Darwinism Design inference Natural selection

Anti-malaria drug resistance requires at least two mutations

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Did design theorist Michael Behe predict this?

Abstract: Mutations in the chloroquine resistance transporter (PfCRT) are the primary determinant of chloroquine (CQ) resistance in the malaria parasite Plasmodium falciparum. A number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to CQ resistance in different parts of the world. Here we present a detailed molecular analysis of the number of mutations (and the order of addition) required to confer CQ transport activity upon the PfCRT as well as a kinetic characterization of diverse forms of PfCRT. We measured the ability of more than 100 variants of PfCRT to transport CQ when expressed at the surface of Xenopus laevis oocytes. Multiple mutational pathways led to saturable CQ transport via PfCRT, but these could be separated into two main lineages. Moreover, the attainment of full activity followed a rigid process in which mutations had to be added in a specific order to avoid reductions in CQ transport activity. A minimum of two mutations sufficed for (low) CQ transport activity, and as few as four conferred full activity. The finding that diverse PfCRT variants are all limited in their capacity to transport CQ suggests that resistance could be overcome by reoptimizing the CQ dosage. Paywall

Behe writes that in his Edge of Evolution (2007),

A major point of the book was that if evolution has to skip even one baby step to attain a beneficial state (that is, if even one intermediate in a long and relentlessly detailed evolutionary pathway is detrimental or unhelpful), then the probability of reaching that state decreases exponentially. After discussing a medically important example (see below), I argued that the evolution of many protein interactions would fall into the skip-step category, that multi-protein complexes in the cell were beyond the reach of Darwinian evolution, and that design extended very deeply into life.

However, at the time the book’s chief, concrete example — the need for multiple, specific changes in a particular malarial protein (called PfCRT) for the development of resistance to chloroquine — was an inference, not yet an experimentally confirmed fact. It was really an excellent, obvious inference, because resistance to chloroquine arises much, much less frequently than to other drugs. For example, resistance to the antimalarial drug atovaquone develops spontaneously in every third patient, but to chloroquine only in approximately every billionth one. About PfCRT I wrote, “Since two particular amino acid changes [out of four to eight total changes] occur in almost all of these cases [of chloroquine resistance in the wild], they may both be required for the primary activity by which the protein confers resistance.” The result would be that “the likelihood of a particular [malarial] cell having the several necessary changes would be much, much less than the case [for atovaquone] where it needed to change only one amino acid. That factor seems to be the secret of why chloroquine was an effective drug for decades.” Still, the deduction hadn’t yet been nailed down in the lab.

Now it has, thanks to Summers et al. 2014 …

He says this is the first of three posts. Evolution News & Views doesn’t allow comments, so feel free to offer them here, especially if you intend to read the paper you are trashing.

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33 Replies to “Anti-malaria drug resistance requires at least two mutations

  1. 1
    bornagain77 says:

    Behe vindicated in the lab. Many Darwinian critics of Behe’s ‘Edge of Evolution’ proven wrong (yet again):

    It’s Tough to Make Predictions, Especially About the Future – Michael Behe – July 16, 2014 (Part 2 of a 3 part series)
    Excerpt: The need for multiple mutations for chloroquine resistance in malaria just wasn’t that hard to see. So why do you think Darwinist reviewers of The Edge of Evolution missed it?
    http://www.evolutionnews.org/2.....87891.html

  2. 2
    Joe says:

    Umm the drug doesn’t require two mutations. Malaria requires two mutations to ward off the drug’s effects on it.
    [UD. Thx Joe. Title updated]

  3. 3
    Axel says:

    Isn’t it a matter of a confusing order of the words, Joe? A clearer order of the words being to have ‘chloroquine resistance’ follow, instead of precede, ‘in malaria’.

  4. 4
    Joe says:

    Confusing the order of the words is a habit that needs to be stopped as our detractors pick up on it and make it seem as if we are dupes.

  5. 5
    jstanley01 says:

    No amount of contrary evidence could be sufficient for members of the Darwin Death Cult. Differential survival rates are The Creator God, period. A God who will have no other gods before Him, Amen. A God who proves His worthiness by being infinitely adaptable, Hallelujah. Whatever it takes…

  6. 6
    Axel says:

    Can’t argue with that, Joe, other than to say that Behe probably said it in his mind with the appropriate stress, as he was writing it – which would have made it clear.

  7. 7
    Axel says:

    … to him!

  8. 8
    Starbuck says:

    looks like single mutations in PfCRT do not confer CQ resistance nor CQ transport activity. You need at least the 75 and the 76 mutations for CQ transport activity and an additional three mutations for CQ resistance.

  9. 9
    Silver Asiatic says:

    I think it’s the headline for this post and not what Behe said.

  10. 10
    PaV says:

    Joe:

    Confusing the order of the words is a habit that needs to be stopped as our detractors pick up on it and make it seem as if we are dupes. they

    If our critics focus on word-order, then this is a de facto admission that they have no substantive response.

    it’s child’s play.

  11. 11
    PaV says:

    wd400:

    What’s your view on this?

    What role does NS play here?

  12. 12
    wd400 says:

    My ‘view’ on what?

    This research shows a trait can only evolve when two mutations are present, and that it is unlikely that either of those mutations produce a fitness benefit by themselves. i.e. , in this case selection only operate when both mutations arise in the same gene. They enumerate other mutational pathways and their likely fitness consequences, which let’s you know how selection will operate once the 2 mutations are in effect.

    I’ve never thought the idea that some traits require two mutations was the major claim Behe was making, but if it is then I’ll happily grant. It’s true in this case, and there are probably many other traits that couldn’t arise by single mutations each with a slight fitness increase.

  13. 13
    Dr JDD says:

    …so what about higher organisms not capable of achieving such a population number to produce the chance needed to give multiple proteins that have undergone 2 simultaneous mutations? What about needing more than 2 mutations?

  14. 14
    wd400 says:

    That’s Behe larger claim, which doesn’t seem to be effected by this result as far as I can tell?

  15. 15
    Joe says:

    PaV- Our critics focus on word-order and anything else they can find because A) they say there isn’t anything to debate and B) because to them it proves we are not worthy of a debate in the first place.

  16. 16
    bornagain77 says:

    So, Michael Behe Was Right After All; What Will the Critics Say Now? – Casey Luskin July 16, 2014
    Excerpt: Will Ken Miller, Jerry Coyne, Paul Gross, Nick Matzke, Sean Carroll, Richard Dawkins, and PZ Myers Now Apologize to Michael Behe?,,,
    Is an apology from Behe’s critics then forthcoming? In a world where debates were conducted with the goal of discovering truth rather scoring points, it sure ought to be. Unfortunately, I’m not sure we live in that world.
    What we’ll probably get is nothing more than PZ Myers’s concession, offered in the context of the rant quoted above,,,
    http://www.evolutionnews.org/2.....87901.html

  17. 17
    PaV says:

    Joe:

    They will never accept our arguments. The arguments we make are self-evident; if they can deny self-evident arguments, then they can deny anything.

    It was Planck, I believe, who said that scientific breakthroughs don’t occur because one side wins the argument, but because one side of the argument ends up dying.

    ID will emerge victorious in another 25-30 years when enough young people will have been exposed to the ID argument and the vacuity of the arguments that Darwinists present. It’s a matter of time. There’s no convincing the critics in the meantime.

  18. 18
    PaV says:

    wd400:

    This research shows a trait can only evolve when two mutations are present, and that it is unlikely that either of those mutations produce a fitness benefit by themselves. i.e. , in this case selection only operate when both mutations arise in the same gene. They enumerate other mutational pathways and their likely fitness consequences, which let’s you know how selection will operate once the 2 mutations are in effect.

    So, you’re saying that NS was completely unable to do anything to make the malarial parasite survive: i.e., it could do nothing at all to make the parasite “fit.” Once it was ‘fit’ enough to survive—all this done without the help of NS—then, and only then, could NS help the organism to become slightly more ‘fit.’

    This is just what most IDist would maintain: NS cannot account for jumps in complexity, but once this jump has occurred, it can then tinker and sort of ‘fine-tune.’ IOW, NS can’t get you ‘macroevolution;’ only ‘microevolution.’

    And, so, Darwin was wrong.

  19. 19
    Acartia_bogart says:

    “ID will emerge victorious in another 25-30 years when enough young people will have been exposed to the ID argument and the vacuity of the arguments that Darwinists present. It’s a matter of time. There’s no convincing the critics in the meantime.”

    The only way this will happen is if all the rational people in the word die. But it’s always nice to have dreams.

    Any theory who’s sole tactic is to poke holes in another theory, without presenting a reasonable and testable alternative, is doomed to failure.

  20. 20
    bornagain77 says:

    AB you claim that ID will not be accepted unless,,,

    “all the rational people in the word die”

    Pray tell AB, how is rationality grounded within your materialistic worldview in the first place?

    “It seems to me immensely unlikely that mind is a mere by-product of matter. For if my mental processes are determined wholly by the motions of atoms in my brain, I have no reason to suppose that my beliefs are true. They may be sound chemically, but that does not make them sound logically. And hence I have no reason for supposing my brain to be composed of atoms. In order to escape from this necessity of sawing away the branch on which I am sitting, so to speak, I am compelled to believe that mind is not wholly conditioned by matter”.
    J. B. S. Haldane [“When I am dead,” in Possible Worlds: And Other Essays [1927], Chatto and Windus: London, 1932, reprint, p.209.

    Myself, I hold that even atheists themselves, when atheists die, will also admit that Design, with a capital D, is all too real:

    Romans 14:11
    It is written: “‘As surely as I live,’ says the Lord, ‘every knee will bow before me; every tongue will acknowledge God.'”

    But sadly, then it will be too late,,,

    Matthew 10:33
    but whoever denies me before men, I also will deny before my Father who is in heaven.

  21. 21
    wd400 says:

    So, you’re saying that NS was completely unable to do anything to make the malarial parasite survive: i.e., it could do nothing at all to make the parasite “fit.” Once it was ‘fit’ enough to survive—all this done without the help of NS—then, and only then, could NS help the organism to become slightly more ‘fit.’

    NS couldn’t make smallpox survive in the face of an eradication program, or mammoths moa or Diprotodon surive the arrival of humans, and it probably want save many other species from climate change. These are not normally persented as evidence that “Darwin was wrong”.

    I don’t see how you are getting from “some traits require two mutations, the first of which is not selected for” to that conclusion. Or, for that matter, why we should care since 21st century evolutionary biology is different from Darwins’ theories.

  22. 22
    Joe says:

    Acartia_bogart:

    Any theory who’s sole tactic is to poke holes in another theory, without presenting a reasonable and testable alternative, is doomed to failure.

    You have just described evolutionism. Nice job.

  23. 23
    Joe says:

    wd400- In what way is 21st century evolutionary biology different from Darwin’s theories? Did someone come up with a new designer mimic or is natural selection still the only mechanism capable of producing designoid features?

  24. 24
    OldArmy94 says:

    “Any theory who’s sole tactic is to poke holes in another theory, without presenting a reasonable and testable alternative, is doomed to failure.”

    Tell that to the iceberg that sank the Titanic.

  25. 25
    bornagain77 says:

    OT: New Paper in Bio-Complexity:
    How the Burgeoning Field of Systems Biology Supports Intelligent Design – July 2014
    Excerpt: Snoke lists various features in biology that have been found to function like goal-directed, top-down engineered systems:
    *”Negative feedback for stable operation.”
    *”Frequency filtering” for extracting a signal from a noisy system.
    *Control and signaling to induce a response.
    *”Information storage” where information is stored for later use. In fact, Snoke observes:
    “This paradigm [of systems biology] is advancing the view that biology is essentially an information science with information operating on multiple hierarchical levels and in complex networks [13]. ”
    *”Timing and synchronization,” where organisms maintain clocks to ensure that different processes and events happen in the right order.
    *”Addressing,” where signaling molecules are tagged with an address to help them arrive at their intended target.
    *”Hierarchies of function,” where organisms maintain clocks to ensure that cellular processes and events happen at the right times and in the right order.
    *”Redundancy,” as organisms contain backup systems or “fail-safes” if primary essential systems fail.
    *”Adaptation,” where organisms are pre-engineered to be able to undergo small-scale adaptations to their environments. As Snoke explains, “These systems use randomization controlled by supersystems, just as the immune system uses randomization in a very controlled way,” and “Only part of the system is allowed to vary randomly, while the rest is highly conserved.”,,,
    Snoke observes that systems biology assumes that biological features are optimized, meaning, in part, that “just about everything in the cell does indeed have a role, i.e., that there is very little ‘junk.'” He explains, “Some systems biologists go further than just assuming that every little thing has a purpose. Some argue that each item is fulfilling its purpose as well as is physically possible,” and quotes additional authorities who assume that biological systems are optimized.,,,
    http://www.evolutionnews.org/2.....87871.html

  26. 26
    Dr JDD says:

    Let us be clear about something. What we are talking about here is micro-evolution. I repeat, this is not a large jump this is merely losing the ability for a drug to bind to a protein thus conferring resistance. There is no novel function gained, no new cellular processes or pathways derived.

    Yet 2 sequential/coordinated mutations are required. And that happens at a rate of around 1×10^20.

    However, we are to believe that the components of a cellular pathway (KREBs cycle, complement pathway, ATP synthesis, etc, etc) does not require mutational events that necessitate > 2 sequential changes?

    Further (as those processes are more realistic with bacterial numbers), the complex genes involved in body plans seen in the animals such as in the Cambrian explosion – are we to accept that these could occur in that short time frame with all those necessary protein components on all <3 sequential mutations from pre-existing material?

    Really?

    Yeah that's right, IDers are the ones who aren't using their brains, honest guv.

  27. 27
    wd400 says:

    Yet 2 sequential/coordinated mutations are required. And that happens at a rate of around 1×10^20.

    How do you know this?

    However, we are to believe that the components of a cellular pathway (KREBs cycle, complement pathway, ATP synthesis, etc, etc) does not require mutational events that necessitate > 2 sequential changes?

    No Even Behe doesn’t claim that pathways requiring > 2 sequential changes are unreachable.

  28. 28
    rhampton7 says:

    Dr JDD,

    You say this is a case of micro evolution that “happens at a rate of around 1×10^20”. Do you think any natural mechanism can account for Anti-malaria drug resistance?

  29. 29
    Dr JDD says:

    Wd400 – because the empirical evidence suggests it? Chloroquine resistance occurs at roughly that rate and necessitates 2 coordinated mutations which is what the maths predicted which is the whole point of this thread. What observable evidence do you have to believe that the probability is unlikely to be that for an average sized protein?

    I should have written 4 coordinated mutations or more are impossible by probability not 3. I.e. 2 sets of coordinated mutations.

    Rhampton – yes that’s the point – due to population sizes the resistance can be accounted for by natural random mutations. But if you required more than 1 set of coordinated mutations to occur, no organism could realistically achieve that given the estimated age of the earth.

  30. 30
    wd400 says:

    Behe appears to have taken this number from a statement in a paper, which is not supported by a calculation or a citation. I see now easy way to get from “rate at which we observe a phenotype” to “rate at which mutations arise” that doens’t include a list of assumptions about the strength of selection, exposure to the drug and the rate at which Plasmodium moves from patient to mossquito so I think it’s a bit rich to call it an empircal fact.

    Behe’s argument (which is flawed) applies only to cases where intermediate sequences have no (or bad) fitness consequences, and specific changes are required in a single gene. So it’s not true that he’d argue 4 or more sequential changes were impossible (perhaps this is what you mean by co-ordinated?)

  31. 31
    bornagain77 says:

    As to wd400’s usual denial of evidence, I would like to add a few points. First is the fact that the modern synthesis, which wd400 holds as true, is now known to be false. As Dr. Nobel succinctly puts it:

    “The genome is an ‘organ of the cell’, not its dictator”
    – Denis Nobel – President of the International Union of Physiological Sciences

    A few more notes along this line:

    “Live memory” of the cell, the other hereditary memory of living systems – 2005
    Excerpt: To understand this notion of “live memory”, its role and interactions with DNA must be resituated; indeed, operational information belongs as much to the cell body and to its cytoplasmic regulatory protein components and other endogenous or exogenous ligands as it does to the DNA database. We will see in Section 2, using examples from recent experiments in biology, the principal roles of “live memory” in relation to the four aspects of cellular identity, memory of form, hereditary transmission and also working memory.
    http://www.ncbi.nlm.nih.gov/pubmed/15888340

    In Embryo Development, Non-DNA Information Is at Least as Important as DNA – Jonathan Wells – May 2012
    Excerpt: Evidence shows that non-DNA developmental information can be inherited in several ways. For example, it can be inherited through chromatin modifications, which affect gene expression without altering underlying DNA sequences. Another example is cytoplasmic inheritance, which involves cytoskeletal patterns and localization of intracellular molecules. Still another example is cortical inheritance, which involves membrane patterns.
    http://www.evolutionnews.org/2.....60031.html

    Not Junk After All—Conclusion – August 29, 2013
    Excerpt: Many scientists have pointed out that the relationship between the genome and the organism — the genotype-phenotype mapping — cannot be reduced to a genetic program encoded in DNA sequences. Atlan and Koppel wrote in 1990 that advances in artificial intelligence showed that cellular operations are not controlled by a linear sequence of instructions in DNA but by a “distributed multilayer network” [150]. According to Denton and his co-workers, protein folding appears to involve formal causes that transcend material mechanisms [151], and according to Sternberg this is even more evident at higher levels of the genotype-phenotype mapping [152].
    http://www.uncommondescent.com.....onclusion/

    etc.. etc.. etc..

    Thus, regardless of whatever wd400 may claim to the contrary, the plain fact of the matter is that he is working from the wrong theoretical foundation in the first place. The cell is best viewed holistically rather than from a ‘bottom up’ reductive materialistic approach. For wd400 to claim otherwise is for him to put his materialistic philosophy ahead of what the empirical evidence is clearly indicating!

    The second point I would like to bring up, that undermines wd400’s materialistic worldview, is ‘context dependency’.

    (A Reply To PZ Myers) Estimating the Probability of Functional Biological Proteins? Kirk Durston , Ph.D. Biophysics – 2012
    Excerpt (Page 4): The Probabilities Get Worse
    This measure of functional information (for the RecA protein) is good as a first pass estimate, but the situation is actually far worse for an evolutionary search. In the method described above and as noted in our paper, each site in an amino acid protein sequence is assumed to be independent of all other sites in the sequence. In reality, we know that this is not the case. There are numerous sites in the sequence that are mutually interdependent with other sites somewhere else in the sequence. A more recent paper shows how these interdependencies can be located within multiple sequence alignments.[6] These interdependencies greatly reduce the number of possible functional protein sequences by many orders of magnitude which, in turn, reduce the probabilities by many orders of magnitude as well. In other words, the numbers we obtained for RecA above are exceedingly generous; the actual situation is far worse for an evolutionary search.
    http://powertochange.com/wp-co.....Myers_.pdf

    Moreover, context dependency is found on at least three different levels of the protein structure:

    “Why Proteins Aren’t Easily Recombined, Part 2? – Ann Gauger – May 2012
    Excerpt: “So we have context-dependent effects on protein function at the level of primary sequence, secondary structure, and tertiary (domain-level) structure. This does not bode well for successful, random recombination of bits of sequence into functional, stable protein folds, or even for domain-level recombinations where significant interaction is required.”
    http://www.biologicinstitute.o.....ned-part-2

    Moreover, many (most?) proteins are now found to be multifunctional depending on the overall context (i.e. position in cell, cell type, tissue type, etc..) that the protein happens to be involved in.

    The Gene Myth, Part II – August 2010
    Excerpt: “Furthermore, many proteins have no intrinsic shape, taking on different roles in different molecular contexts. So even though genes specify protein sequences they have only a tenuous (very weak or slight) influence over their functions.
    ,,,,So, to reiterate, the genes do not uniquely determine what is in the cell, but what is in the cell determines how the genes get used. Only if the pie were to rise up, take hold of the recipe book and rewrite the instructions for its own production, would this popular analogy for the role of genes be pertinent.”
    Stuart A. Newman, Ph.D. – Professor of Cell Biology and Anatomy

    Metamorphic Proteins – 2008
    Summary: Proteins that can adopt more than one native folded conformation may be more common than previously thought.
    http://www.sciencemag.org/cont.....25.summary

    Genes Code For Many Layers of Information – They May Have Just Discovered Another – Cornelius Hunter – January 21, 2013
    Excerpt: “protein multifunctionality is more the rule than the exception.” In fact, “Perhaps all proteins perform many different functions by employing as many different mechanisms.”
    http://www.fasebj.org/content/23/7/2022.full

    Context dependency, and the insurmountable problem it presents for ‘bottom up’ Darwinian evolution is perhaps most dramatically illustrated by the following examples in which ‘form’ dictates how the parts are used:

    An Electric Face: A Rendering Worth a Thousand Falsifications – Cornelius Hunter – September 2011
    Excerpt: The video suggests that bioelectric signals presage the morphological development of the face. It also, in an instant, gives a peak at the phenomenal processes at work in biology. As the lead researcher said, “It’s a jaw dropper.”
    https://www.youtube.com/watch?v=wi1Qn306IUU

    What Do Organisms Mean? Stephen L. Talbott – Winter 2011
    Excerpt: Harvard biologist Richard Lewontin once described how you can excise the developing limb bud from an amphibian embryo, shake the cells loose from each other, allow them to reaggregate into a random lump, and then replace the lump in the embryo. A normal leg develops. Somehow the form of the limb as a whole is the ruling factor, redefining the parts according to the larger pattern. Lewontin went on to remark: “Unlike a machine whose totality is created by the juxtaposition of bits and pieces with different functions and properties, the bits and pieces of a developing organism seem to come into existence as a consequence of their spatial position at critical moments in the embryo’s development. Such an object is less like a machine than it is like a language whose elements … take unique meaning from their context.[3]“,,,
    http://www.thenewatlantis.com/.....nisms-mean

    Of course, much more evidence could be brought against wd400’s position. But for now, it is good for the uninitiated reader to know just how detached from reality wd400’s claims actually are.

  32. 32
    bornagain77 says:

    The Edge of Evolution: Why Darwin’s Mechanism Is Self-Limiting – Michael Behe – July 18, 2014 (Part 3 of 3)
    Excerpt: As science probes ever deeper into the molecular details of life,, grave obstacles to undirected evolution have become manifest. Relatively recent, terrific research using the powerful techniques available to modern biology shows three general, separate barriers to a Darwinian (or, for that matter, to any undirected) evolutionary mechanism.
    (1. random mutation, 2. natural selection, 3. irreducible complexity),,,
    It’s important to notice that these three roadblocks are substantially independent of each other. Sequestration of a system to its current function by natural selection is a different problem from the damage done by adaptive-yet-degradative random mutations, both of which are conceptually distinct from the need for multiple, unselected steps to reach some adaptive states. A result of their independence is that they will work synergistically. Undirected evolutionary change faces multiple overpowering restraints.,,,
    http://www.evolutionnews.org/2.....87971.html

  33. 33
    Mung says:

    wd400:

    Behe’s argument (which is flawed) applies only to cases where intermediate sequences have no (or bad) fitness consequences, and specific changes are required in a single gene.

    Simply false.

    The Edge of Evolution: Why Darwin’s Mechanism Is Self-Limiting

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