There is no contradiction here, not at all. Answering an objection raised by Roy, my analysis pertained to the probability of occurrence in P falciparum of the putative P vivax pathway to CQR, not the probability of occurrence of CQR in P vivax.
It doesn’t follow that the per-parasite occurrence of CQR, which is the relevant parameter in this discussion, is less probable in P vivax than in P falciparum. For example, if the number of parasites within an infected person is lower in P vivax than in P falciparum, then you could be in a situation where the occurrence of CQR in P vivax is less probable than in P falciparum even if the per-parasite occurrence of CRQ is higher in P vivax vs P falciparum.
And it happens that it is precisely the case that parasitemia is much lower in P vivax vs P falciparum. See the passage below…… Malaria parasites are micro-organisms belonging to the genus Plasmodium . The primary host of the parasite is the Anopheles mosquito and vertebrates (primarily humans). Malaria parasites are transmitted from the mosquito to its human host in the form of sporozoites during a blood meal. These immediately migrate to the liver where they invade hepatocytes and form schizonts. When these schizonts rupture, Plasmodium merozoites are released into the blood. This blood stage coincides with malaria symptoms in the host. Plasmodium vivax and ovale have a dormant hypnozoite liver stage. Hypnozoites may remain dormant for months or even years, causing relapsing infection when they finally re-enter the bloodstream.[4] Merozoites of P. vivax only infect reticulocytes unlike other species of malaria which will infect all stages of the red blood cell. This exclusive preference for reticulocytes results in significantly lower parasitemia levels in patients infected with P. vivax as compared to P. falciparum . While parasitemia rarely exceeds 2-3%, P. vivax can still result in significant disease due to increased host immune response[6]. Parasites undergo sexual and asexual multiplication in the human host. The infection spreads when a mosquito takes a blood meal from an infected human continuing the life cycle of the malaria parasite and eventually inoculates its next human host.
……taken from the following source:
I’m having a bit of troubles deciphering the inequalities too.
P vivax infection is more widespread* than P falciparum. I read this as more people infected (annually) with P vivax.
…significantly lower parasitemia levels in patients infected with P. vivax as compared to P. falciparum …
We know that for P falciparum, the per-parasite occurrence of de novo resistance is 1 in 10^20.
So more people infected with P vivax, but fewer paras.ites in those infected. @Faizal_Ali are @Giltil are both partly right.
Estimating the rate of a particular mutation is tricky, since what we observe are (IIUC) resistant cases, not per parasite mutation rates.
Is anyone even looking for the CQR mutation in P vivax?
Gil writes:
So if the P vivax pathway to resistance is possible for P falciparum, then it is at least as improbable as 1 in 10^20, and most probably more improbable since it has never been observed.
I don’t know, but I did manage to turn up the source code if anyone wants to investigate: aminograph 0.0.1 - Docs.rs
True, but isn’t Directed Acyclic Graph space bigger since it is a superset?
Could be, but run time is not linear with the number of sites. I started with the prestin alignment in its entirety for the same species Ewert used and that finished in 24 hours also. And one of my simulated alignments had 3x sites (~2000) and only took 1-2 hours longer.
Many of the resistance mutations in P. falciparum are not found in P. vivax, limiting the value of using orthology to infer resistance mutations in P. vivax . (source)
Incidentally, following up on the above led to finding this:
An important and ubiquitous amino acid substitution in chloroquine-resistant alleles, regardless of origin, is lysine to threonine at position 76. This K76T mutation is always accompanied by multiple additional region-specific mutations. For example, the chloroquine-resistant South American 7G8, African GB4, and Southeast Asian Dd2 PfCRT isoforms harbor five, six, and eight mutations, respectively, compared to the chloroquine-sensitive wild-type 3D7 isoform. The cryo-EM structure of PfCRT was solved for the 7G8 isoform, revealing that all five of its mutations, namely, C72S, K76T, A220S, N326D, and I356L, line the central drug-binding cavity. A minimum of four of these mutations is required to confer chloroquine resistance, suggesting a codependent role for these additional amino acid substitutions (42).
The above two combined with @Dan_Eastwood’s source show that contrary to @Giltil’s claims when introducing CQ in this thread, P. falsiparum and P. vivax have developed resistance in different ways; there are multiple possible biochemical solutions to complex biochemical challenges, some of which have been realized in Plasmodium species; they haven’t converged towards the same solution; the reality is far more complicated than Behe’s and @Giltil’s descriptions; there is no indication that very few solutions exist to solve this or any other problem; and that while this may be relevant to Ewert’s model in that some CQR mutations are interdependent (but not in a way determinable using AminoGraph!), it isn’t relevant in the way @Giltil thought it was.
I’ve never said in this thread that P falciparum and P vivax have developed resistance y in the same way. Quite the contrary in fact. I quote myself: I think it is an abuse of language to define P. Falciparum and P. Vivax as strains. In fact, it seems that they don’t belong to the same species, not even to the same subgenus, only to the same genus. So it is not surprising that these 2 different bugs don’t necessarily converge to the same solution when confronted to chloroquine for their biology are very different.
There is.
Consider the 3 following points pertaining to P falciparum
the per-parasite occurrence of CQR is an extremely rare event (about 1 in 10^20)
CQR has emerged independently several time since CQ is used
in each of these few cases of CQR emergence, overall the same solution was used by the bug to overcome the challenge posed by the drug.
Taken together, these 3 points strongly suggest that very few solutions exist in P falciparum to overcome the challenge posed by CQ. If you think otherwise, please show us your evidence.
Yes, that is a point that Behe and his defenders repeatedly ignore. It is even made explicit in a handy table in the very article from which Behe took his 10-20 figure:
Inexplicably, Behe insists that the occurrence of CQR is determined only by #1, and ignores 2-8.
But, here we are, again falling into the trap of debating minutiae and irrelevancies. I suspect this is just what Behe wants us to do.
I will, instead, repeat the point that @Giltil, and all of Behe’s other defenders, have failed to address:
For the sake of argument, let’s assume Behe is exactly correct that CQR in P. falciparum arises at a rate of 1 in 1020 reproductions.
This does not define some general “edge” to what functional traits can arise thru natural, undirected, evolutionary processes.
To put it another way: Behe has not demonstrated that there are many other examples of traits that are as unlikely to arise as CQR is in P. falciparum. Specifically, he has not shown that there are so many of these that an explanation other than standard evolutionary processes is required.
If anyone disagrees, please show how Behe has demonstrated this.
I would note that even if that were all true it provides no support for ID.
I also note that the first is almost certainly false and that the third depends on what you mean by “the same solution”. We know for a fact that there were a number of variations on the solution.
It’s worth noting that the author of that review pointed out that Behe was misrepresenting him. The existence of this table strongly suggests deliberate deception on Behe’s part.
Also, if Behe truly believes that he understands malaria better than the experts do, why isn’t he actively working on it with funding from the DI? Actions (and inaction) speak more loudly than words.
It’s the best estimate by Nicholas White, one of the world’s foremost malariologists. As Behe wrote « White´s calculation was based on intimate knowledge of many details of the biology and epidemiology of the parasite ». So your are claiming that White´s best estimate is almost certainly false. Ok. So what is your’s!
The solution for the bug seems to pass by acquiring at least the mutations K76T plus either N75E or N326D in PfCRT, ie very specific changes at two very particular amino acid positions in a very particular protein. I think it is fair to describe this as overall the same solution.
Of course it does for it illustrates the two following points:
the idea that many solutions exist to solve problems having the same complexity of CQR in P falciparum is not warranted
Any particular adaptive biochemical feature requiring the same mutational complexity as that needed for chloroquine resistance in malaria is forbiddingly unlikely to have arisen by Darwinian processes and fixed in the population of any class of large animals (such as, say, mammals), because of the much lower population sizes and longer generation times compared to that of malaria. Taken from the source below. Best of Behe: A Quick Reprise of The Edge of Evolution | Evolution News
In biochemistry, far from irrelevant, minutiae are crucial and it is only by considering these minutiae that the plausibility of evolutionary hypotheses can best be assessed. Let quote Behe again : « looking down from an airplane at 30000 feet, the landscape can appear pretty smooth. It can be hard to imagine yourself in the place of pionniers in covered wagons of earlier times, who had to slog over the unclear ground bump by bump, facing rivers, ridges, and ravines. A lot of thinking about evolution over the years has been like looking down from a plane— imagining that an evolutionary trek from one large feature to another wouldn’t be too difficult, that it could even be made while blind-folded and drunk. But in reality life is lived in the ground and, without vision and sober planning, ditches, cliffs, and streams can be impassable »
The first does not give license to assume that there are no alternative solutions available, which is what ID requires. That a“Texas Sharpshooter” argument might happen to be correct by dumb luck does not make it a good argument.
The second is also useless - unless ID researchers can show that a mammalian species has solved a problem of that “complexity” there’s nothing there. (Of course CQR wasn’t actually that “complex” so it seems that Behe has problems finding examples even in simpler organisms).
What does it mean to say that a problem “has the same complexity of CQR in P falciparum?”
If you mean only to say that things that are as constrained as CQR in terms of the number of mutations required and how many different alternative pathways there are to them, are as constrained as CQR, then the statement is meaningless and of no worth when considering different adaptations, or other organisms, in which those adaptations might not be similarly constrained.
We know of other adaptations that require just as many mutations, but have many more pathways available to them through which they can evolve, and thus would have a much easier time evolving. Here’s an old favorite:
If this were an algorithmic task in computer science, we could define the type of complexity. I’d say it can probably be solved in Polynomial time, meaning it’s just a matter of sufficient computing time.
Hard problems in CoSci are said to have Non-Polynomial (NP) computing time, meaning there is no guarantee the problem can be solved in any give fixed amount of time. It seems to me that if your really wanted to define an “Edge” of evolution, then showing the problem to be NP-Hard would be the way to go. This is not Behe’s approach.
Genetic Algorithms are very efficient at solving problems when there is a gradient of improvement (need not be continuous). The CQ problem is not that sort of question tho, or if it is then it’s a trivial case, I think.
Sorry, but seem to be rambling. I just got to thinking about what it really means to have a biological problem too difficult for evolution to solve. Defining the problem in terms of complexity classes would be a good first step.
Directed Acyclic Graphs are a subset of all dependency graphs (since dependencies can be cyclic).
I don’t think Ewert is restricting his search for acyclic graphs specifically. At least I could not find anywhere that he states his dependency graphs are restricted in this way, though I haven’t checked his code and I couldn’t anyway since I’m not a programmer.
In any case, one would hope he implemented some sort of optimization criterion (hill climbing by some sort of permutation or whatever) that makes the program search for increasingly better graphs in an efficient way, instead of computing and then evaluating every possible graph from the alignment.
No, you didn’t say that explicitly. But you did say: “Despite the enormous number of organisms under selective pressure from chloroquine, it is only through a few point mutations in the same pre-existing protein that malaria developed chloroquine resistance.”
Both P. falciparum and P. vivax would fall under your (mis)use of “malaria”. Perhaps you were unaware that P. falciparum was not the only malaria-causing species of Plasmodium.
Context restored:
I didn’t say anything about solutions in P. falciparum. The context of my words, which you omitted, made it clear that I was talking about solutions that exist or could potentially exist across multiple species. Even if your three points were valid (they aren’t), showing that there are few solutions for chloroquine resistance available to P. falciparum does nothing to show that there are few solutions available to other species, closely related or not. It does highlight your willingness to quote-mine, however.
I’ll close by noting that your (flawed) argument that there are few solutions available for chloroquine resistance in a single species has absolutely nothing to do with to the number of solutions available for echo-location across many species of bats and whales. You have painted yourself into a corner of irrelevancy.
In that case, perhaps you would care to address the main points of my comment, and not just two relatively inconsequential sentences. Here, again, is what I would like you to address:
Here is the specific passage where White provides his estimate:
The genetic events that confer antimalarial drug resistance (while retaining parasite viability) are spontaneous and rare and are thought to be independent of the drug used. They are mutations in or changes in the copy number of genes encoding or relating to the drug’s parasite target or influx/efflux pumps that affect intraparasitic concentrations of the drug (Table 1). A single genetic event may be all that is required, or multiple unlinked events may be necessary (epistasis). As the probability of multigenic resistance arising is the product of the individual component probabilities, this is a significantly rarer event. P. falciparum parasites from Southeast Asia have been shown to have an increased propensity to develop drug resistance (12).
Chloroquine resistance in P. falciparum may be multigenic and is initially conferred by mutations in a gene encoding a transporter (PfCRT) (13). In the presence of PfCRT mutations, mutations in a second transporter (PfMDR1) modulate the level of resistance in vitro, but the role of PfMDR1 mutations in determining the therapeutic response following chloroquine treatment remains unclear (13). At least one other as-yet unidentified gene is thought to be involved. 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 1020 parasite multiplications.
As you can see, it is just a very rough guesstimate. This is further demonstrated by the fact that, in another paper, he gives the figure as 1 in 1019.
This is not meant as a criticism of White. The precise figure is of little importance to his work and obtaining a precise number would be an extremely difficult task. I’m not even sure how it could be done. But if Behe is trying to use this figure as a cornerstone of his attempt to overturn one of the best supported theories in all of science, he needs to be much more rigorous and precise in how he determines it. Simply lifting a very approximate back-of-envelope guesstimate from someone else’s paper is just lazy and inadequate (even though it seems to be good enough for his devoted fans.)
And, one more time: It doesn’t matter. The frequency with which CQR arises in P. falciparum is the frequency with which CQR arises in P. falciparum. Period. It has no broader implications for the frequency of other adaptive traits in other organisms.
