but Bruce Gordon seems to argue similarly:
quote:
In conclusion, it is crucial to note that design theory is at best a supplementary consideration introduced along- side (or perhaps into, by way of modification) neo-Darwinian biology and self- organizational complexity theory. It does not mandate the replacement of these highly fruitful research paradigms, and to suggest that it does is just so much overblown, unwarranted, and ideologically driven rhetoric. Intellectual honesty demands that the wide-range of flexibility as regards the interpretation and significance of design theory be made abundantly clear. The dutiful avoidance of dogmatism, an irenic attitude, and a healthy dose of humility will by themselves, I think, do much to dispel the controversy at Baylor and help open the doors for the acceptance of design theorists as dialogue partners in the wider academic community.
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rafe gutman
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posted 07. November 2002 04:17
quote:
dembski, original post:
I also note that there can be cases where all material mechanisms (known and unknown) can be precluded decisively.
this is something i'd be interested in. when i looked through your article for where you spoke of this, it seemed your only support was axe's paper. in fact, the next sentence after the one's quoted by charlie and myself in previous posts is:
quote:
in that case we would be dealing with an in-principle argument not merely that no known material mechanism is capable of accounting for the system but also that any unknown material mechanism is incapable of accounting for it as well.
is the axe paper the only support you have for your assertion?
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Dene Bebbington
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posted 07. November 2002 09:37
William Dembski wrote:
quote:
The logic of design therefore moves from assessing the assertibility of specified complexity in specific circumstances to specified complexity as a reliable marker of design to design itself.
For the inductive generalisation of CSI to carry weight I believe that ID needs to get down to brass tacks. In Dembski's writings I've encountered few worked examples of things known to be designed which exhibit CSI. Specifically, I've only seen examples apparently made up for illustrative purposes.
I'd like to ask Dembski to list all the worked worked examples that are the body of data his induction of CSI is based on. Particularly useful would be some man-made objects.
--
Dene
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Paul A. Nelson
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posted 07. November 2002 09:55
To Frances:
Please say whether you agree or disagree with the following argument from Wilkins and Elsberry:
quote:
...why are we ever forced to a rarefied design conclusion? Surely we can content ourselves with regularities, chance, and "don't know" explanations. (p. 721)
Also, using your own words, please explain the criteria that distinguish ordinary and rarefied design inferences.
Note to Moderator: Charlie D introduced material into this thread that took it in two (or more) directions at once. Would it be possible to move the Axe-related posts to a separate thread, with an appropriate title (something like "Challenges to Axe's Interpretation")? Thanks.
[ 07. November 2002, 10:08: Message edited by: Paul A. Nelson ]
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charlie d.
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posted 07. November 2002 10:07
quote:
Note to Moderator: Charlie D introduced material into this thread that took it in two (or more) directions at once. Would it be possible to move the Axe-related posts to a separate thread? Thanks.
Sounds like a good idea, I'll do it myself.
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