Annoying creationists

[joobz]

I see kleinman still hasn't justified any of his model assumptions nor has he presented ANY reports that support his half baked, Evolution is too slow=stop idea.

 

[kleinman]

Annoying Creationists

I’m not sure what you are having trouble understanding in my statement. Each of the selection conditions in ev does a part of the sorting requirement of the genomes. In order to get an arrangement of bases that satisfy all three sorting conditions simultaneously, it is an extremely slow process for all but the tiniest genomes. This is your so-called function. However, any individual portion of the sorting process can be done much more quickly if done independently of the other sorting conditions. A portion of your total function can be achieved by applying only a single sorting condition.

But a portion of a whole function is not the same function as the whole function, is it? Lots of things in life are made easier by only doing part of the whole task.

Of course things are made easier when you break down a complex task into simpler parts but Paul, any one of the three selection conditions sorts at least 10’s of thousands of times faster than all three conditions together for a 16k genome. And then you have this notion that thousands of genes can be transformed by mutation and selection to evolve reptiles into birds all without any goal. Your model shows what happens to the mutation and selection sorting/optimization process with just three selection conditions. Paul, evolutionbymutationandselectiondidn’tdoit.

Let me help. I get this argument all the time: "you wouldn't be so angry if the Designists/Creationists/Illuminati/Holocaust Deniers/Second Gunmen/Flat Earthers weren't right!" It's a very silly rationale, and no, writing it in a more longwinded style doesn't help.

Welcome to the discussion Olowcow. You certainly seem to be a bit angry with a lot of people. Stick with the discussion, we’ll lift your spirits with a little discussion of the mathematics of mutation and selection and the empirical evidence which substantiates this mathematics.

There's a simple reason why biologists get pissed off with creationists, and it has nothing to do with a "first person ontology" — it's that we have the hard work, the data, the experiments, the whole dang enchilada of the "objective facts of the matter," and pretentious pissants like Mr Wood think nothing of overlooking their own self-admitted ignorance of evolution to pronounce a verdict based entirely on their half-assed psychoanalysis of the universe. We can see quite clearly (especially in this instance) what it is that drives a person to oppose Darwin (as if ol' Chuck had anything to do with the issue at this point): it is the arrogance of incompetence, the self-satisfied smugness of preening ********, the sanctimony of pious lackwits, the insufferable stupidity of pompous windbags who think they can rationalize their superstitions by seeking justification in a kind of gasified cold reading.

Olowcow, it’s only your first post and you are already annoyed. If you are trying out for the job of my favorite annoyee, Adequate already has it. I can’t help it if you evolutionists have already done my work for me. Next time you formulate a mathematically impossible theory, don’t write mathematical simulations of your theory and don’t run the experiments and collect data which show that the mathematical model is correct. Just stick with your speculations and extrapolations and your mathematically impossible world view will be a bit more secure.

Your bubble-headed ******** doesn't bamboozle me, Mr Wood — I think the only person your verbose drivel might persuade is another superficial drone who mistakes diarrhea for depth.

Olowcow, do you have anything to say about the mathematics of mutation and selection? Perhaps you want to break the long drought you evolutionists have had and give us an example of n+1 selection pressures evolving more rapidly than n selection pressures.

I see kleinman still hasn't justified any of his model assumptions nor has he presented ANY reports that support his half baked, Evolution is too slow=stop idea.

Joobz, you have claimed you are going to find irregularities in my PhD dissertation, $10,000 wager says that you can’t find any mathematical or empirical irregularities. Joobz, didn’t you read this citation?
http://www.blackwell-synergy.com/doi/pdf/10.1046/j.1365-3156.2001.00800.x

Resistance genes are generally assumed to be biologically less efficient than the normal susceptible type. For example, an enzyme may escape drug action by a mutation that alters the drug-binding site. As this mutation probably also affects its catalytic capacity, the mutation will be removed from the population by natural selection and their frequency in the naive, non-drug-treated, population will be determined by a mutation/selection balance (Hastings 1997; Koella 1998). If drugs are used in combination, then the frequency of parasites resistant to both drugs will be

very low. For example, if 0.1% are resistant to drug A and 0.005% are resistant to drug B, then parasites resistant to both will initially be present at a frequency of 0.1 x 0.05% = 0.00005% (assuming that the same gene cannot encode resistance to both drugs). Thus using drugs in combination from the outset may greatly increase the useful therapeutic lifespan of the drug, because lowering the starting frequency delays the point at which a significant amount of resistance emerges.

And

One important general point from the models is that use of combination therapy in their initial deployment is invariably better than introducing one drug alone, followed by introduction of the second-line drug once the first becomes ineffective (see, for example, Curtis & Otoo 1986; Smith 1990; Bonhoeffer et al. 1997; for malaria, helminths and bacteria, respectively).

And

If parasites reach high numbers within hosts, then spontaneous mutations to resistance may occur. Infections of P. falciparum may reach 10^11-10^12 individual parasites per host and it seems logical that a small subpopulation may have mutated to drug resistance (for example if the mutation rate to resistance is 10^-8 then there would be 1000±10 000 resistant parasites) which then expands to dominate the infection. This argument seems logically plausible and receives support from observations of humans treated with the antimalarial drug atovaquone, where an infection which was originally susceptible disappears below detectable levels before recrudescing as a resistant infection (Looareesuwan et al. 1996). Measurements of drug sensitivity in vitro before and after treatment show greatly increased levels of resistance in the recrudescent infection. It seems plausible that the same effects may occur in other parasites that reach high population numbers within a host. Once again the effect can be minimized or even eliminated by using drugs in combination. In the above example of 10^11 parasites, mutation rates to resistance of 10^-8, and assuming two drugs were used in combination, then resistance would arise in only 10^16 parasites, in effect rendering the frequency of spontaneous mutations negligible. The implications for the evolution of drug resistance are discussed in Lipsitch and Levin (1997) and White (1999 and references therein).

These authors seem to think they can eliminate drug resistance using combination selection pressures. Joobz, you better tell them that slow doesn’t mean stop.

 

[rocketdodger]

I am just going to stop writing as much, because I see that you pick and choose what you want to respond to in order to dodge the issue at hand, Kleinman.

You claimed that additional optimization conditions always confound sorting / optimization problems. My program shows this to be not true in general. Can you show anyone here why the sorting/optimization algorithm used in my program is, in fact, not a sorting / optimization algorithm?

Here it is, in short:
1) Randomly mutate x number of bases in each creature's genome.
2) Determine the fitness of each creature according to the pressures exerted on the population.
3) Reproduce, such that creatures with higher fitness have more offspring.
4) Go back to 1, stopping when the targeted mutations of all pressures have achieved 80% or more fixation in the population.

 

[sol invictus]

This is why you are asking the wrong question. This is not simply a probability problem; it is a sorting and optimization problem as well. Only those most fit members of the population can accumulate the beneficial mutations. The harmful mutations are causing individuals to be selected out.

Those effects make this process faster, not slower, because individuals with the beneficial mutations will breed more than those without. I'm ignoring that.

But for the sake of discussion, let’s consider your approach but instead of 90% of the individuals undergoing all N mutations, consider a single individual undergoing all N (100) mutations.

If we ask after how much time does an individual have a 90% chance of having all N mutations, it's the same question - so fine.

In the first generation that individual has a (1/(1,000,000))*100 probability of getting a beneficial mutation, if that individual is gets one of those beneficial mutations, in the next generation, that individual has a (1/(1,000,000))*99 probability of getting a second beneficial mutation or a total probability of (1/(1,000,000))*100*(1/(1,000,000))*99 and so on for each additional possible beneficial mutation. The probability of a particular individual getting all one hundred beneficial mutations is (100/1,000,000)*(99/1,000,000)* … *(1/1,000,000).

You're confusing yourself. That's supposed to be the probability after how much time?

Sol, I’ll let you run the numbers for the probability of any individual getting all 100 beneficial mutations in 100 generations, let alone 90% of the population getting all 100 beneficial mutations.

Whoa there, slow down. If the chance of any given mutation is only 1/1,000,000, after 100 generations it's very unlikely any mutations have occurred. What my calculation showed was that however long you have to wait for one mutation, you don't have to wait much longer for many more. It's 1/p that sets that timescale, so in the case p is 1/1,000,000, you'll need to wait around 1,000,000 generations for even one mutation.

The point you are missing is that without selection, you can not improve the frequencies of genetic sequences in the population. You only have a few basic ways of improving these probabilities. You can increase population, number of generations, mutation rates (within limits) or you can reduce down the number of selection pressures.

Again, selection makes this process faster, not slower. I'm just ignoring it for now for simplicity.

So Sol, you are telling us that it only takes 14 times longer to win 100 lotteries as it takes to win 1 lottery? After all, that’s what an individual in the population has to do to get the 100 beneficial mutations and for that individual, the probability of winning one of the lotteries is decreasing with each beneficial mutation the individual wins.

Nope - I'm saying it only takes 14 times longer to win a million lotteries. To win a 100 would only take around 5 times as long. Counterintuitive, huh?

But it's true - and the reason is you're playing all the lotteries at once, and the odds of not winning even one decrease exponentially with the number of chances, once the number is greater than 1/p. So you're extremely unlikely not to have won any given lottery after that point, which is why winning many doesn't take much longer at all (and that exponential also explains where the log comes from).

 

[kjkent1]

There is a huge amount of evidence that particular selection pressures lead to particular mutations increasing in frequency in a population. This phenomenon is used to identify resistance to drugs, pesticides and herbicides. If evolution does not have a goal, why do the same mutations show up over and over to particular selection pressures?

You think that the change from a dinosaur form to a bird form was the result of something other than just an accumulation of various unpredictable biological changes which just happened to have provided their owners a fitness advantage at a particular historical point.

Evolution is not deterministic, Alan. Two trials of an experiment using identical selection pressures will not necessarily produce the same evolutionary outcome, because the "mutation" part of the evolutionary process cannot be predicted in advance.

Too bad that the evidence contradicts your speculations; for example, the use of particular drugs for treatment of HIV leads to increase in the frequency of particular mutations appearing in the viral population. This effect is used to identify when resistance to a particular drug has evolved.

Mutational patterns and correlated amino acid substitutions in the HIV-1 protease after virological failure to nelfinavir- and lopinavir/ritonavir-based treatments.

Garriga C, Pérez-Elías MJ, Delgado R, Ruiz L, Nájera R, Pumarola T, Alonso-Socas Mdel M, García-Bujalance S, Menéndez-Arias L; Spanish Group for the Study of Antiretroviral Drug Resistance.

Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.

Human immunodeficiency virus type 1 (HIV-1) antiviral drug resistance is a major consequence of therapy failure and compromises future therapeutic options. Nelfinavir and lopinavir/ritonavir-based therapies have been widely used in the treatment of HIV-infected patients, in combination with reverse transcriptase inhibitors. The aim of this observational study was the identification and characterization of mutations or combinations of mutations associated with resistance to nelfinavir and lopinavir/ritonavir in treated patients. Nucleotide sequences of 1,515 subtype B HIV-1 isolates from 1,313 persons with different treatment histories (including naïve and treated patients) were collected in 31 Spanish hospitals over the years 2002-2005. Chi-square contingency tests were performed to detect mutations associated with failure to protease inhibitor-based therapies, and correlated mutations were identified using statistical methods. Virological failure to nelfinavir was associated with two different mutational pathways. D30N and N88D appeared mostly in patients without previous exposure to protease inhibitors, while K20T was identified as a secondary resistance mutation in those patients. On the other hand, L90M together with L10I, I54V, A71V, G73S, and V82A were selected in protease inhibitor-experienced patients. A series of correlated mutations including L10I, M46I, I54V, A71V, G73S, and L90M appeared as a common cluster of amino acid substitutions, associated with failure to lopinavir/ritonavir-based treatments. Despite the relatively high genetic barrier of some protease inhibitors, a relatively small cluster of mutations, previously selected under drug pressure, can seriously compromise the efficiency of nelfinavir- and lopinavir/ritonavir-based therapies. (c) 2007 Wiley-Liss, Inc.

PMID: 17854027 [PubMed - indexed for MEDLINE]

Oh oh...D30N and N88D appeared "MOSTLY" in certain patients. But, not "ALWAYS." In some patients, K20T appeared.

So, much for the hypothesis that only one mutational pathway can develop from a particular selective pressure. Kleinman loses again.

 

[Mr. Scott]

Annoying Cognitive Dissonance

I am just going to stop writing as much, because I see that you pick and choose what you want to respond to in order to dodge the issue at hand, Kleinman.

Where previously I'd agree this was a debating tactic of Kleinman (and creationists in general), I now see he's exhibiting the psychological phenomenon known as Cognitive Dissonance. Sufferers of this cope with conflicting information by ignoring information that conflicts with their established beliefs. In this example Kleinman, who's believed in biblical creation since he was too young to think for himself, ignores the decisive proof of evolution to relieve the uncomfortable feeling caused by attempting to reconcile these dissonant ideas. I'd be more sympathetic if he didn't resort to deliberate, smirking viscous denigration of those who disagreed with his infantile beliefs.

Cognitive dissonance is a psychological term describing the uncomfortable tension that may result from having two conflicting thoughts at the same time, or from engaging in behavior that conflicts with one's beliefs, or from experiencing apparently conflicting phenomena.

In simple terms, it can be the filtering of information that conflicts with what one already believes, in an effort to ignore that information and reinforce one's beliefs.

 

[joobz]

Joobz, you have claimed you are going to find irregularities in my PhD dissertation, $10,000 wager says that you can’t find any mathematical or empirical irregularities.

Obviously this is a lie and everyone knows it. I've addressed this point, but you choose to pretend otherwise. This, among other lies, simply exposes your entire method. You ignore truth and present idiotic statements. All this does is make you appear to be a complete inept moron. Coupled with all the science you present, which is horrificly dumb, I'm starting to believe you are a complete inept moron. Are you?

 

[kleinman]

Annoying Creationists

I am just going to stop writing as much, because I see that you pick and choose what you want to respond to in order to dodge the issue at hand, Kleinman.

That’s correct, and the issue at hand is you have claimed you have written a simulation of mutation and selection which shows that n+1 selection pressures evolve more rapidly than n selection pressures. Now it’s time for you to post a real example of your alleged model.

This is why you are asking the wrong question. This is not simply a probability problem; it is a sorting and optimization problem as well. Only those most fit members of the population can accumulate the beneficial mutations. The harmful mutations are causing individuals to be selected out.

Those effects make this process faster, not slower, because individuals with the beneficial mutations will breed more than those without. I'm ignoring that.

You are also ignoring the fact that selection pressures reduce the fitness to reproduce.

In the first generation that individual has a (1/(1,000,000))*100 probability of getting a beneficial mutation, if that individual is gets one of those beneficial mutations, in the next generation, that individual has a (1/(1,000,000))*99 probability of getting a second beneficial mutation or a total probability of (1/(1,000,000))*100*(1/(1,000,000))*99 and so on for each additional possible beneficial mutation. The probability of a particular individual getting all one hundred beneficial mutations is (100/1,000,000)*(99/1,000,000)* … *(1/1,000,000).

You're confusing yourself. That's supposed to be the probability after how much time?

That’s 100 generations sol, each additional generation will improve that probability less than an additively.

Sol, I’ll let you run the numbers for the probability of any individual getting all 100 beneficial mutations in 100 generations, let alone 90% of the population getting all 100 beneficial mutations.

Whoa there, slow down. If the chance of any given mutation is only 1/1,000,000, after 100 generations it's very unlikely any mutations have occurred. What my calculation showed was that however long you have to wait for one mutation, you don't have to wait much longer for many more. It's 1/p that sets that timescale, so in the case p is 1/1,000,000, you'll need to wait around 1,000,000 generations for even one mutation.

The chance of any given mutation is always 1/1,000,000. The chance of any beneficial mutation for a given individual is the sum of the probabilities for each of the possible beneficial mutations.

The point you are missing is that without selection, you can not improve the frequencies of genetic sequences in the population. You only have a few basic ways of improving these probabilities. You can increase population, number of generations, mutation rates (within limits) or you can reduce down the number of selection pressures.

Again, selection makes this process faster, not slower. I'm just ignoring it for now for simplicity.

You are also ignoring that you are not computing the probability of a given individual getting all 100 beneficial mutations.

So Sol, you are telling us that it only takes 14 times longer to win 100 lotteries as it takes to win 1 lottery? After all, that’s what an individual in the population has to do to get the 100 beneficial mutations and for that individual, the probability of winning one of the lotteries is decreasing with each beneficial mutation the individual wins.

Nope - I'm saying it only takes 14 times longer to win a million lotteries. To win a 100 would only take around 5 times as long. Counterintuitive, huh?

But it's true - and the reason is you're playing all the lotteries at once, and the odds of not winning even one decrease exponentially with the number of chances, once the number is greater than 1/p. So you're extremely unlikely not to have won any given lottery after that point, which is why winning many doesn't take much longer at all (and that exponential also explains where the log comes from).

The problem with your calculation is that you are using 1/p (1/1,000,000) as your number. To win this lottery, the individual has to adapt to 100 selection pressures each with a 1/p = 1/1,000,000. The individuals don’t get to play with all these selection pressures. Counterintuitive, huh?

But it’s true, even two strong selection pressures are sufficient to stop most populations from evolving. Even for the very fast replicating virus HIV with high mutation rate, 3 selection pressures profoundly slow the evolutionary process. The exponential gain from selection only occurs with single selection pressures. Once you add additional selection pressures, the different selection conditions confound the sorting process.

Too bad that the evidence contradicts your speculations; for example, the use of particular drugs for treatment of HIV leads to increase in the frequency of particular mutations appearing in the viral population. This effect is used to identify when resistance to a particular drug has evolved.

Mutational patterns and correlated amino acid substitutions in the HIV-1 protease after virological failure to nelfinavir- and lopinavir/ritonavir-based treatments.

And then kjkent1 posts this from his reference:

D30N and N88D appeared mostly in patients without previous exposure to protease inhibitors, while K20T was identified as a secondary resistance mutation in those patients. On the other hand, L90M together with L10I, I54V, A71V, G73S, and V82A were selected in protease inhibitor-experienced patients. A series of correlated mutations including L10I, M46I, I54V, A71V, G73S, and L90M appeared as a common cluster of amino acid substitutions, associated with failure to lopinavir/ritonavir-based treatments. Despite the relatively high genetic barrier of some protease inhibitors, a relatively small cluster of mutations, previously selected under drug pressure, can seriously compromise the efficiency of nelfinavir- and lopinavir/ritonavir-based therapies. (c) 2007 Wiley-Liss, Inc.

Oh oh...D30N and N88D appeared "MOSTLY" in certain patients. But, not "ALWAYS." In some patients, K20T appeared.

So, much for the hypothesis that only one mutational pathway can develop from a particular selective pressure. Kleinman loses again.

Really kjkent1? Does this explain how birds evolve into reptiles? Does this mean that genetic sequencing to identify drug resistance is wrong? Of course it does because kjkent1 says this:

Evolution is not deterministic, Alan. Two trials of an experiment using identical selection pressures will not necessarily produce the same evolutionary outcome, because the "mutation" part of the evolutionary process cannot be predicted in advance.

Kjkent1, does this mean that HIV can now digest nylon?

I am just going to stop writing as much, because I see that you pick and choose what you want to respond to in order to dodge the issue at hand, Kleinman.

Where previously I'd agree this was a debating tactic of Kleinman (and creationists in general), I now see he's exhibiting the psychological phenomenon known as Cognitive Dissonance. Sufferers of this cope with conflicting information by ignoring information that conflicts with their established beliefs. In this example Kleinman, who's believed in biblical creation since he was too young to think for himself, ignores the decisive proof of evolution to relieve the uncomfortable feeling caused by attempting to reconcile these dissonant ideas. I'd be more sympathetic if he didn't resort to deliberate, smirking viscous denigration of those who disagreed with his infantile beliefs.

You kids want to talk about anything but the mathematics of mutation and selection and the empirical evidence which supports this mathematics. Mr Scott, neither you or rocketdodger who claim that n+1 selection pressures evolve more rapidly than n selection pressures are able to produce any empirical evidence of this claim. Who is demonstrating cognitive dissonance? It is you evolutionists who ignore the mathematical and empirical facts of life of how mutation and selection actually works.

Mr Scott, I noticed you removed the line from your posts about the lies your parents told you. Do you now believe your parents?

Joobz, you have claimed you are going to find irregularities in my PhD dissertation, $10,000 wager says that you can’t find any mathematical or empirical irregularities.

Obviously this is a lie and everyone knows it. I've addressed this point, but you choose to pretend otherwise. This, among other lies, simply exposes your entire method. You ignore truth and present idiotic statements. All this does is make you appear to be a complete inept moron. Coupled with all the science you present, which is horrificly dumb, I'm starting to believe you are a complete inept moron. Are you?

Sure you made this claim. Don’t you remember? Here, let me remind you.
http://www.internationalskeptics.com/forums/showpost.php?p=3112268&postcount=6267

… I could critique his PhD for irregularities in his publication track that raise interesting questions. …

So not only are you incompetent in the mathematics of mutation and selection, you are incompetent in the mathematics of PDEs. So are you going to take the $10,000 wager that you can’t find any mathematical or empirical irregularities in my PhD thesis or are you going to continue being a big mouth coward? I believe you will continue to be a big mouth coward. I think you are a fake joobz; no engineer could be so incompetent in mathematics. As for your skills as a chemist, this post of yours reveals you are a fake as well.

Envision a system of millions of forming and destructive chemical reactions. Now, envision that intermediates of there reactions associate through non-covalent means and that this complex becomes protected against the destructive reactive pathway, perhaps by a reversible precipitation. These new complexes result in a localized increased of new chemical species. These chemical species then progress in a new series of reaction... that is what I mean through cooperative means. I acknowledge this is complete speculation, but well within the range of chemical possibility. As long as there was enough free energy for these reaction to occur.

Joobz, if the sun shines on lead long enough does it turn into gold?

So, while you evolutionists look for citations which show that n+1 selection pressures evolve more rapidly than n selection pressures, I’ll keep posting citations which show that combination selection pressures profoundly slow the evolutionary process.
http://www.blackwell-synergy.com/doi/full/10.1046/j.1365-2672.92.5s1.10.x

infections are caused by high bacterial numbers of 10^9 to 10^10 cfu ml1, which means that significant numbers of single-step mutations are likely to arise conferring low level antibiotic resistance. In the presence of suboptimal, low antibiotic concentrations at the site of infection (Table 5), these single-step mutations may confer survival advantage leading to their selection, multiplication, clinical treatment failure and/or spread. It is desirable to maintain antibiotic concentrations at the site of infection at levels which are high enough to ensure that two mutations are required to confer useful survival value. Consequently, the chances of these double mutations occurring are statistically minimal and the mutant prevention concentration (MPC) has been reached. (Drlica 2001) For example, if the chances of a single mutation arising and conferring survival value are 10^7 then the chances of a double mutation conferring survival value are 10^14. Given that few, if any, infections are caused by bacterial numbers as high as > 10^10 to 10^11 then this implies that double mutations are highly unlikely to occur in individual patients. The clinical evidence, albeit incomplete, bears this out although it has to be accepted that these mutation rates are extrapolated from in vitro work and mutation rates appear to be more frequent in vivo, when exposed to antibiotics (Table 4).

Current pharmacodynamic-based dosing schedules for quinolones (in particular the new quinolones) and aminoglycosides may achieve MPCs against selected pathogens in easily accessible sites. This, however, does not necessarily apply to the whole dosing interval, nor in sequestered sites of infection. A well-recognized way round this is combination therapy, particularly when treating with aminoglycoside. This approach has been used for many years.

Theoretically, using two antibiotics simultaneously will negate the need to achieve MPC concentrations, but the two drugs must have similar pharmacokinetic properties to ensure continued presence of both at supra-MIC concentration over the dosing interval. This is clearly not the case with the current trend of once daily aminoglycoside dosing. There are also problems with antituberculous therapy although this approach has been used for many years with varying degrees of success in the treatment of tuberculosis. The main reasons for using combination therapy in the past, however, were the desire to achieve greater bactericidal activity by synergistic interaction with β-lactam and to broaden the spectrum of therapy.

Sol, do you see why you can’t look at mutation and selection as a simple probability problem?

http://www.mja.com.au/public/issues/186_04_190207/sas10773_fm.pdf

The concept of combination therapy has long been established as the paradigm of therapy for a number of chronic infections. In the late 1940s, it was first shown that combination therapy with streptomycin and p-aminosalicylic acid could prevent the rapid emergence of streptomycin resistance during therapy for tuberculosis.4 More recently, the HIV pandemic has given us greater insights into the management of chronic viral diseases. Studies such as the Delta trial using hard clinical endpoints (eg, mortality) unequivocally demonstrated the superiority of combination dual antiviral therapy over monotherapy. Moreover, these early studies showed that initiating dual therapy in treatment-naïve patients gave a superior outcome compared with using a second drug in treatment-experienced patients, proving that an upfront combination that prevented resistance was superior to sequential monotherapy.5 More recently, it has been shown that triple therapy for HIV infection (ie, adding a protease inhibitor) is superior to dual therapy, thereby further strengthening the case for combination therapy.6 By contrast, current Australian (Section 100) and international prescribing guidelines for HBV infection either mandate or recommend lamivudine monotherapy for HBV in treatment-naïve patients, resulting in the almost inevitable development of antiviral resistance and setting the scene for the emergence of multidrug resistance.

So why does combination treatment work? It works because multiple selection conditions confound the ability of the population to evolve to the multiple sorting conditions simultaneously.

Now if any of you evolutionist want to post an example of n+1 selection conditions evolving more rapidly than n selection conditions, that would make this an interesting debate. Perhaps if joobz took up my $10,000 wager with him, that would make this discussion a bit more interesting but I doubt it, we all know what joobz is.

 

[joobz]

So not only are you incompetent in the mathematics of mutation and selection, you are incompetent in the mathematics of PDEs. So are you going to take the $10,000 wager that you can’t find any mathematical or empirical irregularities in my PhD thesis or are you going to continue being a big mouth coward? I believe you will continue to be a big mouth coward. I think you are a fake joobz; no engineer could be so incompetent in mathematics. As for your skills as a chemist, this post of yours reveals you are a fake as well.

http://www.internationalskeptics.com/forums/images/smilies/doglaugh.gif
Joobz, if the sun shines on lead long enough does it turn into gold?

So your answer is that you are a raving idiot?
Is this why you only had 2 journal publications, neither with the same advisor?
Is this why you are unable to actually justify your assumptions of your idiotic theory?

 

[kleinman]

Annoying Creationists

So not only are you incompetent in the mathematics of mutation and selection, you are incompetent in the mathematics of PDEs. So are you going to take the $10,000 wager that you can’t find any mathematical or empirical irregularities in my PhD thesis or are you going to continue being a big mouth coward? I believe you will continue to be a big mouth coward. I think you are a fake joobz; no engineer could be so incompetent in mathematics. As for your skills as a chemist, this post of yours reveals you are a fake as well.

Joobz, if the sun shines on lead long enough does it turn into gold?

So your answer is that you are a raving idiot?

Is this why you only had 2 journal publications, neither with the same advisor?
Is this why you are unable to actually justify your assumptions of your idiotic theory?

So not only are you are incompetent in the mathematics of mutation and selection, incompetent in the mathematics of PDEs, you are also incompetent in doing literature searches. If you had any competence at all, you would find that I have more than 2 journal publications. Care to make a wager on that issue as well or has the Madagascar rain forest waterlogged your brain.

So joobz, if the sun shines long enough on lead, does it turn into gold?

Here joobz, let me show you how to find and post a citation supporting a hypothesis that combination selection pressures profoundly slow the evolutionary process.
http://www.blackwell-synergy.com/doi/full/10.1046/j.1365-3156.2001.00800.x

Mathematical models of the evolution of drug resistance in infectious diseases are predominantly concentrated in three main areas: antimalarial, antibiotic and anthelmintic resistance. There appears to be little or no cross-reference between them. This literature was examined to identify factors that influence the evolution of drug resistance irrespective of the species and drug under study. The aim is to provide non-technical readers with a basic qualitative understanding of the issues and pitfalls involved in designing drug treatment regimens to minimize the evolution of resistance. The principal factors determining the rate at which resistance evolves appear to be (i) the starting frequency of resistance, (ii) the level and pattern of drug use, (iii) the drug's pharmacokinetic properties, (iv) the number of genes required to encode resistance, (v) the level of sexual recombination in the parasite population, (vi) intrahost dynamics and, in particular, whether 'crowding' effects are present, (vii) the genetic basis of resistance and (viii) the number of individual parasites in an infection. The relative importance of these factors depends on the biology of the organisms under consideration and external factors such as the extent to which the infrastructure of health care delivery constrains the practicalities of drug regimens.

That’s you joobz, the non-technical reader (are you a reader joobz?).

Resistance genes are generally assumed to be biologically less efficient than the normal susceptible type. For example, an enzyme may escape drug action by a mutation that alters the drug-binding site. As this mutation probably also affects its catalytic capacity, the mutation will be removed from the population by natural selection and their frequency in the naive, non-drug-treated, population will be determined by a mutation/selection balance (Hastings 1997; Koella 1998). If drugs are used in combination, then the frequency of parasites resistant to both drugs will be very low. For example, if 0.1% are resistant to drug A and 0.005% are resistant to drug B, then parasites resistant to both will initially be present at a frequency of 0.1 × 0.05%=0.00005% (assuming that the same gene cannot encode resistance to both drugs). Thus using drugs in combination from the outset may greatly increase the useful therapeutic lifespan of the drug, because lowering the starting frequency delays the point at which a significant amount of resistance emerges.

and

One important general point from the models is that use of combination therapy in their initial deployment is invariably better than introducing one drug alone, followed by introduction of the second-line drug once the first becomes ineffective (see, for example, Curtis & Otoo 1986; Smith 1990; Bonhoeffer et al. 1997; for malaria, helminths and bacteria, respectively).

and

The Holy Grail of drug development is to discover a drug to which resistance cannot evolve. It appears impossible to select resistance in vitro to the antimalarial artemisinine and one explanation is that the drug may disrupt iron metabolism in a manner that can only be overcome by (impossible) mutations that transcend the laws of physical chemistry. Figure 1, the calculations on starting frequency made above, and prior experience with other drugs suggest that such a seductively optimistic interpretation be judged with caution. Figure 1 shows that the frequency of resistance may be extremely low during much of the evolution of resistance and it is very difficult to detect these low levels. This is not to say that such drugs cannot be developed, merely to stress that the working hypothesis must be that resistance is present, albeit at low frequencies, and that drug deployment should be designed with this in mind. A similar effect is seen with the antimalarial quinine where it is very difficult to select for resistance in vitro. One plausible explanation is that quinine has widespread metabolic effects, several genes may be required to encode resistance, and starting frequencies of resistance may, therefore, be very low. The calculations of starting frequency made above assumed a one gene/one drug relationship but can be extended to take account of numerous metabolic effects. Continuing the above calculation, if resistance to metabolic effect A is 0.1%, resistance to effect B is 0.05% and resistance to effect C is 0.01%, then the frequency of parasites resistant to the total effects of the drug is 0.000000005%.

An increasing number of genes required to encode resistance has two effects, one direct and one indirect, which delay the emergence of resistance. The first, indirect, effect is that the starting frequency of resistance is decreased: if gene A is present at frequency f(a) and gene B at frequency f(b) and both are required to encode resistance, then the starting frequency of resistance is much lower, i.e. f(a) multiplied by f(b). The second, direct, effect occurs in organisms that are sexual or partially sexual. The greater the number of genes, the greater the loss of resistance during sexual recombination (Figure 3) and the slower the development of resistance (Hastings 1997). The most common and convenient method of increasing the number of genes required to encode resistance is to combine several drugs into a mixture (e.g. Peters 1984, 1998; White 1999 and references therein).

This citation is just for you joobz, the non-technical reader who lacks the mathematical skills to understand how mutation and selection works. The more genes which must evolve simultaneously the slower the process, understand rubberband? These authors have the audacity to think that the evolution of resistance not only can be slowed, it can be stopped, ring a bell ding-a-ling?

So joobz, I wager you $10,000 that you can’t back up your claim that I have irregularities in my PhD thesis or for that matter in any of my publications, even the ones you can’t find, either mathematical or empirical. Are you going to take up the wager or are you just a big mouth coward?

 

[joobz]

Nice job. Keep the crazy coming!
Perhaps you'll eventually justify your model assumptions.
Perhaps you'll eventually explain away the evidence for evolution.
Perhaps you'll tell us again how probablity can be greater than 1.
Perhaps you'll tell us all about how nuclear and chemical reactions are the same.
Perhaps you'll eventually explain why hardly anyone referenced your publications.

I have a feeling the last 3 points are related.

 

[kleinman]

Annoying Creationists

Nice job. Keep the crazy coming!

Perhaps you'll eventually justify your model assumptions.
Perhaps you'll eventually explain away the evidence for evolution.
Perhaps you'll tell us again how probablity can be greater than 1.
Perhaps you'll tell us all about how nuclear and chemical reactions are the same.
Perhaps you'll eventually explain why hardly anyone referenced your publications.

I have a feeling the last 3 points are related.

Let’s see, you attribute Dr Schneider’s model to me. You are wrong.

Whatever concocted interpretation of the evidence you allege for the theory of evolution does not include the mathematics of mutation and selection and the vast amount of empirical evidence which contradicts your mathematical irrational and illogical theory. You are wrong.

Hey, you are correct; I made a mistake about the effects of increasing population on the probabilities of a mutation occurring at a particular locus. I thought that doubling the population would double the probability but this probability is not additive, it only makes the theory of evolution less likely. I acknowledged Myriad’s correction of my error. Now when are you going to take up the $10,000 wager that you can not find any mathematical or empirical irregularities in my PhD thesis or any of my other publications? Oh, that’s right; you are a non-technical big mouth who makes claims that he can’t backup.

Oh, and I see, any chemical reaction is possible as long as you have enough free energy but there is not enough free energy in the sun to turn lead into gold?

Joobz, when are your going to tell us how to form ribose non-enzymatically? Then you can tell us what the half life of ribose is if you miraculously could tell us how the ribose could form. You do remember what the half life of ribose is, don’t you? Or is that too technical of a question for someone of your technically challenged abilities? You are wrong again.

Then lastly, you would never reference my publications because you are mathematically incompetent, you have no idea how to do the mathematics, you after all are non-technical but you are an expert speculationist, but don’t let that stop you from taking up my $10,000 wager with you that you can’t prove your claim about any of my publications. You are wrong. Let’s see you put your money where your big mouth is.

Since we all know you are nothing more than a big blow hard, let me once again show you how to post a citation to support a hypothesis that combination selection pressures profoundly slow the evolutionary process.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1865999

Mutation is the basis of adaptation. Yet, most mutations are detrimental, and elevating mutation rates will impair a population's fitness in the short term. The latter realization has led to the concept of lethal mutagenesis for curing viral infections, and work with drugs such as ribavirin has supported this perspective. As yet, there is no formal theory of lethal mutagenesis, although reference is commonly made to Eigen's error catastrophe theory. Here, we propose a theory of lethal mutagenesis. With an obvious parallel to the epidemiological threshold for eradication of a disease, a sufficient condition for lethal mutagenesis is that each viral genotype produces, on average, less than one progeny virus that goes on to infect a new cell. The extinction threshold involves an evolutionary component based on the mutation rate, but it also includes an ecological component, so the threshold cannot be calculated from the mutation rate alone. The genetic evolution of a large population undergoing mutagenesis is independent of whether the population is declining or stable, so there is no runaway accumulation of mutations or genetic signature for lethal mutagenesis that distinguishes it from a level of mutagenesis under which the population is maintained. To detect lethal mutagenesis, accurate measurements of the genome-wide mutation rate and the number of progeny per infected cell that go on to infect new cells are needed. We discuss three methods for estimating the former. Estimating the latter is more challenging, but broad limits to this estimate may be feasible.

and

A treatment strategy for preventing the evolution of significant or complete resistance could be combination therapy with several mutagens or with a mutagen in combination with other antiviral drugs.

Joobz, you better tell these authors that slowing evolution does not mean stop. Here is another citation for you joobz which shows that combination selection pressures profoundly slow the evolutionary process.
http://www.journals.uchicago.edu/JID/journal/issues/v189n7/31334/31334.web.pdf

Limited studies have suggested that, in areas where drug usage has decreased, the spread of resistance has also decreased [36, 37]. These findings are in agreement with our observation in eastern Sudan and emphasize the need for better drug deployment policies, to combat evolution of drug resistance. For example, the use of combination therapy in this region would reduce the risk of multidrug resistance emerging and spreading, helped by the short transmission seasons, when drug pressure, the low number of paraiste generations during this period, and natural section against resistance alleles allow for only 1 or 2 parasite generations. Such information is important for predicting the spread of drug resistance in areas where multiple clones of P. falciparum infection are common.

Hey joobz, did I miss addressing any of your ridiculous speculations? Joobz, do you want me help you find some references for your speculations on abiogenesis? Try doing a google search of the SciFi channel.

 

[joobz]

Kleinman, you never fail. I write a few sentences and you respond with paragraphs of stupidity.

Thank you for making my night.

 

[kleinman]

Kleinman, you never fail. I write a few sentences and you respond with paragraphs of stupidity.

Thank you for making my night.

Oh, I get it, slow doesn’t equal stop, slow equals joobz, slow to understand how mutation and selection actually works.

 

[rocketdodger]

That’s correct, and the issue at hand is you have claimed you have written a simulation of mutation and selection which shows that n+1 selection pressures evolve more rapidly than n selection pressures. Now it’s time for you to post a real example of your alleged model.

You claimed that additional optimization conditions always confound sorting / optimization problems. My program shows this to be not true in general. Can you show anyone here why the sorting/optimization algorithm used in my program is, in fact, not a sorting / optimization algorithm?

 

[sol invictus]

But for the sake of discussion, let’s consider your approach but instead of 90% of the individuals undergoing all N mutations, consider a single individual undergoing all N (100) mutations. In the first generation that individual has a (1/(1,000,000))*100 probability of getting a beneficial mutation, if that individual is gets one of those beneficial mutations, in the next generation, that individual has a (1/(1,000,000))*99 probability of getting a second beneficial mutation or a total probability of (1/(1,000,000))*100*(1/(1,000,000))*99 and so on for each additional possible beneficial mutation. The probability of a particular individual getting all one hundred beneficial mutations is (100/1,000,000)*(99/1,000,000)* … *(1/1,000,000).

That’s 100 generations sol, each additional generation will improve that probability less than an additively.

OK, let's focus on this nice concrete statement of yours - which is completely wrong. You are claiming the following: that, if there are 100 mutations, each with probability 10^{-6} per generation, the odds of all 100 occurring after 100 generations are (100*10^{-6})*(99*10^{-6})*... = 100! 10^{-600}. This is wrong - it's off (in this case) by a mere 40 orders of magnitude. It's the kind of mistake someone that doesn't understand probability at all would make.

There are many ways to see why it's wrong. Let's take the first step. You seem to be under the misapprehension that 100*10^{-6} is the probability that one mutation will take place in the first generation. Tell me - is that the prob. for one and only one mutation? Because that's the wrong answer. What about exactly two mutations? Nope, wrong again.

In case you'd like to know, the probability that one and only one mutation took place in the first generation is 100 p (1-p)^99. The probability that at least one mutation took place is 1-(1-p)^100. No mutations at all? (1-p)^100. Shall I go on?

How much math have you studied?

The correct answer was in my previous post. If there are N mutations, each with probability p, and G generations, the odds that all N mutations have occurred after G generations are (1-(1-p)^G)^N. That's extremely basic, and can be derived in five minutes by anyone with any passing knowledge of probabilities. I'd be happy to explain the derivation again if you'd like to learn how to do it yourself.

Once again, the time required for all N mutations to happen grows extremely slowly with N. This is an absolutely fundamental fact in this debate, and I recommend you attempt to understand it.

 

[kleinman]

Annoying Creationists

That’s 100 generations sol, each additional generation will improve that probability less than an additively.

OK, let's focus on this nice concrete statement of yours - which is completely wrong. You are claiming the following: that, if there are 100 mutations, each with probability 10^{-6} per generation, the odds of all 100 occurring after 100 generations are (100*10^{-6})*(99*10^{-6})*... = 100! 10^{-600}. This is wrong - it's off (in this case) by a mere 40 orders of magnitude. It's the kind of mistake someone that doesn't understand probability at all would make.

Sol, if you think you can use probability theory to prove the theory of evolution by mutation and selection then go for it. Since the probability above is less than about 1 in 10^400, I’ll accept your value of 1 in 10^360 probability. I don’t claim to be an expert in probability theory, what I claim is that I know something about the mathematics of mutation and selection and the empirical data which supports this mathematics. So let’s see you use probability theory to prove otherwise. Why don’t you tell us what the probability is to form a particular 100 amino acid protein is by the random addition of amino acids? Then you can tell us how natural selection will improve that probability especially when there are multiple simultaneous selection conditions acting simultaneously. Let’s see if your knowledge of probability theory extends to the mathematics of mutation and selection.

 

[kleinman]

How much math have you studied?

Most of my mathematical experience is in solving non-linear partial differential equations by iterative techniques. As I said above, I claim no expertise in probability theory but mutation and selection is an iterative problem. What you probably don’t realize that mutation and selection is a sorting/optimization problem that shares many features with iterative solutions to partial differential equations. The first thing you should know about these problems is that the number of sorting conditions has a profound affect on the convergence. This is what Dr Schneider’s simulation shows and this is what the hundreds of empirical examples cited of mutation and selection demonstrates. The sorting of beneficial and detrimental mutations when you have multiple selection conditions is confounded by the multiple sorting conditions. Without selection, the ability to increase frequencies of beneficial sequences is eliminated.

 

[sol invictus]

Sol, if you think you can use probability theory to prove the theory of evolution by mutation and selection then go for it. Since the probability above is less than about 1 in 10^400, I’ll accept your value of 1 in 10^360 probability. I don’t claim to be an expert in probability theory

OK, good - we're making progress. You admit you were wrong and that you don't understand probabilities. As for those numbers, they are yours, not mine. Where did 100 generations come from?

You might ask yourself how many generations of organisms have there been in the last 3 billion years (or do you think it's only been 6,000 years?). Quite a few more than 100, don't you agree? Quite a few more than 1,000,000, in fact. Which means that an essentially infinite number of mutations with odds of far less than 1/1,000,000 have occurred.

So let’s see you use probability theory to prove otherwise. Why don’t you tell us what the probability is to form a particular 100 amino acid protein is by the random addition of amino acids? Then you can tell us how natural selection will improve that probability especially when there are multiple simultaneous selection conditions acting simultaneously. Let’s see if your knowledge of probability theory extends to the mathematics of mutation and selection.

You're making exactly the same mistake all over again. The odds of generating that protein are extremely small if it has to happen all in one shot. But it doesn't - because evolution didn't happen all at once.

Or even all in six days.

 

[kjkent1]

Oh oh...D30N and N88D appeared "MOSTLY" in certain patients. But, not "ALWAYS." In some patients, K20T appeared.
So, much for the hypothesis that only one mutational pathway can develop from a particular selective pressure. Kleinman loses again.

Really kjkent1? Does this explain how birds evolve into reptiles? Does this mean that genetic sequencing to identify drug resistance is wrong?

Ahem...obviously you're a bit rattled by being instantly demonstrated wrong via a peer reviewed article on your favorite HIV subject matter. Otherwise you wouldn't have written that "birds evolved into reptiles," rather than the reverse!

But, back on point, the article demonstrates how evolution can take different paths from the same selective condition, due to the unpredictable nature of mutations. Which does, in fact, show how substantial morphological change can occur over time, when such unpredictable mutations provide a fitness advantage.

Perhaps as important, though, this little dialog proves that you can't admit when you're just plain wrong on a point. You asked me to provide evidence that more than one resistance mechanism could arise from the same selective pressure, and I did.

Your response, instead of admitting the evidence falsifies your contention, was to ridicule it.

That just makes you an intellectual coward, Alan, because you can't admit the possibility of error and learn from it. That is a truly inadmirable characteristic -- especially for a physician and a scientist.