Annoying creationists

[delphi_ote]

[derail]Joobz: I know I've seen your sig somewhere before, and my head is going to go all Scanners on me if I don't figure this out. Where is it from???[/derail]

GIVE MOBYSEVEN TRINKET

 

[joobz]

How did you make that connection? The Wikipedia description of fitness landscape gives a precise description of why multiple selection pressures slows evolution.

Can you post again what part of the wiki entry you think states this? Feel free to include some sentence diagrams to show this.

 

[joobz]

[derail]Joobz: I know I've seen your sig somewhere before, and my head is going to go all Scanners on me if I don't figure this out. Where is it from???[/derail]

You cannot get ye Flask.
And you must sit there wondering why, on earth, can I not get Ye Flask!?!?

 

[Mobyseven]

Ah, of course. That reminds me to check my video podcast subscriptions...

CURSES! A load bearing podcast!!!

 

[kleinman]

Annoying Creationists

[...]Whoops, you can’t describe how ribose could be created in the primordial RNA world[...]

I am going to assume that, given that this thread has gone on for 3492 posts, anything that I have to say will not make kleinmann suddenly renounce his denial of evolution. However, I couldn't pass up an opportunity to pass up how utterly incorrect this statement is. I will not try to summarize the vast corpus on pre-biotic chemistry because it has already been done for me by Leslie Orgel in a masterful

review published in 2004. Suffice it to say, if kleimann deigns to read it, it should answer many of his questions of how many of the simple biological molecules could have been formed from the formation of sugars by the condensation of formaldehyde in the formose reaction to the formation of nitrogenous bases by the condensation of hydrogen cyanide with itself and various other simpler nitrogenous compounds to a proposal of a simpler system than RNA (i.e, threose nucleic acid [TNA]) as a stepping stone from the formose reaction and the various HCN condensations to RNA. This review is meant to be a supplement to the oft mentioned Miller-Urey experiment because the main focus on these forums seems to on the creation of amino acid, but here we also have another explanation of the formation of nucleotides.

There are no end to evolutionists’ ridiculous speculations. If you believe the formose reaction will produce ribose, produce the experiment that does this. If you take the time to study the physical properties of ribose, you will find out this is an unstable molecule. Even if you could design an experiment in which you could produce ribose non-enzymatically (which you can’t), the ribose produced would be unstable and have a half life of only a few years and also be a racemic mixture.

The Wikipedia description of fitness landscape gives a precise description of why multiple selection pressures slows evolution.

Even though I explicity wrote two fitness functions in Java-like code that demonstrate precisely the opposite? What you're saying here is a blunder equivalent to "the more integers you add, the bigger the result."

Are you talking about those code fragments you posted earlier? That’s a good example of an evolutionist idea of a proof. Put those code fragments into ev and see what kind of numbers you generate.

I'm really trying to spoon feed you here. Help me help you. How can I mathematically represent calculations on strings in a way you'll understand?

Delphi, you have worked on the concept of mutation and selection and you still have difficulty understanding the mathematics of this phenomena. Since you have difficulty grasping what ev is showing and you have difficulty comprehending why triple therapy is used for the treatment of HIV, let’s try another important clinical medical example.

Multiple drug therapy is often used in an attempt to treat cancer. In addition, radiation therapy is also used. These multiple selection pressures are used to suppress the reproduction of these malignant cells. These multiple treatment modalities are used in an attempt to cause extinction of these cell lines as well as prevent the emergence of more malignant cell lines. This is another example of how multiple selection pressures are used to modify the fitness landscape and slow or stop evolution.

This is how mutation and selection works. Multiple selection pressures do not speed up evolution, they interfere with each other and prevent evolution. This is what the mathematics shows, this is what the real world shows.

Hey! I said that over 4 months ago:

I know, but Dr. Kleinman doesn't seem to get it. Why, I'm not sure, but I think it's A) He's not educated in computer models and simulations, and B) a bronze age holy book has disabled half of his gray matter.

Well, if you read this thread carefully, A) you would find reference to my PhD thesis which is a computer simulation of a biological system, the results of which have been published. I have also published another computer simulation which pertained to the solution of a non-linear partial differential equation. I have also been paid for commercial work using and writing computer simulations and have taught at the university level both undergraduate and graduate level thermodynamics and heat transfer. Included in this teaching was the instruction of the writing and use of computer simulations. B) Are you sure it is not you who has had half of his gray matter disabled by a rust age theory.

If there are, for example, 10 processes that enable evolution, and a computer simulation models 8 of them, then it's not valid to draw a conclusion like "evolution is too slow" unless the other two are also modeled. Ev does not model gene duplication, and the concensus is it's a critical process in "speeding up" evolution compared to evolution without duplication.

Mr Scott, it does not matter what the mechanism of mutation is, it is the multiple selection conditions which interfere with evolution. This is the mathematical and real fact you have yet to come to grips with. No mechanism of mutation will change this fact.

It's as if Kleinman is saying that, because a 4-cylinder car is shown to not be able to reach a destination in time, it's proven an 8-cylinder car couldn't. Real world evolution runs on many more cylinders than Ev models, and we are still discovering more as science continues to penetrate the beautiful, open-ended clockwork of evolution.

Your 8-cylinder car has 5 flat tires (spare tire included), no fuel and your destination is beyond the ends of the observable universe. Multiple selection processes interfere with evolution. The more selection conditions you have the slower the evolution. The fundamental mechanism of mutation and selection which you allege drives the theory of evolution does not work this way. This is shown mathematically and by real examples of the phenomena. No mutation mechanism will change this basic mathematics.

This is the fatal error in Dr. Kleinman's reasoning. He has not refuted it, so it's necessary to repeat it.

Denial does not constitute a valid scientific argument. If you deny the results of ev, put whatever mutation mechanism you want in the model and see whether it will overcome the effect of multiple selection conditions. This I will continue to repeat. This is one of the fatal errors in the theory of evolution. Another fatal error is you have no selection process that can evolve a gene from the beginning.

Ev represents a best case scenario for the theory of evolution. All creatures are affected equally and there is no extinction.

How is that a best case scenario for evolution? That looks to me like an equilibrium scenario -- all creatures affected equally over space and time. That isn't how evolution works.

What ev does is maintain a stable unchanging set of selection pressures with no possibility of extinction. Even under these simple, stable conditions the evolution process is profoundly slow. Changing the selection conditions will slow evolution further.

How did you make that connection? The Wikipedia description of fitness landscape gives a precise description of why multiple selection pressures slows evolution.

Can you post again what part of the wiki entry you think states this? Feel free to include some sentence diagrams to show this.

Certainly, I’ll repost the entry.

Fitness landscapes are often conceived of as ranges of mountains. There exist local peaks (points from which all paths are downhill, i.e. to lower fitness) and valleys (regions from which most paths lead uphill). A fitness landscape with many local peaks surrounded by deep valleys is called rugged.

and

Apart from the field of evolutionary biology, the concept of a fitness landscape has also gained importance in evolutionary optimization methods such as genetic algorithms or evolutionary strategies. In evolutionary optimization, one tries to solve real-world problems (e.g., engineering or logistics problems) by imitating the dynamics of biological evolution. For example, a delivery truck with a number of destination addresses can take a large variety of different routes, but only very few will result in a short driving time. In order to use evolutionary optimization, one has to define for every possible solution s to the problem of interest (i.e., every possible route in the case of the delivery truck) how 'good' it is. This is done by introducing a scalar-valued function f(s) (scalar valued means that f(s) is a simple number, such as 0.3, while s can be a more complicated object, for example a list of destination addresses in the case of the delivery truck), which is called the fitness function or fitness landscape. A high f(s) implies that s is a good solution. In the case of the delivery truck, f(s) could be the number of deliveries per hour on route s. The best, or at least a very good, solution is then found in the following way. Initially, a population of random solutions is created. Then, the solutions are mutated and selected for those with higher fitness, until a satisfying solution has been found.

Evolutionary optimization techniques are particularly useful in situations in which it is easy to determine the quality of a single solution, but hard to go through all possible solutions one by one (it is easy to determine the driving time for a particular route of the delivery truck, but it is almost impossible to check all possible routes once the number of destinations grows to more than a handful).

Joobz, pay attention in particular to the last paragraph of the above quote from Wikipedia. Ev is an evolutionary optimization scheme. Convergence of ev occurs when three selection conditions are satisfied. The three selection conditions are 1) binding sites are located where they should be, 2) no spurious binding in the gene region and 3) no spurious binding sites in the non-gene region of the genome. It is the requirement that all three selection conditions be satisfied simultaneously that causes evolution to be profoundly slow. If you require that only a single selection condition be satisfied at a give time, ev converges very rapidly. Ev is showing exactly what that last paragraph of the post from Wikipedia is saying. Multiple selection conditions profoundly slow down the evolutionary process. This is also seen in reality.

 

[fishbob]

This is how mutation and selection works. Multiple selection pressures do not speed up evolution, they interfere with each other and prevent evolution. This is what the mathematics shows, this is what the real world shows.

Half truth - typical.
Multiple selection pressures can interfere to diminish or intensify.
This is what the real world really shows.

 

[joobz]

Certainly, I’ll repost the entry.

Evolutionary optimization techniques are particularly useful in situations in which it is easy to determine the quality of a single solution, but hard to go through all possible solutions one by one (it is easy to determine the driving time for a particular route of the delivery truck, but it is almost impossible to check all possible routes once the number of destinations grows to more than a handful).

[....cut for brevity...]

Joobz, pay attention in particular to the last paragraph of the above quote from Wikipedia. Ev is an evolutionary optimization scheme. Convergence of ev occurs when three selection conditions are satisfied. The three selection conditions are 1) binding sites are located where they should be, 2) no spurious binding in the gene region and 3) no spurious binding sites in the non-gene region of the genome. It is the requirement that all three selection conditions be satisfied simultaneously that causes evolution to be profoundly slow. If you require that only a single selection condition be satisfied at a give time, ev converges very rapidly. Ev is showing exactly what that last paragraph of the post from Wikipedia is saying. Multiple selection conditions profoundly slow down the evolutionary process. This is also seen in reality.

I believe your reading comprehension is lacking. A good thing to try is to stop thinking of ways to lie and pay attention to what is written.

The Ev. Opt technique is useful when understand each baby step, but can't figure out a priori the total response, which is the sum of the baby steps.

We know and can model how a simple water molecule moves in isolation. But time it takes to run a simulation of 1ml of water is extrememly long. Does this mean that 1 ml of water doesn't exist?

 

[kleinman]

Annoying Creationists

This is how mutation and selection works. Multiple selection pressures do not speed up evolution, they interfere with each other and prevent evolution. This is what the mathematics shows, this is what the real world shows.

Half truth - typical.

Multiple selection pressures can interfere to diminish or intensify.
This is what the real world really shows.

Simple enough fishbob, I have given multiple examples both mathematical and real which demonstrate my hypothesis. Where is your mathematics or examples which show that multiple selection pressures intensify (whatever that means) evolution? You don’t even make half a case - typical.

 

[Ichneumonwasp]

What ev does is maintain a stable unchanging set of selection pressures with no possibility of extinction.

Yes, equilibrium.

Even under these simple, stable conditions the evolution process is profoundly slow.

Yes, equilibrium conditions. Slow change, the theory predicts this.

Changing the selection conditions will slow evolution further.

How's that? Based on what data? We have great data with HIV and triple therapy (your own pet example). Multiple weak selection pressures with certain forms of triple therapy and no change in conditions (good compliance) -- resistance develops. Strong selection pressure with other forms of triple therapy and good compliance -- no resistance develops (over the short course). Strong selection pressure with that same form of triple therapy with poor compliance -- taking med, stopping, taking med again, stopping, taking med again, etc. -- resistance develops. Same thing with TB treatments -- the single best predictor of resistance development is por patient compliance -- changing selection conditions over time.

 

[delphi_ote]

Multiple selection pressures do not speed up evolution, they interfere with each other and prevent evolution.

If you can point me to a way of mathematically representing fitness landscapes for you, I will show you that you're wrong. In some cases, selection pressures can reenforce one another (as in the example code I posted.) In some cases, they have no impact on each other. In some cases, they interefere with each other.

I'd be more than happy to show you what this looks like in a mathematical context, but you don't seem to understand what I type. If you'd care to point me to a way I can explain this to you, I'll do my best. If, on the other hand, you'd rather continue this discussion by flagrantly repeating this false statement, fine. Just please stop being so very proud of your ignorance.

 

[kleinman]

Annoying Creationists

Evolutionary optimization techniques are particularly useful in situations in which it is easy to determine the quality of a single solution, but hard to go through all possible solutions one by one (it is easy to determine the driving time for a particular route of the delivery truck, but it is almost impossible to check all possible routes once the number of destinations grows to more than a handful).

I believe your reading comprehension is lacking. A good thing to try is to stop thinking of ways to lie and pay attention to what is written.

A grammatically challenged alchemical engineer now thinks he can lecture on reading comprehension.

The Ev. Opt technique is useful when understand each baby step, but can't figure out a priori the total response, which is the sum of the baby steps.

Ev can’t figure it out, you can’t figure it out, no evolutionist can figure it out but you think it is scientifically true? Is this the kind of slop you teach in your alchemical engineering classes? Make sure you remain anonymous.

We know and can model how a simple water molecule moves in isolation. But time it takes to run a simulation of 1ml of water is extrememly long. Does this mean that 1 ml of water doesn't exist?

How does modeling of the dynamics of water molecules have anything to do with the acquisition of information by mutation and selection? You must have just finished a hearty meal at kjkent1’s table, red herring, string cheese and whine.

Joobz, your idea of a scientific proof is if you can’t do the computation it must be true. Well, your proof is complete. Abiogenesis is true because you can’t show how ribose is produced nonenzymatically and the theory of evolution is true because you can’t prove it mathematically. You are a credit to the field of alchemical engineering.

What ev does is maintain a stable unchanging set of selection pressures with no possibility of extinction.

Yes, equilibrium.

You better check Wikipedia for the definition of equilibrium.

Even under these simple, stable conditions the evolution process is profoundly slow.

Yes, equilibrium conditions. Slow change, the theory predicts this.

You don’t understand your own theory of evolution so why should I think you understand the meaning of equilibrium.

Changing the selection conditions will slow evolution further.

How's that? Based on what data? We have great data with HIV and triple therapy (your own pet example). Multiple weak selection pressures with certain forms of triple therapy and no change in conditions (good compliance) -- resistance develops. Strong selection pressure with other forms of triple therapy and good compliance -- no resistance develops (over the short course). Strong selection pressure with that same form of triple therapy with poor compliance -- taking med, stopping, taking med again, stopping, taking med again, etc. -- resistance develops. Same thing with TB treatments -- the single best predictor of resistance development is por patient compliance -- changing selection conditions over time.

Choose any case you want in ev, allow information to accumulate than turn off selection and watch the information disappear. Your own example demonstrates this, drug resistant TB occurs more readily when you reduce the number of selective pressures. Why do you think multiple drugs are used to treat TB? Use a single drug and resistance to that drug rapidly appears. Take multiple drugs and maintain the multiple selective pressures and resistant strains are much slower to appear. It doesn’t take long for poor compliance (eliminating the multiple selection pressures) with treatment to yield resistant strains.

Ichneumonwasp, do you think you will get drug resistant strains of microbes if you don’t use any drugs at all?

Multiple selection pressures do not speed up evolution, they interfere with each other and prevent evolution.

If you can point me to a way of mathematically representing fitness landscapes for you, I will show you that you're wrong. In some cases, selection pressures can reenforce one another (as in the example code I posted.) In some cases, they have no impact on each other. In some cases, they interefere with each other.

Ev is mathematically representing a fitness landscape. Have Paul put your code into ev and see whether you can speed up evolution. What is so nonsensical about your concept is that you think the mathematics will proceed more quickly the more complex you make the selection conditions. You are proposing the exact opposite of your Wikipedia link to fitness landscape. There are no fitness landscapes that become easier to optimize by adding more selection conditions to satisfy.

I'd be more than happy to show you what this looks like in a mathematical context, but you don't seem to understand what I type. If you'd care to point me to a way I can explain this to you, I'll do my best. If, on the other hand, you'd rather continue this discussion by flagrantly repeating this false statement, fine. Just please stop being so very proud of your ignorance.

Delphi, the only way you are going to represent any real fitness landscape is by functional notation. You can map the surface by generating data points with a computer model like ev. Somehow you are under the delusion that adding more selection conditions will make it easier to find an optimum on this surface. If you think this is true, define multiple selection conditions that converge rapidly and have Paul put them in ev and demonstrate your argument.

Until then, ev demonstrates that multiple selection conditions slow evolution, the examples of the treatment of HIV, cancer and now Ichneumonwasp example of the treatment of TB with multiple selection pressures slows evolution and your link to Wikipedia which describes fitness landscapes shows that multiple selection pressures slows evolution. Delphi, when are you going to give an example (either real or mathematical) which shows that multiple selection pressures speeds up evolution?

 

[Ichneumonwasp]

Choose any case you want in ev, allow information to accumulate than turn off selection and watch the information disappear.

That's not the analogy. Exposure, remove, exposure, remove, exposure, remove, rinse, repeat.

Your own example demonstrates this, drug resistant TB occurs more readily when you reduce the number of selective pressures.

No, wrong. No drug exposure, no drug resistance. Resistance develops when people take the drug, then stop, then take the drug, then stop, then take the drug, then stop, rinse, repeat. This is not an example of reducing the number of selection pressures in some bland way. It is an example of multiple exposures and periods of remission for a given strong selection pressure(s). There is a big difference. You've not modelled this at all, so can make no comment about it. We know what happens without the selection pressure being placed -- no drug resistance. And with good patient compliance -- limited to no drug resistance. It is repeated exposures, followed by remission with a chance for the population to grow with new varieties, repeat exposure, etc. that results in drug resistance.

Come on, this phenomenon is very well known and well studied. Don't pretend that placing a selection pressure and removing it in any way mimics what I am talking about.

Take multiple drugs and maintain the multiple selective pressures and resistant strains are much slower to appear.

Nope, not always. You did check the link I provide above regarding the situation with HIV. It is, in fact, compliance with the drug regimen that causes drug resistance, even with multiple drugs in the regimen if the selection pressure of the multiple drugs is not high enough.

It doesn’t take long for poor compliance (eliminating the multiple selection pressures) with treatment to yield resistant strains.

If you take a drug and stop it (one instance of each), no resistance arises. That is the analogy you are providing with ev -- place selection pressure and then remove it. Resistance only arises when people take drugs in a sporadic fashion.

 

[joobz]

Ev can’t figure it out, you can’t figure it out, no evolutionist can figure it out but you think it is scientifically true? Is this the kind of slop you teach in your alchemical engineering classes? Make sure you remain anonymous.

ahh your back to gibberish

Kleinman method:
Dismiss a clearly explained concept by quoting random words from said concept in a contemptable manner.

How does modeling of the dynamics of water molecules have anything to do with the acquisition of information by mutation and selection?

Simple. Molecular dynamics is a method of simulating a system by appling simple force rules over and over again. It looks at each interaction and adjusts the setting as a function of time. It is quite similar in function to ev. the exact mechanics differ, but the idea of optimization is the same.

 

[kleinman]

Annoying Creationists

Choose any case you want in ev, allow information to accumulate than turn off selection and watch the information disappear.

That's not the analogy. Exposure, remove, exposure, remove, exposure, remove, rinse, repeat.

Ok, that’s an interesting challenge. Are you proposing exposure to single or multiple selection pressures? The example you give with developing drug resistant TB occurs when taking only one or two medications rather than the three or four that is recommended, this same affect is seen with HIV and poor compliance with treatment.

So how do you propose to demonstrate this effect? Paul, maybe you can help here and we can see what comes out in the wash.

Your own example demonstrates this, drug resistant TB occurs more readily when you reduce the number of selective pressures.

No, wrong. No drug exposure, no drug resistance. Resistance develops when people take the drug, then stop, then take the drug, then stop, then take the drug, then stop, rinse, repeat. This is not an example of reducing the number of selection pressures in some bland way. It is an example of multiple exposures and periods of remission for a given strong selection pressure(s). There is a big difference. You've not modelled this at all, so can make no comment about it. We know what happens without the selection pressure being placed -- no drug resistance. And with good patient compliance -- limited to no drug resistance. It is repeated exposures, followed by remission with a chance for the population to grow with new varieties, repeat exposure, etc. that results in drug resistance.

Come on, this phenomenon is very well known and well studied. Don't pretend that placing a selection pressure and removing it in any way mimics what I am talking about.

If you look at what happens with compliance with multi-drug therapy is that patient’s often time won’t take particular drugs because of adverse reactions to those medications. In addition, taking multiple medications, multiple times a day often times leads to confusion on a patient’s part. They often forget to take medications. The mathematics dictates that drug resistance occurs quickly when taking only single medications. This is why public health departments have gotten involved in the treatment of TB. Patients must be witnessed taking their medications to insure they take all their medications.

The question here is whether turning on and off multiple selection pressures will speed up evolution. The mathematics shows that turning off all but one selection pressure will speed up evolution for that selection condition. Whether you can speed up evolution by turning on and off all selection conditions will not work in ev. This can be easily shown by turning selection on and off in the middle of a run. You also have the problem of how do you extend this concept to macroevolution. Turning off selection for a particular condition stops selection for beneficial mutations for that condition. This will slow evolution. The purpose of having selection is that increases the frequency of beneficial genetic sequences in the population. Any time you turn off selection you are losing this effect. But feel free to propose your idea to Paul and see whether your mathematics will work out.

Take multiple drugs and maintain the multiple selective pressures and resistant strains are much slower to appear.

Nope, not always. You did check the link I provide above regarding the situation with HIV. It is, in fact, compliance with the drug regimen that causes drug resistance, even with multiple drugs in the regimen if the selection pressure of the multiple drugs is not high enough.

I missed your link. Post it again with appropriate quotes posted that you think makes your point.

Three weak selection pressures may not be adequate to cause extinction but they do slow the evolution of triple resistant strains. Give the drugs serially and you will get triple resistant strains much more quickly than if you give the drugs simultaneously.

It doesn’t take long for poor compliance (eliminating the multiple selection pressures) with treatment to yield resistant strains.

If you take a drug and stop it (one instance of each), no resistance arises. That is the analogy you are providing with ev -- place selection pressure and then remove it. Resistance only arises when people take drugs in a sporadic fashion.

You are incorrect. What ev shows, with a single selection condition, that condition quickly evolves. When people take single drug therapy for HIV and TB, resistance to that drug rapidly appears. The problem of patient compliance with multi-drug treatment regimens is not getting them to take one drug; it is getting them to take all the medications consistently. Then you slow evolution of the drug resistant strains. If the selection pressure is strong enough, you can cause the microbe to go extinct (at least with respects to that person).

Ev can’t figure it out, you can’t figure it out, no evolutionist can figure it out but you think it is scientifically true? Is this the kind of slop you teach in your alchemical engineering classes? Make sure you remain anonymous.

ahh your back to gibberish

Kleinman method:
Dismiss a clearly explained concept by quoting random words from said concept in a contemptable manner.

There you go Paul; joobz has clearly explained how to fix the profoundly slow rate of acquisition of information in ev. He hasn’t produced any data just some silly analogies.

How does modeling of the dynamics of water molecules have anything to do with the acquisition of information by mutation and selection?

Simple. Molecular dynamics is a method of simulating a system by appling simple force rules over and over again. It looks at each interaction and adjusts the setting as a function of time. It is quite similar in function to ev. the exact mechanics differ, but the idea of optimization is the same.

The problem with this silly analogy is that ev does compute a rate of information acquisition that is profoundly slow. The reason it is slow is the multiple selection conditions. This effect becomes apparent before you reach a genome length of 100,000. The simulation of the molecular dynamics of a gram of water requires tracking 3E+22 particles each with at least 6 degrees of freedom for each particle. That is why this computation is so slow. Your scientific analogies are as incoherent as your grammar.

 

[Dr Richard]

The fitness landscape in HIV

...is almost as interesting as joobz's avatar...

From the abstract: Fitness landscape of HIV-1 protease quasispecies

"Here we show, at a high resolution (1%), the HIV-1 protease gene quasispecies landscape from three infected naïve individuals. A huge range of genetic configurations was found--67%, 71%, and 80% of the nucleotide clones, respectively, from the three individuals were different, --and these created a dense net that linked different parts of the viral population. Similarly, a vast diversity of different protease activities was also found. Importantly, 65% of the analyzed enzymes had detectable protease activity, and 11% of the minority individual variants showed similar or better fitness than the master (most abundant) enzyme, suggesting that the viral complexity in this genomic region does not exclusively depend on the enzyme's catalytic efficiency. Several high-fitness minority variants had only one substitution when compared to the master sequence, supporting the possibility that the rugged HIV-1 protease quasispecies fitness landscape may be formed by a continuous network that can be traversed by single mutational steps, without passing through defective or less-adapted proteins"

And from the discussion:

Overall, the three quasispecies analyzed displayed a number of notable features. First, within each quasispecies there were a large number of fitness optima or peaks. Because fitness optima were frequent, (65% of all analyzed proteases displayed a detectable enzymatic activity and 11% showed similar or better fitness than the master, most abundant enzyme), the HIV-1 potease quasispecies complexity does not exclusively depend on the enzyme’s catalytic efficiency. Moreover, in one quasispecies population (Fig. 9B), the master sequence was not the fittest sequence but rather represented a middle or low adaptive peak. Selective pressures in another region of the HIV-1 genome might favor a less-fit protease variant (14, 25, 29,41). Second, the fitness landscape was rugged. Several single substitutions were lethal and led the master sequence to drop down the peak. However, at other positions, single substitutions sent the master sequence to a new local optimum or peak, suggesting that the master sequence may walk through the quasispecies fitness landscape by single mutational steps without being trapped at suboptimal alleles (34, 56, 61). Third, although the three analyzed quasispecies shared some traits, such as the presence of several fitness optima, every protease quasispecies formed distinctive individual fitness landscapes. This is particularly interesting because the three quasispecies had similar nucleotide diversity (Fig. 1), suggesting that different selective constraints may have been acting on different quasispecies. Even quasispecies N and O, which had similar
amino acid diversity (Table I), formed very different fitness landscapes. Quasispecies N seemed to be composed of variants formed by different combinations of a reduced number of substitutions that generated a high proportion (>70%) of fit proteases. In contrast, within the O quasispecies there were many different amino acid changes all over the viral protease, the majority of these variants (>60%) being defective enzymes (Fig. 2 and 6). This result, together with the higher ds/dn ratio found in the O quasispecies, strongly suggests an absence of positive selective forces shaping this protease quasispecies. Therefore, random genetic drift and selection pressures within the protease coding region or in other viral genomic regions could be acting all together to generate the protease quasispecies landscape (4, 50, 51).

Note that there are several important points in this paper relevant to this discussion:

1. The sheer number of HIV virions in a single patient: 10^9 PER DAY. Again, makes Kleinmans population of erm... 64 seem a tad conservative.
2. The existence of many, many varieties of HIV within a single individual, creating the landscape as mapped.
3. The fact that each fitness landscape is different in each individual, due to different selection pressures
4. The fact that each landscape as mapped is for the protease only.
5. The fact that small populations of less fit virions are kept "in reserve" in case a new selection pressure manifests.


In summary, this paper demonstrates that multiple different selection pressures in fact increase the genetic diversity of the population and therefore accelerate evolution.

Thank you Kleinman for coming up with the example of HIV - the evolution present within one infected person is sufficient to refute your theory by providing many, many selection pressures and a massive population. You can turn off your PC now...

P.S. the Wiki article on Fitness Landscapes also links to a paper on HIV fitness landscapes modelling >3 loci http://arxiv.org/PS_cache/q-bio/pdf/0603/0603034v2.pdf. I it is a bit more complex than Kleinman seems to think...

 

[Ichneumonwasp]

The example you give with developing drug resistant TB occurs when taking only one or two medications rather than the three or four that is recommended, this same affect is seen with HIV and poor compliance with treatment.

No, that is wrong. Drug resistance with TB drugs and with HIV triple therapy occurs with multiple drugs used when compliance is poor. Not just with one or two. There are well documented effects with particular HIV regimens using three drugs where resistance occurred with good compliance when the regiment itself did not supply enough selection pressure and multiple drug regimens in which no resistance occurs in compliant groups but resistance does emerge from the poor compliance groups. There are even arguments that we not introduce the drugs into some third world countries because of concerns over compliance -- this will result in the development of drug resistance as has been already shown.

I thought you knew this literature.

Of course, resistance occurs more easily with single drugs, especially with poor compliance. But there are actually triple therapy HIV regimens in which good compliance is the deciding factor for resistance to emerge -- again, those regimens that do not provide the strongest selective pressures.

Potency of selective pressure, differences in exposure across populations, and differences of exposure over time are all important factors in teh emergence of drug resistance.

Are you proposing exposure to single or multiple selection pressures?

I'm not proposing anything (just pointing out that your evidence does not fit the situation), but if you want to model it you should do both. It will depend on the strength of the selection pressure as to which protocol will be most likely to produce drug resistance. For strong pressures -- your multiple selection pressures, it would be a protocol with poor compliance, so you would need to expose and relent repeatedly across generations.

If you look at what happens with compliance with multi-drug therapy is that patient’s often time won’t take particular drugs because of adverse reactions to those medications. In addition, taking multiple medications, multiple times a day often times leads to confusion on a patient’s part. They often forget to take medications. The mathematics dictates that drug resistance occurs quickly when taking only single medications. This is why public health departments have gotten involved in the treatment of TB. Patients must be witnessed taking their medications to insure they take all their medications.

Yes, I know, and totally beside the point. I'm not speaking of patient motivations, but the effects of non-compliance on drug resistance. Studies including non-compliance as an outcome measure keep a very close eye on their patients and check for compliance usually in multiple ways -- pill counts, patient reports, reports of other witnesses, drug levels, etc.

Whether you can speed up evolution by turning on and off all selection conditions will not work in ev. This can be easily shown by turning selection on and off in the middle of a run. You also have the problem of how do you extend this concept to macroevolution. Turning off selection for a particular condition stops selection for beneficial mutations for that condition. This will slow evolution. The purpose of having selection is that increases the frequency of beneficial genetic sequences in the population. Any time you turn off selection you are losing this effect. But feel free to propose your idea to Paul and see whether your mathematics will work out.

If that is true, then ev doesn't mimic the real world. Turning off selection loses information only if the selection pressure is kept off. When the selection pressure is re-instituted, the situtation that you see is this: big selection pressures limit reproduction (the definition of a profound selection pressure). The surviving offspring are those most likely to be slightly resistant to the selection pressure. When the selection pressure is removed, then the population is allowed to grow in size with new variations. Some of those variations have a chance of surviving the next big instance of the same selection pressure. Repeat selection pressure -- possible big kill off, or if resistance has already magically developed, then one clone grows in size -- if the population dramatically declines, only those with the potential good changes survive. Release selection pressure -- clones increase with new variations. Repeat selection pressure, etc. That is what we see with drug resistance, even with multiple agents in both HIV and TB.

Three weak selection pressures may not be adequate to cause extinction but they do slow the evolution of triple resistant strains. Give the drugs serially and you will get triple resistant strains much more quickly than if you give the drugs simultaneously.

Of course, but that is not the model we are working with here. With both TB and HIV we use multiple drug cocktails. With the particular cocktails that are not as strong selective pressures as the newer ones, drug resistance occurs more readily. Of course, multiple drugs hit the organisms more and decrease population size, which decreases variability, etc. But when the selection pressures are not particularly strong, resistance can develop with good compliance. It depends critically on the strength of the selection pressures being employed. That's what I've been on about all along.

What ev shows, with a single selection condition, that condition quickly evolves. When people take single drug therapy for HIV and TB, resistance to that drug rapidly appears.

That is not an reply to what I said. What I said was that if you apply a single pressure and remove it, then no resistance will occur. Of course reistance develops with single drug exposures kept in place over a long time. Quick exposure and removal will not do much, though.

The problem of patient compliance with multi-drug treatment regimens is not getting them to take one drug; it is getting them to take all the medications consistently.

Yes, that is what I have been saying. Several times now.

Then you slow evolution of the drug resistant strains. If the selection pressure is strong enough, you can cause the microbe to go extinct (at least with respects to that person).

No, that is not what happens. When patients take antimicrobials inconsistently resistance develops more readily with strong selection pressures. The situation is more complex than this, though, because weaker selection pressures can produce drug resistance (even with multiple drugs in the cocktail) in the face of (and seemingly depending on) good compliance.


Here is the link regarding resistance in HIV

It isn't all that long. The important issues are that while resistance clearly develops in single drug therapies, it may also develop in multi-drug therapies that are not as good at suppressing the viral load. There are many other studies demonstrating that poor compliance to the commonly used and much better triple therapy programs is a result of poor compliance. For one teaser that does not include the multi-drug users.........

The widely accepted premise that non-adherence breeds resistance is now being challenged, at least as it pertains to anti-HIV therapy. Recent data from cohorts of individuals with well-characterized measures of adherence suggest that resistance to both protease and nucleoside reverse transcriptase inhibitors occurs primarily in highly adherent patients.9 In separate studies, Walsh et al.19 and Howard et al.20 demonstrated linear and direct associations between adherence and the number of drug resistance mutations. Gallego et al.21 found protease inhibitor resistance was limited to those individuals reporting more than 90% adherence.

 

[kleinman]

Annoying Creationists

Several single substitutions were lethal and led the master sequence to drop down the peak. However, at other positions, single substitutions sent the master sequence to a new local optimum or peak, suggesting that the master sequence may walk through the quasispecies fitness landscape by single mutational steps without being trapped at suboptimal alleles (34, 56, 61).

This is an interesting post Dr Richard and I took a particular portion of the quote and reposted it above. The reason I took this particular portion of the quote is because it describes what must be done to navigate a fitness landscape.

When only single drug therapy is being used to treat HIV, the single selection process is determining the direction of the walk. If a second drug is used, selection caused by this second drug will affect the direction of the walk through the fitness landscape. Each additional drug used (selection pressure) interferes with the direction of the walk that would prevent the master sequence from walking through the quasisspecies fitness landscape by single mutational steps without being trapped at suboptimal alleles.

1. The sheer number of HIV virions in a single patient: 10^9 PER DAY. Again, makes Kleinmans population of erm... 64 seem a tad conservative.

You still don’t understand the mathematics of mutation and selection and how population affects the rate of evolution. Doubling the population does not double the probability that a particular mutation will hit at a particular loci. For small populations, you can approximate population as having an additive affect on this probability but as your populations get larger and larger, this effect is much less than additive. I have run a series with a population of 10^6 and the effect of increasing population is becoming very small. Paul is supposed to be running another population series and you will see this effect once again.

2. The existence of many, many varieties of HIV within a single individual, creating the landscape as mapped.

How did this individual get so many varieties of the HIV virus? Did this individual receive three antiretroviral medicines consistently or was he treated with monotherapy?

3. The fact that each fitness landscape is different in each individual, due to different selection pressures

Certainly, different antiretroviral medicines (selection pressures) should lead to different genetic sequences in the viruses. However, a given antiretroviral medication should lead to particular genetic sequence that confers resistance to that medication. I’ve heard infectious disease lectures on the topic and particular mutations and given loci confirm the particular drug resistance.

4. The fact that each landscape as mapped is for the protease only.

If drugs which target other enzymes are in virus are introduced, it only makes it more difficult for the virus to evolve.

5. The fact that small populations of less fit virions are kept "in reserve" in case a new selection pressure manifests.

Again, from the infectious disease lectures I have heard, the drug resistant strains of HIV are less fit than the wild strain of the virus. Drug resistant viruses can not reproduce as quickly as the wild virus. The least fit of the viruses that are still able to reproduce will be the ones with the most drug resistance.

In summary, this paper demonstrates that multiple different selection pressures in fact increase the genetic diversity of the population and therefore accelerate evolution.

Of course there is more diversity if there are more selection pressures. If there are no selection pressures, the virus (and it’s corresponding genome) that reproduces most rapidly will quickly take over the population. Each selection pressure added to that virus slows the reproduction of that genome and allows other variants genetic sequences to appear. If you have sufficient selection pressure, you stop the reproduction of the virus completely. So Dr Richard, are you arguing that monotherapy should be used to treat HIV? If not, why? You are arguing that multiple selection pressures accelerate the evolution of the virus so physicians should use few drugs, not more drugs.

Thank you Kleinman for coming up with the example of HIV - the evolution present within one infected person is sufficient to refute your theory by providing many, many selection pressures and a massive population. You can turn off your PC now...

Far from refuting my theory, your paper supports my theory; see the quote I took from your post. Again, I ask you, does this paper support the use of monotherapy or triple antiviral agents for the treatment of HIV? You have alleged that multiple selective pressures increase the variants of the virus. By your logic, monotherapy should be used.

P.S. the Wiki article on Fitness Landscapes also links to a paper on HIV fitness landscapes modelling >3 loci

http://arxiv.org/PS_cache/q-bio/pdf/0603/0603034v2.pdf. I it is a bit more complex than Kleinman seems to think...

And it should reference these types of papers, multiple selection pressures applied simultaneously slow evolution of resistant strains. Apply the selection pressures one at a time and the master sequence of the virus much more easily walks the fitness landscape to evolve a resistant strain. Of course you seem to be arguing that monotherapy is the way to treat HIV, that way you won’t be making the virus evolve as quickly.

Here is the link regarding resistance in HIV

It isn't all that long. The important issues are that while resistance clearly develops in single drug therapies, it may also develop in multi-drug therapies that are not as good at suppressing the viral load. There are many other studies demonstrating that poor compliance to the commonly used and much better triple therapy programs is a result of poor compliance. For one teaser that does not include the multi-drug users.........

This article was published in 2004 meaning the data are at least a couple years older. I have attended CME lectures on the topic within the last year and triple therapy with monitoring and sequencing of the virus for drug resistant strains is the standard of care. The reason this is done is so the virus can not easily walk the fitness landscape and evolve new resistant strains.

This is what the mathematics of mutation and selection shows and this is what the clinical response to these types of therapies show. Multiple selection pressures when applied simultaneously slow evolution.

The widely accepted premise that non-adherence breeds resistance is now being challenged, at least as it pertains to anti-HIV therapy. Recent data from cohorts of individuals with well-characterized measures of adherence suggest that resistance to both protease and nucleoside reverse transcriptase inhibitors occurs primarily in highly adherent patients.9 In separate studies, Walsh et al.19 and Howard et al.20 demonstrated linear and direct associations between adherence and the number of drug resistance mutations. Gallego et al.21 found protease inhibitor resistance was limited to those individuals reporting more than 90% adherence.

This is why I asked you if you can obtain drug resistance without using the drug. You can’t. If you don’t have fatal selection pressures against the virus, given enough time you will evolve drug resistant strains to that medication. If you administer the drug as monotherapy, that resistance comes about more quickly. If administered in combination with other medications, that resistance comes about more slowly because the virus has a more complex walk in the fitness landscape in order to develop the drug resistance.

Standard of care uses three drugs with monitoring for signs of resistance to any of the drugs. As soon as resistance to any one of the drugs is detected an attempt is made to substitute to a new drug.

Here’s a question for you and Dr Richard. If the person has a strain of HIV that is resistant to a particular drug and that drug is withdrawn, what happens to that population of the virus when that drug is withdrawn?

 

[Ichneumonwasp]

This article was published in 2004 meaning the data are at least a couple years older. I have attended CME lectures on the topic within the last year and triple therapy with monitoring and sequencing of the virus for drug resistant strains is the standard of care. The reason this is done is so the virus can not easily walk the fitness landscape and evolve new resistant strains.

This is what the mathematics of mutation and selection shows and this is what the clinical response to these types of therapies show. Multiple selection pressures when applied simultaneously slow evolution.

How nice that you keep up. Now answer the issues reaised, please. You've not even attempted to do so. The standard of care is not the issue. The issue revolves around the mechanisms of drug resistance and the creation of resistant strains in patients who are not compliant.

If administered in combination with other medications, that resistance comes about more slowly because the virus has a more complex walk in the fitness landscape in order to develop the drug resistance.

Standard of care uses three drugs with monitoring for signs of resistance to any of the drugs. As soon as resistance to any one of the drugs is detected an attempt is made to substitute to a new drug.

OK, I think I get it now. You completely misregard any information with which you cannot deal and pretend that you are answering a challenge by posting competely unrelated material.

My first impulse was correct. You guys have fun playing this silly game for the forseeable future. I have better things to do with my time.

 

[kjkent1]

OK, I think I get it now. You completely misregard any information with which you cannot deal and pretend that you are answering a challenge by posting competely unrelated material.

There is no fact (in my opinion) that you could possibly present which would cause kleinman to reject his belief system.

That's why it's called a "belief" system: facts are irrelevant.

 

[joobz]

OK, I think I get it now. You completely misregard any information with which you cannot deal and pretend that you are answering a challenge by posting competely unrelated material.

Welcome to the Kleinman method:
Dismiss a clearly explained concept by quoting random words from said concept in a contemptable manner.