## Friday, August 01, 2014

### Taking the Behe challenge!

Michael Behe thinks the main thesis of his book, The Edge of Evolution, has been vindicated by a recent paper (Summers et al., 2014). He is wrong, as I discussed in a previous post [Michael Behe and the edge of evolution].

PZ Myers and Ken Miller have already made the same points that I make but the IDiots never listen when their view are challenged. Instead, they go on the attack and claim that the latest publications refute evolution and support Intelligent Design Creationism.

Behe is certain that he's right. He's so certain that he has issued a challenge to Myers and Miller [An Open Letter to Kenneth Miller and PZ Myers]. I'm going to try and do some calculations to meet his challenge but I'm not certain if I'm doing them correctly. Please help me find any mistakes.

Here's the Behe challenge.
Dear Professors Miller and Myers,

Talk is cheap. Let's see your numbers.

In your recent post on an earlier reviews of my book The Edge of Evolution you toss out a lot of words, but no calculations. You downplay FRS Nicholas White's straightforward estimate that—considering the number of cells per malaria patient (a trillion), times the number of ill people over the years (billions), divided by the number of independent events (fewer than ten)—the development of chloroquine-resistance in malaria is an event of probability about 1 in 1020 malaria-cell replications. Okay, if you don't like that, what's your estimate? Let's see your numbers.
I can't speak for Myers and Miller but I don't have a problem with the idea that chloroquine resistance in Plasmodium falciparum is a rare event. As the Summers et al. paper shows, effective resistance requires several mutations. This has been known for a long time. That's why it's rare.
The malaria literature shows strong population genetics evidence for fewer than ten independent origins of resistance. The riddle is, why so few? Show us all your calculation for that. Here's a number to keep in mind—1012. That's roughly the number of malarial cells in one sick person. Here's another—10-8. That's a generous rounding-up of the mutation rate for malaria. (Multicellular eukaryotes are an order of magnitude less.) That means on average ten thousand copies of each and every point mutation of the malarial genome will be present in every person being treated with chloroquine.
Hmmm ... something doesn't sound right. Let's assume that Behe is right about the total number of cells in an infected individual (= one trillion, 1012). Let's also assume that this applies to patients who are being treated with chloroquine.

Theme
Mutation
-definition
-mutation types
-mutation rates
-phylogeny
-controversies
His number for the mutation rate seems too low. The reference he gives is a paper by Paget-McNicol and Saul (2001). They estimated that the mutation rate in P. falciparum is 2.5 × 10-9 per base pair per replication. That seems a bit high since typical eukaryotic mutation rates are 10-10 and some unicellular eukaryotes have mutation rates that approach 10-11 (Sung et al., 2012). But if Michael Lynch agrees with that estimate (Sung et al., 2012) I'll go with it.
Here's another—3. That's the number of patients it takes for spontaneous resistance to atovaquone to appear. That makes a lot of sense since resistance to atovaquone needs only one point mutation. If atovaquone were used as widely as chloroquine, we'd expect about a billion or more origins of resistance to it by now, not a measly handful. So how do you quantitatively account for that difference—give or take an order of magnitude?
Let's see what the calculation would look like if we guesstimate the probability of two mutations arising sequentially in the same gene. We'll only deal with two mutations even though we know that more are required for effective chloroquine resistance. We'll assume that both mutations, by themselves, are neutral as the Summers et al. paper indicates.

What I am going to do is try and get an estimate of the probability of creating a two-mutation chloroquine resistant strain in a single individual via a two-sequential mutations pathway. Behe seems to think that the data can only be explained by assuming that one or other of the mutations is deleterious.
What's puzzling to me is your thinking the exact route to resistance matters much when the bottom line is that it's an event of probability 1 in 1020. From the sequence and laboratory evidence it's utterly parsimonious and consistent with all the data—especially including the extreme rarity of the origin of chloroquine resistance—to think that a first, required mutation to PfCRT is strongly deleterious while the second may partially rescue the normal, required function of the protein, plus confer low chloroquine transport activity. Those two required mutations—including an individually deleterious one which would not be expected to segregate in the population at a significant frequency—by themselves go a long way (on a log scale, of course) to accounting for the figure of 1 in 1020, perhaps 1 in 1015 to 1016 of it (roughly from the square of the point mutation rate up to an order of magnitude more than it). So how do your calculations account for it?
We need to know the size of the Plasmodium falciparum genome. Data from the sequenced genomes at the Broad Institute show us that the genome sizes of various strains range from 20.88 Mb for strain Dd2 to 29.53 Mb for strain HB3. Let's assume 25 Mb.

We can calculate the average number of mutations that occur every time a Plasmodium cell divides. It's the mutation rate times the genome size times two (diploid).

(2.5 × 10-9) × (25 × 106) × (2) = 125 × 10-3

What that means is that each of the two cells resulting from a replication/cell division will contain, on average, 0.125 mutations.

Now let's think about what happens when a single cell infects an individual and starts to multiply. After 30 divisions there will be one billion cells (109). One more round of replication/division gives us two billion cells and during that round there will be ...

(109) × (125 × 10-3) = 125 × 106 new mutations

Since the haploid genome size is 25 Mb and there are two copies per cell, this means that almost all of the base pairs will be mutated in the entire population in that round of replication. They were mutated once in the previous generation and half were mutated in the generation before that etc. If you add them all up you can assume, for the sake of argument, that after 30 generations (one billion cells) every base pair will have been mutated several times. There are three possible substitutions for each base pair so it might take another generation to ensure that all possible mutations have happened. (This is important since the mutations to chloroquine resistance required specific substitutions.)

Let's assume that after 30 generations (one billion cells) all possible mutations are present in the population. It's a reasonable assumption. The probability of this happening in an infected individual is essentially one (1). It's practically guaranteed. The majority of mutations will have occurred in the last few generations.

Now, according to Michael Behe, there are one trillion parasites in an infected person. Let's assume that somewhere around the billion cell stage one of the required mutations has occurred. We now have a single cell with one the mutations needed for chloroquine resistance.

What is the probability that the second mutation will occur in its descendants? Going from one billion cells to one trillion cells requires 10 more cell divisions. Thus, each of the cells in the population of one billion will produce 1000 descendants before the entire population reaches one trillion cells. Recall that there are 1.5 × 10‐4 mutations per cell per generation so that means that the lineage with the required mutation will accumulate an additional ....

(1000) × (125 × 10-3) = 125 mutations

The probability that the other required mutation will occur is roughly 125/25 Mb = 5 × 10‐6, or about five in a million. It's actually half that value since the second mutation has to occur on the right chromosome out of the pair. But it's double that number because according to Summers et al. (2014), it doesn't matter what order the mutations occur. It's one third that value because only one third of the possible mutations is effective.

What this means is that if you start with an infection by a cell that has none of the required mutations then you will only get the right pair of mutations once in one million infected people. We know that the right pair of mutations (e.g. K76T + N75E) is not sufficient to confer resistance to chloroquine so the actual frequency of chloroquine resistance is far less.

Even if the right genotype arises (two mutations), the resistant cells have to be transferred to a mosquito and then on to another individual in order to establish a resistant strain. I have no idea what the probabilities are. What I do know is that it's a big step from mutation to fixation (or significant frequency) in the population. It's wrong to assume that simply calculating the probability of mutation will give you the probability of the chloroquine resistant strain being established and detected.

The bottom line is that mutation to chloroquine resistance is going to be rare even if only two mutations are required and they occur sequentially. If four mutations are required for substantive chloroquine resistance then it's not at all surprising that so few resistant strains have been observed. There's no need to invoke simultaneous mutations and no need to assume that one of the mutations is deleterious.

Is this correct? Have I met the challenge?

[There are lots and lots of additional complications that Michael Behe never considers. For example, it's possible that there's a steady-state level of one trillion parasites that keep dividing and losing half the population due to overcrowding. This affects the calculations. We know that there are existing populations of Plasmodium that already have a high frequency (fixed?) of one or more of the required mutations (Summers et al. 2014). In some cases, a strain will only require a single additional mutation to become resistant to chloroquine. You can't possibly calculate reliable probabilities for a species with hundreds of different strains and so much variability.]

Image Credit: Malaria figures are from Wikipedia.

Summers, R. L., Dave, A., Dolstra, T. J., Bellanca, S., Marchetti, R. V., Nash, M. N., Richards, S. N., Goh, V., Schenk, R. L., Stein, W. D., Kirk, K., Sanchez, C. P., Lanzer, M. and Martin, R. (2014) Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite’s chloroquine resistance transporter. Proceedings of the National Academy of Sciences. published online April 11, 2014. [doi: 10.1073/pnas.1322965111]

Sung, W., Ackerman, M. S., Miller, S. F., Doak, T. G. and Lynch, M. (2012) Drift-barrier hypothesis and mutation-rate evolution. Proceedings of the National Academy of Sciences 109:18488-18492. [doi: 10.1073/pnas.1216223109]

Paget-McNicol, S. and Saul, A. (2001) Mutation rates in the dihydrofolate reductase gene of Plasmodium falciparum. Parasitology 122:497-505. [doi: 10.1017/S0031182001007739]

#### 108 comments :

1. What about selection? When you say all possible mutations would be present after 30 generations, wouldn't many have been deleterious and those cells lost? And (I have no idea) perhaps the individual mutations K76T and N75E confer reduced fitness on their own. If so then there would be a reduced likelihood that one would remain in the population and available for generation of the second site mutation? Both of those would make the co-occurrence even less likely, wouldn't they? Maybe I'm missing something since this is way outside my expertise.

1. I'm assuming that K76T and N75E are neutral on their own in order to show that chloroquine resistance is still rare.

2. From previously literature I hazily remember from 2007, I bet K76T is actually highly deleterious/nonviable on its own. This would suggest it can only survive in a context where an enabling mutation has already occurred. Yes, this reduces the probability, yes, it was obvious that something like this was going on before Behe's book came out so, no, it's not a vindicated prediction of Behe's. Also, no, it doesn't mean the mutations had to be simultaneous and, no, it doesn't confirm Behe's preferred probability estimate of 1 in 10^20. Behe gets that number from a paper that offers it only as an informal, offhand estimate. It's not the product of a serious study, and it's not clear that the author (White, IIRC) even knows very much about population genetics.

As I pointed out in my review of Behe in 2007, just because there are, say, about a dozen independent originations of chloroquine resistance (CQR), doesn't mean you can take this number, divide by the cumulative population size of malaria since chloroquine was introduced, and call it a day. Those dozen are just the CQR originations that were (a) successful and (b) widespread enough to be detected as of 2004. But it could be that CQR would originate 10 times a year in each population, but the only one you will detect is the first one that is lucky enough to get to whatever minimum frequency guarantees selective sweep through the population. New CQR mutations after the sweep is on won't have a chance.

But the whole friggin' debate over CQR is pointless anyway, because Behe isn't really interested in the evolution of CQR, which, after all, he admits happens by natural evolutionary processes. What he does is claim, based on basically NOTHING, that protein-protein binding sites are equivalent to CQR, and thus he bootstraps the bogus probability of CQR into a bogus probability for protein-protein binding sites. Normal people might think that, well, most resistance traits evolve in stepwise fashion by selection of progressively improving single mutations, maybe protein-protein binding sites can evolve that way too. Not Behe, he takes the care case and extrapolates from that one. Never mind all the evidence that protein-protein binding sites can and do evolve like anything else.

3. And he's not done yet. With all of the above under his belt, Behe then asserts that multiprotein systems require the evolution of two binding sites SIMULTANEOUSLY, which coupled with the assertion that each of those binding sites MUST have involved simultaneous point mutations themselves, puts the evolution of multiprotein systems beyond the "edge of evolution". Therefore his irreducible complex argument was right after all! Never mind that the only way you can argue that the evolution of two binding sites had to be simultaneous was with the IC argument in the first place, and you have to ignore cooption and the other routes by which multipart systems can evolve stepwise rather than in an all-or-nothing way.

And there are other problems, e.g., it is one thing to calculate the probability of a specific change (e.g. evolving two binding sites) from a specific, randomly chosen starting point (e.g. three proteins with no prior history of interaction), and it is a TOTALLY DIFFERENT THING to calculate the probability of SOMETHING interesting happening anywhere amongst thousands of genes and thousands of species over millions of years. When the modern scientist discovers that interesting evolutionary change, it is totally illegitimate to forget about all of the things that didn't happen. The evolutionary reality is probably that all protein sequences are drifting around in sequence space, duplicating, their host species are continually encountering different environments, different foods, different diseases, etc. On occasion some protein drifts to a point where some beneficial mutation becomes non-horrible, and selection fixes the change. This will only happen for some individuals of some species some of the time. This is not a problem, since since most individuals don't leave descendants long term, and neither do most species. Yes, there are lots of "edges" to evolution -- myoglobin can't just mutate into a flagellum any time it's needed. But no, this doesn't mean complex things can't evolve at all from any of the millions of continually mutating and drifting starting points in millions of species over millions of years. The latter is what Behe is trying to prove. And he is failing miserably to even get the Evolution 101 stuff right.

4. "care case" should be "rare case"

5. Nick: What he does is claim, based on basically NOTHING, that protein-protein binding sites are equivalent to CQR, and thus he bootstraps the bogus probability of CQR into a bogus probability for protein-protein binding sites.

I don't think that's the correct interpretation of what Behe did, Nick. He provides independent calculations for arriving at the probability of evolving a protein binding site. Then he compares it to the probability of evolving chloroquine resistance, to see if his calculations of the former are in the ball park of the latter. It's a way of trying to confirm that his calculations aren't way off. I'm willing to let the major leaguers slug it out in deciding who's right.

6. Nick Matzke wrote,

Also, no, it doesn't mean the mutations had to be simultaneous and, no, it doesn't confirm Behe's preferred probability estimate of 1 in 10^20. Behe gets that number from a paper that offers it only as an informal, offhand estimate. It's not the product of a serious study, and it's not clear that the author (White, IIRC) even knows very much about population genetics.

Exactly. Back in 2007, I tracked down this number. It comes from N. J. White, "Antimalarial drug resistance" Journal of Clinical Investigation 113, 8 (2004): 1084--92.

Resistance to chloroquine in P. falciparum has arisen spontaneously less than ten times in the past fifty years (14). This suggests that the per-parasite probability of developing resistance de novo is on the order of 1 in 10^20 parasite multiplications.

Reference 14 is X. Su et al., "Complex Polymorphisms in an ∼330 kDa Protein Are Linked to Chloroquine-Resistant P. falciparum in Southeast Asia and Africa" Cell 91, 5 (1997): 593--603. What that paper says is that at the time, chloroquine resistance had been observed in two different places. (Later, this number went up to four.) But that's not the same as saying that the mutation itself occurred twice in all of history.

7. Wait, one of the mutants is N75E? Look at the genetic code-- wouldn't changing Asn (N) to Glu (E) require two base pair substitutions?

As for K76T, a peek at the genetic code shows that starting from any codon for Lys (K) and changing the middle bp of the triplet to C will do the trick.

But is N75E correct?

8. Blake, thank you for looking up Be he's references.

Did X. Su et al. say that, when chloroquine resistance was observed twice, there was genetic evidence that both were the same phenotype and derived from a common ancestor?

Even if that were true, 10°20 is an unreliable number because there is an X factor, X= probability of a chloroquine resistant strain AFTER it mutates being detected by scientists and its ancestry traced back. Behe just assumes X= 100%, so the number of instances of scientists observing and assaying a chloroquine resistant strain = number of times it mutated.

But if, say, X = 1/1000, then the double mutant might independently occur 1000 = 1/X times for each time it gets assayed by scientists.

Of course, one cannot say it is an empirical fact that the probability of a chloroquine resistant strain is 1 / 10^20 until one has assayed 10^20 parasites. So Behe is making huge assumptions, like X = 100%, but his assumptions are wrong.

The correct way to answer the question is: First, how many strains of malaria have been assayed for chliroquine resistance? Call that N. If only n of those is resistant to chloroquine, then you start with probability n/N. Then you have to correct this because mutants will occur that never spread through the population. A better estimate of the EMPIRICAL probability of chloroquine resistane would be n/(N*X).

Then you have to estimate X by considering how beneficial the mutation is, i.e. the selection coefficient s. Since a mutant must occur 2/s times before it spreads through the population, X < s/2.

In fact, X would be s/2 times some factor representing sampling coverage, that is, his likely it is for a strain or subpopulation to be assayed by scientists. Call that sampling coverage R.

Then X= Rs/2

And the estimated EMPIRICAL probability of a chloroquine resistant phenotype evolving is

prob =~ n/(N*X) = 2n/ NRs

Here Behe is screwed by the factor s. Behe always always calls intermediate evolutionary steps "sickly" and "degraded" which is how his Church describes gays. Perhaps he thinks evolutionary intermediates are gay. But if he quantifies that, and sets s to a "sickly, degraded" low value, it INCREASES the probability of the resistant mutant occurring.

9. I meant K76T, apologies...

10. Nick, wouldn't N75E require two bp substitutions?

11. Genetic code:

asN = AAT, AAC

glu (E) = GAA, GAG

12. Looks like it, but IIRC K75E is not required in all paths but K76T is.

13. "I don't think that's the correct interpretation of what Behe did, Nick. He provides independent calculations for arriving at the probability of evolving a protein binding site. Then he compares it to the probability of evolving chloroquine resistance, to see if his calculations of the former are in the ball park of the latter. It's a way of trying to confirm that his calculations aren't way off. I'm willing to let the major leaguers slug it out in deciding who's right."

No, IIRC he just assumes that the evolution of a new binding site would require multiple simultaneous mutations, rather than a stepwise path. It's that assumption which needs to be verified. In my review, I pointed out a lot of evidence for the stepwise view. You're a big boy, Bilbo, read up on the evidence yourself, this "let the heavyweights battle" stuff is BS false equivalence of authority at this point. It's all in my TREE review but you seem to be too chicken to read it and address its points in detail. Behe mostly dodged the TREE review also.

14. Hi Nick,

I challenge your claim that Behe assumes a new binding site would require multiple simultaneous mutations, rather than a stepwise path. I'm not afraid to read your review, Nick. Just don't have the time to wade through your massive verbosity.

15. My TREE review of Behe was just 800 words or something. Surely this does not exceed your verbosity capacity...

16. Nick,

When you can't even re-state Behe's arguments correctly, why take anything else you have to say about him seriously?

17. Predictable. Because I presented evidence exposing Behe's blunders, Bilbo asserted that I'm a liar and all evidence I present should be ignored.

Now he does the same with Nick. Bilbo hasn't read Nick's review of Behe, but he doesn't need to, because Nick should not be taken seriously.

Further proof that ID is non-falsifiable. If evidence is presented showing that ID is falsified, just say the person who presented the evidence was lying.

2. I'm going to re-copy here my comment from the immediately previous Behe thread.

Besides Behe's other problems, I'll add on that his "challenge" is, at best, demanding that we compute a probability density. But in classical statistics, no hypothesis can be tested or refuted by computing a a probability density no matter how small; only a computation of a probability mass can test a hypothesis.

Here's the difference: you may have heard of the "Bridge Hand Fallacy." You win a game of bridge, then you compute the probability density of getting the specific combinations of cards that you used to win the game, by assuming a process of random shuffling and selection. This probability will undoubtedly be very tiny but who cares, it can't test the hypothesis that "God made me win the game of bridge" because it's a probability density and that can't test a hypothesis.

To compute a probability mass you would have to

1. First define your hypothesis well, e.g. "The cards with which I won the game must have been chosen by a non-stochastic process",

2. Then compile a list of all possible card hands by which you could have won the game, even though you never saw most of those conceivable hands (this step is called defining a rejection region.)

3. Then you compute a probability density for each hand of cards by assuming a specific process, e.g. totally stochastic shuffling and selection.

4. The you sum the probability density from step 3 over all conceivable winning hands from step 2. The integral is called the probability mass. This and this only can test or refute your hypothesis.

The "Bridge Hand fallacy" consists of using a probability density instead of a probability mass to test a hypothesis. This is how IDcreationists tell church audiences that statistics is done.

Do you think Behe ever attempted steps 1, 2, 3 and 4 above? Do you think he got past steps 1 and 2?

In what Bilbo calls "the Behe challenge", did Behe define his hypothesis (beyond "God did it by magic") and define his rejection region? If so, what is his rejection region? Please tell us Behe's rejection region.

No? Does Behe want us to be dummies and compute probability densities and call them probability mass? No way. Teaching that to church audiences and calling that shit "statistics" just makes them dumber. It's Behe's life's work.

3. Larry, seems to me the size of the genome is irrelevant to the calculation, since you already have the mutation rates per base.

1. True. That just confuses matters.

2. @unknown,

It's true that the genome size cancels out in the calculation but I couldn't think of a better way of explaining the situation for the average reader. Can you?

4. Hi Larry,

Thanks for taking "the Behe challenge." I'll be curious to see what Behe's response is. Meanwhile, you wrote:

The probability that the other required mutation will occur is roughly 125/25 Mb = 5 × 10‐6, or about five in a million.

I'm curious. Does that mean that if a third mutation was required, then the probability would be 5x10-6 x 5x10-6? And if a fourth mutation was required, would the probability be 5x10-6x5x10-6x5x10-6?

5. Ugh. It seems to me that Larry's envelope calculation is way off and that a more precise calculation with the same assumptions gives very different numbers. I've computed better numbers than Larry's... but first I am going to RANT.

I'm computing this under protest and before I report any numbers, I want to make clear that whatever number we get is entirely irrelevant, because Behe's entire line of argument is invalid, so it doesn't make a goddamn difference what the numbers are, and they want us to acknowledge their bullshit logical fallacies! Hell NO! It's the creationists' job to make their church audience DUMBER-- it's not our job! We do not acknowledge the validity of your bullshit logical fallacies!

Which include:

1. Behe's bullshit method invokes the Bridge Hand fallacy, the Texas Sharpshooter fallacy (drawing the bull's eye after you shot your load), etc. as I protested above, in my discussion of probability density vs. probability mass. Behe is "challenging" us to compute a probability density, not a probability mass, thus the resulting number can never test nor refute any hypothesis, not evolution and not any other hypothesis.

Probability density is how IDcreationists have taught their church audiences that hypotheses are tested (vs. their default explanation: "God did it") for 50 years, and I've had it. We have to have a zero tolerance policy for bullprob calculations that use probability density as if it were probability mass. You wanna teach your church audiences that probability density is used to test hypotheses, do you, Behe? Bridge hand fallacy you teach them, Behe? Well \$%*& you! You make Christians dumber! No wonder evangelical Christians are the most underrepresented group in science!

2. The second reason this is all bullshit is because Behe and all ID creationists just multiply probabilities together, which is only mathematically valid when events are independent-- the "AND" trick which assumes independence of dependent events. Thus Behe isn't satisfied with 10^20 which he calls his "Chloroquine Complexity Cluster", oh nooo. He then SQUARES it, and says any complex system has a probability of 10^40!!! Hell no!

Behe imagines in his head one particular mutant appearing, then he imagines that one mutant dying, and since he imagined that one pathway killing the animal, he's proven that the ten trillion other possible pathways would also kill the animal. Then he says, "Well den, dem dere double mutants gotta be simulty- tanemus." Ah %\$&# you! We don't care what you imagined! Imagining a single mutant dropping dead is not proof that the other ten trillion possible pathways would kill the animal! %\$#! that shit was old when Bryan tried it at the Scopes trial.

You need experimental proof in which you eliminate all combinatorial pathways. Combinatorial problem? = Your problem! If there are ten trillion pathways, then hop to it Behe! Creationist imagination don't cut it! Go read Joe Thornton's papers. Thornton shows how to explore combinatorial space. "Materials and Methods" section. There are these things called "experiments" Mike, you should try one sometime.

1. Again, before I report any numbers, I will finish my ran-- protest.

3. Yeah we saw that shit you pulled where you just assumed that your "Chloroquine Complexity Cluster" of 1/10^20 applied to every protein-protein binding site everywhere-- in fact, you had no evidence 1/10^20 applied to ANY protein-protein binding site ANYwhere! Do you know anything about protein functional sites? Oh no you don't, because you said that no protein-protein binding site could ever evolve. How'd that work out for ya Mike?

Remember ERV? The lovely blogger ERV. It's coming back to you now, remember now Mike? You said no protein-protein binding site had ever evolved or ever could evolve in the HIV virus and she instantly pulled up Vpu, which you could have found with a Google search. Ooh, that musta stung like Dover!

Let's recall a bit of the lovely ERV!

"To put this the simplest way possible, Vpu involves the evolution of at least two protein-protein interaction sites—one to interact with CD4, one to interact with the pathway that degrades the CD4.

The second function is to act as an ion channel in the host cell plasma membrane6. Five Vpu proteins come together to form a Na+K+ viroporin 7. This has been shown to assist in particle release... This involves the evolution of more protein-protein interactions—the individual Vpu proteins must interact to form the pentamer, plus an action site that can be used to block ion flow 8."
[ERV schools Behe on protein-protein binding sites]

You just coulda googled it, Mike. A simple google could've avoided that, like that other time in cross-examination when they piled 50+ papers on the evolution of the immune system in front of you and you looked like a possum trapped in NASA mission control. Next time, before you tell your church audience "But no scientist in the world knows the answer!", try googling, just one goddamn time. Ask your kids how.

2. No, I'm not done on the subject of what bullshit it is for Behe to set 1/10^20 as the probability of evolving every protein binding site everywhere-- or ANY one ANYwhere. Behe has repeatedly demonstrated he has egregious misapprehensions of the properties of protein functional sites in general. How can you compute the probability of the evolution of a thing if you don't know anything about the properties and structure of the thing?

This is the same Mike Behe who said, at the "Great Debate" in 2002 with him and Dembski vs. Pennock and Miller, said the following outrageous thing:

"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... Binding sites, however, are composed of perhaps a dozen amino acid residues, and binding is generally lost if any of the positions are changed." [Michael J. Behe. April 23, 2002. From the "Great Debate” at the American Museum of Natural History, 2002, with Dembski & Behe vs. Pennock & Miller, Part 2 of the MP3, timestamp about 17:40, NCSE Transcript here, DI text here]

What!? WHAT!?? BullSHIT. Have you read anything on protein functional site tolerance to mutations? James Wells' papers on alanine scanning mutagenesis back in the 90's totally kills this: he showed that most, sometime all of the binding energy in protein-protein binding sites is tied up in a small "hot spot" of one, two, maybe three amino acids.

Can you name one, even one protein, upon which alanine scanning mutagenesis has been done, with a dozen amino acids in its functional site, proving that none of the dozen amino acids can be mutated without abolishing function? Oh I don't think so. Two maybe, three if you're really lucky-- but a dozen? Bullshit. Alanine scanning mutagenesis has been popular since the 90's, no reason not to try it.

4. I protest Behe's and Ann Gauger's attempts to redefine the meaning of the word "simultaneous". When you say "simultaneous mutations" to your church audience, you know exactly how they interpret it, and you know it's wrong. No, you don't get to redefine "simultaneous" and you know what it means, and you know how your church audience interprets it. \$%&! you for trying. You wanna suck us back into word games where you equivocate, like you did with every other word in your definition of "Irreducible Complexity"! How many definitions of IC do you have now? A half dozen? A dozen? I lost count.

Now I'm done rant-- protesting. Some math is next.

3. Having finished my protest, I will now report a better calculation than Larry's.

I used the same assumptions as Larry, i.e. the single mutants are neutral, and same mutation rate of 2.5 x 10^-9, but I computed the fraction of single mutants and double mutants (among all cells) in each generation by multiplying up from the previous generation, up to 40 generations, making a population of 1.1 trillion. I ignored back mutation. That is (same equation for single mutants K76T and N75E):

(fraction of single mutants in generation i) =
(fraction of single mutants in generation i-1)
+ ((1 - fraction of single mutants in generation i-1)* (mutation rate per base pair per generation)*2/3)

The "*2" factor is because they're diploid, and the "/3" factor is because a mutant can be to any of 3 nucleotides, but only one of those is correct.

For the fraction of double mutants in each generation:

(fraction of double mutants in generation i) =
(fraction of double mutants in generation i-1)
+ ((fraction of K76T in generation i-1)* (mutation rate per base pair per generation)/3)
+ ((fraction of N75E in generation i-1)* (mutation rate per base pair per generation)/3)

Note that I ditched the factor of "*2" because the second mutation must be on the same chromosome, but I kept the factor of "/3".

Then I just iterated to the 40th generation.

The total number of mutants in each generation is, obviously, the fraction of such mutants as given above, times the population size, which doubles each generation.

After 30 generations:
Population size = 1.07 billion
# single mutants = 53.7
# double mutants = 0.0000013

After 40 generations:
Population size = 1.1 trillion
# single mutants = 73301
# double mutants = 0.00238

This last number means that one double mutant cell will appear in every 420 infected individuals.

Now Behe will reply, "Wah it's deleterious, natural selection should eliminate it." If someone gives me hard numbers on the selection coefficient for the single mutants, I can plug that in.

4. If Behe says, "No no, you were supposed to get 1/10^20, that's the right answer", can you guess what my reply will be?

5. If you make the assumption that both mutations must occur simultaneously (I mean really simultaneously) in the same organism, then after 40 generations, and a population of 1.1 trillion cells, the odds of having a double mutant in a given infected individual are 0.000061.

That is, a parasite with simultaneous double mutations in a single organism will appear in 1 out of every 16,371 infected individuals.

This "simultaneous" computation, vs. the computation above for sequential mutations, is different by a factor of 39 after 40 generations. The more generations go by, the larger this "simultaneity error factor" is.

Let us assume that this double mutant has a selection coefficient of s= 0.01. Under the usual rule, the mutant must occur 2/s before it will spread and get fixed in the population. If s = 0.01, then the double mutant must occur 50 times before it will spread and become fixed.

If mutations can occur "sequentially" in one organism, and s = 0.01 for the double mutant, 21,000 people must become infected before the double mutant gets fixed and established in the population.

If mutations must occur "simultaneously" in one organism, and s = 0.01 for the double mutant, 818,500 people must become infected before the double mutant gets fixed and established in the population.

6. A simple check of the malaria life cycle shows that the malaria parasite has sex while in their mosquito hosts. So one can simply invoke the Fisher-Muller hypothesis, which is that sexual populations increase their variation well above their individual mutation rate b/c they combine genomes by mating. It seems to me that a cell with one of the mutations can combine genomes with a cell carrying one or more of the other needed mutations. No math is needed. I think Michael Behe should check on basic biology before he waves his not-so-magic wand trying to dazzle us with bullshit.

7. Thank you, Diogenes! I remember well when Behe neglected to block comments on one of his Amazon postings and ERV was in there like a mongoose! Hilarity ensued. The best part was when Behe was babbling on about Vpu and ERV pointed out that he had an illustration in his own book showing Vpu! Oh, that was rich, and I think the only time Behe was shut up on a subject.

Loved the rant! Next time paint half your face blue and wear a kilt. Freedom!

8. Larry: What this means is that if you start with an infection by a cell that has none of the required mutations then you will only get the right pair of mutations once in one million infected people.

There are one trillion malaria cells in each infected person, so if we only get the right pair of mutations once in one million infected people, that's

1 x 10-12 x 10-6 = 1 x 10-18. Not that far from Behe's 1 x 10-20.

1. Not that far? It's off by a factor of 100.

Moreover, I showed above that Larry's math is wrong. If single mutants are neutral, the double neutral will occur in 1 in 420 people. So Behe is off by five or six orders of magnitude.

If both single mutants were lethal by themselves, and thus both must occur simultaneously, Behe is still wrong by more than two orders of magnitude.

And you did not address his other severe errors and fallacies that Nick and I detailed. This is not a probability MASS, and it is not equivalent to the probability of protein-protein interaction sites evolving, as he claimed, and it was totally unjustified for him to SQUARE the number 10^20 and make it 10^40,
which is equivalent to him requiring four or more simultaneous mutations, each of which is lethal by itself. No justification for that.

Nope, for the double neutral case, the number should be 10^12 times 420. So Behe's factor of 10^40 is off by 26 orders of magnitude, or 100 trillion trillion. Admittedly, a small error by creationist standards.

2. Just waiting for Larry to concur with your calculations, Diogenes.

3. I didn't set up a spreadsheet to check Diogenes' calculation but the theory is sound. I was trying to show the same thing by just concentrating on the single doubling of the population after 30 generations. The calculations show that you can get the double mutant quite easily just by having a population that already contains one of the mutants at high frequency. (Summers et al. detected such a strain in the wild.)

What Diogenes shows is that the simultaneous double mutant is possible in Plasmodium. But that's what Behe claims as well.

Behe's mutation probabilities are far too high because he thinks that as soon as the mutation occurs it will be detected as a chloroquine resistant strain. He doesn't seem to understand the difference between mutation rate and fixation.

Note that Behe is using a mutation rate that's 10X higher than the value I am using (and Diogenes). That means that the double mutant will occur simultaneously at a much higher frequency than even Diogenes calculates. The fact that chloroquine resistance is so much rarer than expected from his mutation rate leads him to speculate that the individual mutations are disadvantageous.

That doesn't appear to be true using the assay that Summers et al developed but the real problem is Behe's assumption that only two mutations are required for effective chloroquine resistance. It looks like you need a minimum of four mutations to get the major chloroquine resistant strains that are detected.

This is why meeting the Behe challenge is so difficult. There are too many variables and too many unknowns.You can't calculate the probability because real evolution is much more complicated than Behe imagines.

4. Hi Larry,

So just to be clear, when you said, What this means is that if you start with an infection by a cell that has none of the required mutations then you will only get the right pair of mutations once in one million infected people,

would that mean one in 10^18 parasites gets the right pair of mutations? And are you now saying that your original calculation was mistaken, and that Diogenes is correct, and that the probability of a parasite getting the right pair of mutations is much higher? And since you think that four mutations were required, not two, what was the probability of one parasite getting the right four mutations?

9. Not sure if my first post was accepted; possible repost.

If malaria resistance is support of intelligent design, this is implying that the creator stepped in and tinkered with malaria to give it resistance rather than it evolving naturally, right?

Does this not imply that the intelligent designer then WANTS malaria to continue killing humans and ACTS on that want?
Is this a comforting thought for the average Christian? Er, IDist?

1. Behe doesn't argue that the malaria parasite's resistance to chloroquine was intelligently designed. However, later in the book he admits that if his arguments for intelligent design are correct, then it would follow that the malaria parasite had been designed. No, it is not a comforting thought, nor does Behe try to gloss it over. Instead he quotes an old Jewish proverb; "If God lived on earth, his windows would be broken," presumably from people throwing stones at his house. Of course, we Christians do believe that God lived on earth. His windows weren't broken, and he didn't die of malaria, but I wouldn't call it a happy death, either.

2. Ah, fun.

Do IDists actually discuss this topic of murderous assholish god/aliens/whatever or do they just ignore it like they ignore how ID itself is nonsensical?

3. I don't ignore the problem of evil, and I don't ignore the issue of whether ID is nonsensical.

4. How do you resolve the problem of evil to your satisfaction? Or do you believe that God is evil?

5. John, Behe is not saying God recently intervened to make malaria more lethal. Behe's much sneakier and more dishonest than that.
Behe is trying to "prove" that protein binding sites are too complex to ever evolve, and that we should ignore all experimental investigations into their structure. Behe uses his bass-ackwards empirical "probability" calculation as a way of proving to church audiences that they shouldn't listen to molecular biologists-- protein binding sites are much more complex than molecular biologists have shown, they need a dozen amino acids similtaneously and if even one changes, the function is abolished, says Behe.

Of course, molecular biologists know this isn't true because they investigate the structure of functional sites experimentally, by methods like site-directed mutation and alanine-scanning mutagenesis. So Behe's proven dead wrong, but he tries to do an end run around experiments with his bass-ackwards "probability" calculation.

Ever since "Darwin's Black Box" Behe has been claiming that protein binding sites can never evolve. Above, I quoted him saying that in 2002. There are many other such quotes from Behe.

Our friend Bilbo doesn't like seeing his ID authorities exposed as boobs, so he bleats that I am not a "serious" debater and all evidence that I present must be ignored. Thus Bilbo proves ID is non-falsifiable: because anyone who presents evidence that it has been falsified is "not to be taken seriously."

6. Diogenes,

Thanks, but that's all irrelevant to my question. Let me repeat. Behe may not think chloroquine resistance is designed, but he most certainly thinks that the malaria parasite is designed. So how does he resolve the problem of a loving god who designs nasty diseases? Do you know?

For that matter, how does Bilbo resolve that?

7. Hey Bilbo,

All true xtians know that Christ is a phantasm (you know, like Casper the Friendly Ghost) who animated the fleshy hulk of Jesus and amscrayed back to paradise central to party hearty with his dad leaving the dead carcass of Jesus to face the music and as such is incapable of pain or death.*

Sheesh, the sheer hubris and gall of speaking for "we christians', your humility is exceeded only by your unwillingness to engage in rational discourse.

* This is actually true, well true in the sense that it was a heresy promulgated by 2nd century Docetists who strangely enough are no longer with us as the dominant "we christians" of that period slaughtered the other "we christians" of that period and destroyed (almost) all of their books.

8. Hi John,

I don't know why God allows evil, though there are certain speculative answers that I favor. If you want, we can discuss these. What Christians (besides Docetists, which is sorta' what Muslims are) believe is that God became a human being and suffered just as we do, even unto death. A faith where the god must take his own medicine at least makes for an interesting story. I believe that story is true and it gives me reason to trust that such a god has allowed evil to happen for good reasons.

9. Hi Diogenes,

I see you still haven't provided the citations I asked you for. I would rather not call you a liar. I'll just say that you are being very untruthful.

10. Hi Steve,

Docetism was not the earliest view in Christianity. I wouldn't know who slaughtered who. People of all faiths or non-faiths get upset when others disagree with their core beliefs or non-beliefs, and all sorts of bloodbaths result.

11. People of all faiths or non-faiths get upset when others disagree with their core beliefs or non-beliefs, and all sorts of bloodbaths result

"All faiths or non-faiths"?
Flattening argument: since Christians did bad things, that proves everyone did those bad things.

No. Not all faiths. Christians and Muslims were the worst, followed by Jews. These religions are the exceptions.

By contrast, Buddhists and Jains don't kill people for infidelity. In China, Daoism, Buddhism, Confucianism and the traditional Chinese religion (worship of Tian, Shangdi etc.) coexisted and competed for influence for 2,000 years without even once burning someone for infidelity or heresy.

Burning heretics and infidels was invented by monotheists. Even Hindus didn't have religious violence on a large scale until after the Muslims invaded.

Bloodbaths are for monotheists. Religious violence on a large scale is the exception generally, except among monotheists.

12. I see you still haven't provided the citations I asked you for. I would rather not call you a liar. I'll just say that you are being very untruthful.

Not true and not relevant. Not true because I already cited one quote from Behe saying protein binding sites need a dozen amino acids and if any one is changed, function is abolished. That's bullshit, then he says protein interaction sites in general are irreducibly complex. I cited that speech from 2002, and there are others.

And if you clicked the link I provided, and read it, you'd hear Behe in the same speech saying that disulfide bridges are IC too.

Besides not being true, your attack is not relevant. I said I would provide citations if you answered my questions about if ID could be falsified. You never answered my questions, except to say that nothing Behe said could ever falsify ID anyway. And any quote provided by me would be "out of context" and untrustworthy and you would ignore all evidence provided by me, even 2+2=4, if it comes from me, and 2+2=4 is as easily verifiable as the probabilities I gave above, but you'll also ignore math that you could double check yourself if it falsifies ID.

So why should I provide citations when you don't answer my questions, and you've already said no quote I give is reliable, and could never prove ID predictions are falsified?

13. ======
John HarshmanSunday, August 03, 2014 5:51:00 PM
Diogenes,

Thanks, but that's all irrelevant to my question. Let me repeat. Behe may not think chloroquine resistance is designed, but he most certainly thinks that the malaria parasite is designed. So how does he resolve the problem of a loving god who designs nasty diseases? Do you know?

For that matter, how does Bilbo resolve that?
======

Behe addresses this fairly head-on at the end of Edge of Evolution. I don't have the book handy, but IIRC his answer boils down to something that is essentially a conservative Catholic response, namely that suffering is part of God's good plan, even if we can't understand it. IIRC there is something about how we are actors on a divinely constructed stage, and each of us has an entrance and an exit and a role to play, and the suffering part of it sucks but without that certain kinds of good wouldn't be possible.

There is also some reflection on the line from the Book of Job about how we are "Fearfully and Wonderfully Made", emphasizing the fearfully part and the divine mystery. Or something. Read the last chapter if you want his theodicy. I think it's actually the best part of the book as it at least for once has some honest wrestling with the real theological issues ID raises -- this is basically unique amongst ID literature. The rest of the book is worse because it doesn't really wrestle with the real scientific data and research, instead it relies on the kinds of slipshod work we've been discussing in the thread.

14. Bilbo, I didn't ask why your god ALLOWS evil.

I asked why he PARTAKES IN EVIL ACTS TO PURPOSEFULLY MURDER COUNTLESS PEOPLE.

THAT was my question.
Your god isn't just a lazy oaf who sits back and ignores the world anymore. If you are to believe this "edge of evolution" stuff (which I think is crap, but that's not the topic at the moment), your god becomes actively evil, not passively evil.

15. I don't know why God allows evil, though there are certain speculative answers that I favor. If you want, we can discuss these.

Sure. What do you have? You might want to focus on malaria, just to stay on topic. Why did god create malaria, which causes so much apparently pointless misery?

Is that explanation, whatever it may be, better than a simple evolutionary explanation, i.e. that malaria is a response to an environmental opportunity?

16. John, I don't intend my answer as any sort of substitute for Bilbo's; he can speak for himself. I think for people who believe, yes, a deity who creates apparently pointless misery may indeed be preferable to natural processes unguided by intelligence. Think of a child with an abusive parent. The child might fear abandonment more than living in the abusive household.

17. Diogenes wrote:

"Bloodbaths are for monotheists. Religious violence on a large scale is the exception generally, except among monotheists."

The only religion I can think of that hasn't been involved in any conflicts, including religious, are Jehovah's Witnesses. They would rather go to jail then pickup a weapon, not to mention to assault someone over differences or nationality. Are you aware of that?

Perfect example of that are their big conventions, where both Israelis and Palestinians are sitting next to each other in peace. Same applies to members of former Yugoslavia or Rwanda.

18. As for JWs, I am aware of that, and I have to give them credit for it. I'll even add to it by pointing out that they were the only religion in Germany that genuinely resisted Nazism. The Protestants supported Nazism enthusiastically, and Catholics supported it after the Machtergreifung. But the JWs resisted to the point of being executed. Have to give them credit for it.

All the religions (yes I include the pro-Nazi Confessing Church) behaved horribly in the Nazi era, except the JWs.

Morally, it is difficult to fault *pacifistic* monotheism.

19. Hi UE and John,

Assuming Behe is correct and malaria was designed, then who was the designer? Behe seems to assume that it was God and gives what I guess (if Nick is correct) might be a standard Catholic answer to the problem.

But is God the only possible designer. What is interesting is that the New Testament Gospels were written during a period in Judaism when the idea that the world was under the control of Satan was prevalent among many Jews. And some scholars are now beginning to think that the Gospels were written with that idea in mind. Watch, for example, this 25 minute youtube video by Christopher Skinner: https://m.youtube.com/watch?v=-iu4v_uIU2Y

If it is true that Satan is in control of the present world order, is it possible that he could have designed malaria, and all the other diseases that we consider evil? It's a view that I am willing to take seriously.

Of course, that creates other questions, such as how Satan came to be in control of this world, and why God would let him. As to the first, both J.R.R. Tolkien and C.S. Lewis propose in their fictional works that Satan was originally a good angelic being who partook in the creation of the world, and may have even been put in charge of it, but later rebelled against God, and has done his best to ruin God's creation. And I think that's a view that has possibilities.

But again, what makes me trust that there is a good explanation for why God's goodness and the existence of evil can be reconciled is that I believe that God became a human being and suffered as we have suffered. I'm willing to trust that kind of god, even if I don't have all the answers right now.

20. And some scholars are now beginning to think that the Gospels were written with that idea in mind.

Beginning? These ideas started with 19th century German biblical scholarship, and gained additional currency in the 20th century with the discovery of the Dead Sea Scrolls. It is fair to say that it is the dominant view among Bible scholars today, and is probably what your minister was taught at seminary unless he or she belongs to a literalist evangelical sect.

21. Bilbo,

So to summarize: you have no idea at all why there is pointless suffering, but since your god was willing to engage in some himself, you trust that everything is for the best. OK, but I hope you realize that such a claim (you can't really call that an argument) is convincing only to the already committed believer.

22. But you have to give Biblo credit for saying "I don't know" (for once.)

Lots of sophistimicated theologians pretend they DO know.

Theologian Richard Swinburne says that theologians have solved the problem of evil. He says that a universe with Auschwitz in it is the best of all possible worlds, because Auschwitz gave the Jews an opportunity to display courage as they and their children and parents were being herded into the gas chambers. A universe without naked people being shoved into gas chambers would be less perfect than Auschwitz-containing universe, says Swinburne because argle bargle argle bargle blah blah I have to go bleach my brain now.

William L. Craig once said (I'm sorry I don't have the reference for this) that our universe is the best of all possible worlds because God set it up to maximize the number of people who become Born Again Christians and therefore, go to Heaven. Any change to our Auschwitz-containing universe would reduce the number of Born Again Christians and therefore, any change (such as, no Auschwitz) would make our universe less perfect. The advantage of this hypothesis, said Craig, is that the atheists can't falsify it.

You will note, John, that the problem of evil derives from the requirement of claiming God is both all-powerful and benevolent. So the theologian must equivocate somehow. All "resolutions" amount to:

1. Redefine benevolence, or

2. Redefine omnipotence, or

3. Both.

Word games, word games to make their beliefs non-falsifiable. That's it.

23. Job 1:7-18

Satan questions Job's motives and accuses God of partiality. Evidently, it has been an ongoing issue,(motives and integrity) since God immediately turns his attention to Job. To resolve the controversy, God allows Job's motives to be tested BY SATAN.

"7 Then Jehovah said to Satan: “Where have you come from?” Satan answered Jehovah: “From roving about on the earth and from walking about in it.”+ 8 And Jehovah said to Satan: “Have you taken note of* my servant Job? There is no one like him on the earth. He is an upright man of integrity,*+ fearing God and shunning what is bad.” 9 At that Satan answered Jehovah: “Is it for nothing that Job has feared God?+ 10 Have you not put up a protective hedge around him+ and his house and everything he has? You have blessed the work of his hands,+ and his livestock has spread out in the land. 11 But, for a change, stretch out your hand and strike everything he has, and he will surely curse you to your very face.” 12 Then Jehovah said to Satan: “Look! Everything that he has is in your hand.* Only do not lay your hand on the man himself!” So Satan went out from the presence* of Jehovah."

24. Diogenes,

W. L. Craig is extremely good at accentuating the positive. Shortly after the Sandy Hook elementary school shooting he philosophised aloud, in a video, how tremendously nice it was of God to remind us all what Christmas was about -- with a subtle allusion to the Massacre of the Innocents.

25. Job 13-18

" Now it came to be the day when his sons and his daughters were eating and drinking wine in the house of their brother the firstborn.+ 14 And there came a messenger+ to Job, and he proceeded to say: “The cattle themselves happened to be plowing+ and the she-asses were grazing at the side of them 15 when the Sa·be′ans*+ came making a raid and taking them, and the attendants they struck down with the edge of the sword; and I got to escape, only I by myself, to tell you.”+

16 While this one was yet speaking that one came and proceeded to say: “The very fire of God fell from the heavens+ and went blazing among the sheep and the attendants and eating them up; and I got to escape, only I by myself, to tell you.”

17 While that one was yet speaking another one came and proceeded to say: “The Chal·de′ans+ made up three bands and went dashing against the camels and taking them, and the attendants they struck down with the edge of the sword; and I got to escape, only I by myself, to tell you.”

18 While this other one was yet speaking, still another one came and proceeded to say: “Your sons and your daughters were eating and drinking wine+ in the house of their brother the firstborn. 19 And, look! there came a great wind*+ from the region of the wilderness, and it went striking the four corners of the house, so that it fell upon the young people and they died. And I got to escape, only I by myself, to tell you.”

26. Newbie,

Laziness is a deadly sin, and Jehovah may punish you for it. When you copy and paste all this stuff, you could at least have the decency to edit out all those plus signs, asterisks, and the stress marks for semi-literate idiots in "Sa·be′ans*+" and "Chal·de′ans+".

27. Perfect example of that are their big conventions, where both Israelis and Palestinians are sitting next to each other in peace. Same applies to members of former Yugoslavia or Rwanda.

A few weeks ago I gave some classes to visiting PhD students from Israel. There were both Jews and Arabs among them, and they sat together in peace (despite the fact that back at home the Gaza conflict was gaining momentum). In my experience, it's much easier for people to get on well with one another if they have a common interest in something else than religion.

28. Sorry Piotr, but after my comment disappeared for the second time I totally forgot to remove the formatting, asterisks and other reference symbols when I cut and pasted the Bible text. I have learnt the hard way that I need to be logged in before typing comments.

29. Piotr wrote:

"A few weeks ago I gave some classes to visiting PhD students from Israel. There were both Jews and Arabs among them, and they sat together in peace (despite the fact that back at home the Gaza conflict was gaining momentum). In my experience, it's much easier for people to get on well with one another if they have a common interest in something else than religion."

You and I are talking about two totally different things. You allude to both Jews and Palestinians, who due to their scientific interests put away temporarily their differences in a foreign land. You don't know what would happen even in the foreign land if a member of one of those attending your lecture died in the conflict.

I, on the other hand, talk about people who permanently set their differences aside by following Jesus' commend found in John 13:35

“By this all will know that you are my disciples if you have love among yourselves.”

Those people often risk their life to attend convention like the one I mentioned earlier or even daily for attending their meetings or even associating with people who are their spiritual brothers from other side of the conflict.

Recent conflict in Rwanda is another perfect example of Jehovah’s Witnesses neutrality and true brotherly love.

http://wol.jw.org/en/wol/d/r1/lp-e/2013043?q=rwanda+hutu&p=par

30. The pacifism of Jehovah's Witnesses is admirable, but of course they are not nearly the only pacifists.

31. Bilbo,

///a good explanation for why God's goodness and the existence of evil can be reconciled is that I believe that God became a human being and suffered as we have///

So what about animal suffering, then? God did not become an animal and suffered. Yet thousands of animals are brutally murdered and eaten by other animals every second. Why?
Even microscopic bacterial cells are infected and killed by viruses called bacteriophages!

Why did an asteroid impact bring about untold suffering to the dinosaurs and wiped them out of existence 65 million years ago?
Why did the Permian extinction wreak havoc on ecosystems worldwide and obliterate 90% of species 250 million years ago?
Remember, these events happened long before any human ever appeared on the planet. So there was no sin or anything for God to retaliate against.

32. Is any one even reading this bible shit?

33. Newbie wrote:

"Satan questions Job's motives and accuses God of partiality. Evidently, it has been an ongoing issue,(motives and integrity) since God immediately turns his attention to Job. To resolve the controversy, God allows Job's motives to be tested BY SATAN."

I'm not sure I fully understand what you implying here... Can you elaborate further or provide a link...?

The way I see it is Satan is causing evil to people like Job but God allows it.... just purely based on Job's example...

If yes.... my next question is: Why?

Also, do you know how to explain the resurrections that are found in the Bible...? Specifically Lazarus vs other... did they come to life with the same bodies or new ones...?

I'm just curious how JW's explain those issues as I have not been able to find any reasonable ones so far....

Anybody has any interesting ideas on the above...?

10. Question: Is Behe proposing that "God" produced the resistant plasmodia?

1. See my reply to Uncivilized Elk just above.

2. And likewise, see my reply below his.

11. Recombination. In this sexual species, the probabilities are boosted significantly.

1. I think Jie Felsenstein would disagree with that. His argument is that if you have a high rate of recombination, it can combine two mutations on the same chromosome... but then it can also split them apart, and put the two point mutations on different chromosomes.

2. In finite populations linkage disequilibrium occurs randomly. Linkage between two beneficial mutations A and B retards the fixation of both, because the boost for genotypes AB does not cancel the drag experienced by genotypes Ab or aB (this is the so-called Hill-Robertson effect). Combine drift in finite populations, linkage disequilibrium and the Hill-Robertson effect, and you roughly get what Felsenstein said: that recombination removes linkage disequilibira and thereby accelerates the simultaneous fixation of beneficial mutations.

3. Insert underlined words in second sentence above:

Linkage between _two_loci_with_ beneficial mutations A and B retards fixation of both.

4. P.S.: I think Behe simply evades the issue of recombination by assuming that both mutations must occur simultaneously in one and the same individual in order to be beneficial. He simply assumes that they cannot be beneficial in separate individuals and maybe he even assumes they are detrimental in separate individuals.

12. When Behe's book first came out I was a bit shocked that he didn't consider recombination. He must teach the topic in basic biology classes so he couldn't have forgotten it. The only thing I can think of is that there is no recombination in Plasmodium but he didn't bother to mention that.
I did some calculations way back when that I don't feel like resurrecting but I think I calculated the odds of an intraprotein recombination event at roughly 1- 10 million times the mutation rate. This means ( I think) that mutations will usually occur in different lines and then come together later.
Nick Mat pointed out that all this is irrelevant. Behe claims that what we've learned from Plasmodium suggests that most protein interactions could not evolve. I don't feel like slogging through all the arguments and counter arguments but as I understand it it comes down to this: Everyone agrees that CR is extremely unlikely. Behe wants to show that only 2 aa changes are required for this while everyone else says the evidence suggests its more. The reason for this is that if Behe can show that a mere 2 aa changes are so unlikely it makes most of the interactions in a human cell more likely to be 'designed'

1. Anyone who thinks protein interaction sites cannot evolve should read about affinity maturation of antibodies. Random mutation of antibody binding sites followed by selection for more efficient variants happens billions of times around the world every day.

2. Good comment, Chris. I've also always wondered myself everytime I hear these crap arguments why people don't just mention antibodies. According to Behe, God would have to be intervening at every minute in every single organism all the time to produce all those functional variants.

3. Well, the IDiots say that antibody evolution is not really evolution because the immune saytem has the "information" for all possible foreign binding epitopes programmed in it already ("information" not defined and not detectable.)

Here's a question we could ask them: if we synthesize a new chemical that never existed before, and inject it in your body, would you evolve antibodies to it? If no, testable prediction; if yes, how did God know the structure of the chemical, and its binding epitope, and program that into the immune system of ALL animals at the beginning of time?

4. Hi Diogenes,
If IDcreationists understood affinity maturation, they would know antibodies do not have the information for all possible foreign binding epitopes. At the point of affinity maturation, the shuffling of antibody genes has already happened. During affinity maturation, the binding regions of antibodies undergo what is called 'somatic hypermutation', a poorly understood mechanism where random mutations are made, creating a large pool of variants. The variants that bind the target antigen better go on to continue replicating while the poorer binding variants do not receive the proper growth cues and are eliminated.

Thus, in effect, every instance of affinity maturation generates new information by random mutation followed by selection for improved variants.

5. One of the points that Behe makes is that what happens with P. falciparum is a 'life and death' struggle. This is NS/evolution at its fiercest. And yet all that NS can muster is a two a.a. change. IOW, in terms of 'adapting to your environment', the environmental pressure can get no greater. And yet all we get is a 2 a.a. change.

As for the 'two lines coming together,' first, this won't help the malarial parasite, and second, both a.a.s , per Summers, are 'neutral.' How long will it take to 'fix'? What are the odds that the 'fix' will become 'unfixed,' i.e., replaced by another neutral substitution? And what then are the odds of both "lines" having just the right 'neutral' mutations? I would think it would be of the order of one over the total number of 'neutral' mutations the genome allows raised to the power of 2. So, if 10^7 of the 10^9 bases in the mammalian genome, e.g., were capable of 'neutral' substitutions, which is less than 1%, this would be of the order of 1 x 10^-14.

As far as recombination, if this 'could' help, then why didn't it?

6. Lino, your math is way the freak off, and your questions have already been answered. Please look at my calculations above.

13. As far as I can tell, neither Bilbo nor Diogenes has responded to the question in any relevant way.

1. I did answer the question: no.

Re-read the ORIGINAL question, from Uncivilized Elk and Photosynthesis, which had to do with chloroquine resistance, not the creation of malaria.

Behe thinks God created malaria and designed malaria's irreducibly complex systems. How he resolves the problem of evil is not the ORIGINAL question.

Behe would deny that chloroquine resistance is irreducibly complex, therefore it's the product of natural processes.

2. Well, I was curious what IDists who thought malaria resistance couldn't evolve "on its own" were thinking about the nature of their designer. I am induced to puking far too easily to wander into the ID forums and actually try to check myself.

I already have a hypothesis in mind though, because religious people dismiss mass indiscriminate murder of their god all the damn time and think it's not a problem whatsoever.

If god can be praised for saving a child in a plane crash while a hundred others around that child became blended burning flesh, it seems like it will be easy for IDists/Xtians/whomever to continue calling their creator a fellow who loves you despite tinkering with malaria so it can kill us better.

3. Diogenes, I'm talking about the question I asked, to which you were supposedly responding when you replied to me. If you don't know the answer, that's fine, but in that case it would be better not to "reply".

4. Yes John, I was mistaken to address my reply to you when I was actually replying to Elk.

14. Bilbo writes,

===========
If it is true that Satan is in control of the present world order, is it possible that he could have designed malaria, and all the other diseases that we consider evil? It's a view that I am willing to take seriously.

Of course, that creates other questions, such as how Satan came to be in control of this world, and why God would let him. As to the first, both J.R.R. Tolkien and C.S. Lewis propose in their fictional works that Satan was originally a good angelic being who partook in the creation of the world, and may have even been put in charge of it, but later rebelled against God, and has done his best to ruin God's creation. And I think that's a view that has possibilities.

But again, what makes me trust that there is a good explanation for why God's goodness and the existence of evil can be reconciled is that I believe that God became a human being and suffered as we have suffered. I'm willing to trust that kind of god, even if I don't have all the answers right now.
===========

Bilbo,

I don't care much either way about peoples' theology, but surely you've got to see that the Satan-caused-malaria view takes medicine right back to the Dark Ages.

On the other hand, evolution gives us practical leads. Malaria cells have organelles called apicoplasts. Phylogenetic analysis indicates that the group that includes malaria descends from a photosynthetic ancestor, and that the apicoplast descends from a chloroplast, which descends from cyanobacteria. This suggests that certain herbicidal chemicals which act against chloroplasts would also be successful against the apicoplasts of malaria. This opens up a whole new area of possible anti-malarial drugs, which is handy since malaria has been adapting to chloroquine and the other common ones we have now.

I Am Not Making This Up:
http://www.ncbi.nlm.nih.gov/pubmed/20491664

Google "malaria herbicide evolution" for more (I only get 1 link per post I think).

Would the Satan theory lead to this? I think not.

1. Hi Nick,

If Satan wasn't able to create actually new organisms, but could only bio-engineer pre-existing organisms, then yes, the Satan theory would lead to this.

2. But there are theological problems. Either god is unable to prevent Satan from intervening (and so is not omnipotent), or he doesn't know what Satan is doing (and so is not omniscient), or he allows Satan to intervene (and so is to some degree responsible and therefore less than omnibenevolent). You just can't fit all three omnis into one package, even if Satan is the direct agent.

Of course you can fall back on "who are you to question" or "god moves in mysterious ways" if you like. But I wouldn't call that a worthy position.

3. Hi John,

Yes, even if Satan was directly responsible for designing evil things like the malaria parasite, we still have the question of how a good God could allow him to do it. In other words, we still have the problem of evil. There have been attempts to answer the problem. My own view is that even though I don't know why God allows evil to exist, since I believe that God has somehow gone through the same sort of suffering that the rest of his creation has gone through, I have reason to trust that he has a good grounds for allowing it to happen. I understand that this isn't a good enough answer for you. And that's okay. It doesn't have to be good enough for you. Just good enough for me.

4. Is it OK with you if your answer isn't good enough for anyone other than you?

I have always found the concept of substitutionary atonement to be a very silly application of sympathetic magic. And here you offer another wrinkle. Why should god being willing to suffer make his infliction of suffering on others OK? Why would it even be effective in convincing you that it must be OK even though you don't understand it? If I shoot myself in the foot, would that convince you that I would be justified in shooting you too?

5. "Bilbo Wednesday, August 13, 2014 10:01:00 AM
Hi Nick,

If Satan wasn't able to create actually new organisms, but could only bio-engineer pre-existing organisms, then yes, the Satan theory would lead to this."

Forgive me, but this is particularly appropriate here: the hell it would! To get the Satan Theory to lead to this treatment pathway, you had to (1) insert yet another arbitrary free parameter (how Satan is peculiarly constrained to act), and (2) it, mysteriously, just happened to be that Satan acts by descent with modification, just like evolution. Satan is doing nothing in this "theory" except assuaging whatever emotional problems you have with evolution.

Bilbo, do you seriously think the pages of Nature and Science should be taking the Satan Theory seriously? Do you even want this? Or are you just yanking our chain?

This is the kind of junk that ID rapidly leads to. Its only real function is as a wing of conservative Christian, mostly conservative evangelical, apologetics.

15. Hi Larry, if I may, I would like to mention something about that 10^20 number that shows up in Edge of Evolution. I was puzzled how Dr. Nicholas White could know that number, so I went back and read his articles. He was actually trying to figure out where resistance arises in the population and whether or not it might be worthwhile to concentrate efforts at some aspect of that population. In the model for the infection, about 10 to 30 sporozoites enter the blood stream and enter the liver, where they go through about 15 rounds of replication and emerge as a population 100,000 to 300,000 and begin that 48-hour cycle. The population becomes detectable when they reach about 10^8 and the patient is considered well enough when it falls below 10^8 again. It is not possible to support 10^14 parasites but 10^13 can be supported.

What Dr. White did is estimate the number of clinical cases in a given time frame and multiply by the higher number, 10^13 - this is the 10^20 figure. Since fewer than 10 cases of resistance had showed up in that period, he reckoned the population size required to allow one resistant strain to emerge at 10^19 parasites.

So, where where these 10^19 parasites? It turns out that they would probably be in a child under the age of five who was being treated by chloroquine (there is some in nearly every person in some countries). Given the reasoning above, it would also be in a child who had been infected and suffered recrudescence of the infection. That means, as Diogenes pointed out, that you are not calculating the likelihood of a double mutation, but a double mutation in a population of human hosts who actually survived the first attack - and that is a group of people where the death toll from Malaria is the highest.

1. I see I left out a sentence. The gametocytes, for the most part, come from that first population to emerge from the liver and not the later population. Those later parasites, the bulk of them, are either killed by the treatment or die with the patient.

16. Behe has responded to Larry's and Diogenes's calculations: http://www.evolutionnews.org/2014/08/laurence_morans088811.html

1. Yes, and he lied about what I calculated. Shame on Behe. I showed his math is off by a factor of ~10,000, even if his assumptions were granted. Besides his math blunders, experimentally we know his assumptions were wrong.

17. Larry:

You write this:

e bottom line is that mutation to chloroquine resistance is going to be rare even if only two mutations are required and they occur sequentially. If four mutations are required for substantive chloroquine resistance then it's not at all surprising that so few resistant strains have been observed. There's no need to invoke simultaneous mutations and no need to assume that one of the mutations is deleterious.

I think you're making a mistake in your use of "simultaneous mutations."

You seem to be saying that Behe's usage of "simultaneous mutations" means that BOTH mutations must occur at the same time. How is that possible? How can any two mutations occur at the same 'instant of time'?

What is meant by simultaneous, is not simultaneity in time of occurence, rather simultaneity of 'presence." That is, BOTH mutations have to present in the SAME individual genome!

IOW, if only ONE mutation were necessary, then, after 30 generations (by your numbers), the malaria parasite would have already developed resistance, would therfore survive, and continue to reprodue. Instead, BOTH mutations need to be found in ONE malarial organism "at the same time."

So, it's not that the "mutations" have to occur "simultaneously"--which no one on the ID side would even consider logical--it's that the mutations have to be within ONE organism "at the same time." This is what Behe means regarding "simulataneous" mutations. This isn't "step-wise" or "sequential" in the sense that if ONE mutation occurs, survival is established, and an indefinite amount of time can occur before the next mutation can occur.

Your numbers simply verify that 10^6 persons x 10^12 organisms/person = 10^18 replications are needed for resistance to occur; i.e., where BOTH mutations are "simultaneously" present.

And BTW, the numbers that White uses show that "in vivo" the mutation rate for a single mutation is 10^12, and not the expected 10^8 (=genome size/ mutation rate). White's 10^20 figure is 10^12 x 10^8 (second mutation). There apparently is a difference between "in vivo" and "in vitro" rates. I didn't dig into it, and, IIRC, White makes the distinction without comment.

1. Lino trying to redefine the meaning of the word "simultaneous" after Behe and Gauger were proven wrong. They said simultaneous and they meant simultaneous, and they were way the hell off-- way off-- their assumptions were experimentally disproven, and even if their assumptions were right, their math is also wrong by a factor of ~10,000 as I showed above.

18. Bilbo,

Don't forget the Resurrection. In fact, taken literally, Jesus had a bad weekend for your sins. Many many humans have undergone much worse suffering (not to mention animal suffering).

19. A follow up on this story: It seems Behe was more than a little disingenuous in issuing this challenge. On another discussion board I frequent (where Mikkel Rumraket Rasmussen is also a member) a creationist drew attention to this article:

Waiting for Two Mutations: With Applications to Regulatory Sequence Evolution and the Limits of Darwinian Evolution
Rick Durrett and Deena Schmidt
Genetics November 2008 vol. 180 no. 3 1501-1509
http://www.genetics.org/content/180/3/1501.full

It's a bit of a mystery why this creationist cited this article, because it actually consists of a calculation (a mathematical model, to be precise) of exactly the sort that Behe demands in his "challenge". True, most of the study concentrated, not on malaria, but two other organisnms, namely Drosophilia and Homo sapiens. However, this should be of little concern, since if Behe's claim is correct it should be evident no matter which organism it is applied to. And since these two species are among those whose genetics have been most thoroughly investigated, and their life cycles considerably more simple than that of the malaria parasite, they probably produce more reliably generalizable data.

Moreover, the authors directly address Behe's argument from the "Edge of Evolution" and, using their model, demonstrate that Behe overestimated the time required to produce a trait requiring two mutations by factor of 5 million. This figure was later revised down to about 160,000, but that is still a substantial error.

So why did Behe make no mention of this in his "challenge"? Surely it is relevant to cite previously published efforts to perform the sort of calculations he is demanding from his interlocutors. Ordinarily, it could be speculated that he simply was not aware of this study. However, that cannot be the case here because Behe actually wrote a letter to the editor in response to the article, which was published along with a reply from the authors:

http://www.genetics.org/content/181/2/819.full?ijkey=84117603262edaee0b5455ea5c66238acc621b86&keytype2=tf_ipsecsha

http://www.genetics.org/content/181/2/821.full

Isn't that odd? Why, when Michael Behe issued the "challenge" to his critics, did he fail to mention that someone had already performed a rigorous mathematical calculation of the time required for a "CCC" to arise thru evolutionary processes, and leave the impression that the guesstimated figure he had lifted from Nicholas White's paper was still the best data available on the subject? Is his memory really that bad?

Surely the fact that this study demonstrated that Behe's estimate was grossly in error was not a factor in his selective amnesia.

20. Hello there. Jacob Blaustein, Agnostic Athiest and ID-denier here.
So I've found Behe's response to you and one of your commentors here: http://www.evolutionnews.org/2014/08/laurence_morans088811.html
It feels like an argument from assertion, in that his only complaint is that you two assume (with good reason I feel) that the mutations are neutral (after insulting Darwinists with him claiming that they are afraid of his 'big numbers')
What gets me is what he says here: "What if the first necessary mutation isn't neutral? What if -- as seems very likely from the failure of malaria cells with one required mutation (K76T) to thrive in the lab -- the first mutation is rather deleterious?"
...except what he links too (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1173140/) contradicts him and says this: . Using allelic exchange, we show that removal of the single PfCRT amino-acid change K76T from resistant strains leads to wild-type levels of CQ susceptibility, increased binding of CQ to its target ferriprotoporphyrin IX in the digestive vacuole and loss of verapamil reversibility of CQ and quinine resistance" Which meant that K76T was very fucking important towards the parasite's drug resistance!
And as Ken Miller pointed out: "In fact, it seems to have no effect on transport activity at all. A neutral mutation like this can easily propagate through a population, and field studies of the parasite confirm that is exactly what has happened. In fact, a 2003 study recommended against using the K76T mutation to test for chloroquine resistance since that same mutation was also found in 96% of patients who responded well to chloroquine. Clearly, K76T wouldn’t have become so widespread if it were indeed “strongly deleterious,” as Behe states it must be. This is a critical point, since Behe’s probability arguments depend on this incorrect claim."
So he scoffs at the fact you two assume something...that for all appearances us correct. So much so that it is less an assumption and more of a stated fact.
And as you pointed out he assumes that mutations must have the same 10^20 odds...even though there is no reason for this. And then he says "The commenter estimated that, too (and also added another consideration, a selection coefficient), and came up with a value of one new double mutant per 818,500 patients. Let's relax the admirable precision a bit and round the number up to a million." Considering that he complains about tweaking the numbers moments later, this is fucking dishonest of him. He can't handle that his calculations are very off, and has to lie about it!
What gets me is that he seems to have all the qualifications so he should know better, yet wastes his time on things like this for no good reason. I think deep down he knows this, but has fallen into the sunk cost fallacy; he's spent too much time into this, so now he feels that he is stuck.

1. I don't understand why Behe is being so disingenuous about chloroquine resistance. I suspect it's because he made a blatently false claim about "predicting" that two mutations were required and now he doesn't know how to weasel out of the corner he painted himself into.

We all agree that chloroquine resistance is rare because multiple mutations are required and that whenever multiple mutations are required for a new function that will also be a rare event.

We all agree that there are certain combinations of mutations that are beyond the edge of evolution.

I think that Behe is trying to convince his followers that he was completely right about chloroquine resistance and the leading scientists were wrong. Thus, according to this rationale, Behe is likely to be right about everything else and the Darwinists are wrong. It's the only way I can explain why he is being so pig-headed about the evolution of chloroquine resistance.

2. At this stage in Behe's ID career he's now come to actively rely on his acolytes utter absense of skepticism towards his claims. I suspect they don't even read what Behe actually writes, they simply note in the minds that "Behe has responded, Behe is someone whom we agree with". In this sense it doesn't matter what the context is or what the debate is about, It's Behe vs the evil darwinists, so Behe merely responding is all it takes.

They live in a world of absolute authority where nothing is ever checked or followed up upon. Subjects are settled in their communities by appealing to some kind of "ultimate authority" type text, with some "trusted interpreters". Normally those would be the priests giving their interpretations of religious scriptures(the bible), but in the case of scientific matters the trusted authority is Michael Behe. What he says is true no matter what, no need to check or think about it. Behe has spoken the matter is settled. Behe has never been called out internally in the ID movement, so why should he suddenly start correcting himself when everyone around him still buys his books and blindly copy-paste their contents as if they were divinely inspired wisdom?

Behe isn't really "trying to convince" his followers of anything, they are already convinced and have been since the beginning. Now Behe merely has to give a response of some sort once in a rare while and it will be mindlessly copy-pasted as gospel truth no matter what it actually says.

3. "I suspect it's because he made a blatently false claim about "predicting" that two mutations were required and now he doesn't know how to weasel out of the corner he painted himself into." More like he was shocked to be told that the mutations involved weren't simultaneous like he thought (I am pretty sure that the paper mentioned this) let along that sequencial mutations are the rule for evolution and his calculations relied on that NOT being the case. Along with the fact that it didn't require 5 to 6 mutations happening in a particular order (fewer mutations and like you point out it doesn't have to be in order & has multiple pathways)
In fact Mr. Moran, my biggest problem is that Behe (and by extension IDots) think all mutations aren't neutral and are actively harmful...considering that we have 125 mutations per generation, they really NEED to be neutral. Otherwise we'd all be dead...this seems like something you don't need to be a biologist to know about

"I think that Behe is trying to convince his followers that he was completely right about chloroquine resistance and the leading scientists were wrong. Thus, according to this rationale, Behe is likely to be right about everything else and the Darwinists are wrong. It's the only way I can explain why he is being so pig-headed about the evolution of chloroquine resistance."
Then the man is doing a diservce towards his followers, since again he has to lie about how the mutation came about. Not to mention that rare doesn't mean impossible (especially since it isn't as rare as he likes to think)