There is no conflict here. ID proponents emphasize the odds against finding a complementary shape space from scratch. But they understand that the IS doesn’t find complementary shapes from scratch but from a library of preexisting genomic segments that recombine randomly during B cell development. IOW, the successful search for complementary shapes is only possible because most of the required functional information is built in in the system.
There is a huge contradiction.
But evolution does very little from scratch, so that’s a gross misrepresentation.
It’s as close to being “from scratch” as most evolution is. And we should point out that the ID gurus like to pretend that recombination isn’t an enormous source of variation–they pretend it’s all point mutations.
The search is from a library of only 10^8 random peptides. It uses selection.
It isn’t. Most of the required information is created by recombination and mutation.
If most of the information is already there, we would expect identical twins, or mice of the same inbred strain, to produce antibodies with identical V-region sequences. We don’t see anything of the sort.
If most of the information is already there, we would expect people who lack the components of that system to be generally OK. They aren’t. They have severe combined immunodeficiency. Maybe you should tell their parents that they don’t need protection any more because of your vast knowledge?
And if you truly believe that “most of the required functional information is already there,” what should happen if we remove a whole bunch of V segments from the mouse genome? Will that produce severe immunodeficiency, Gil?
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Yep. And in any case, when and where things do evolve “from scratch” the odds of finding some matching surface just isn’t that rare at all. In fact it’s really less about shape than it’s about similar polarity among the binding partners that is different from solvent.
For water soluble proteins it really doesn’t take much else than a hydrophobic patch somewhere on the surface to make them prefer to associate with each other in that spot, rather than having solvent molecules/ions stick to it.
It’s like ID-creationists never took basic organic chemistry. Do any of these guys around here like @Marty @Giltil @lee_merrill @colewd even know what electronegativity is? Have they read about polarity? Column chromatography? It’s like if you actually paid attention in high school chemistry, already that basic stuff would dispose of so many completely fundamental misconceptions ID-creationists have about molecular evolution and biochemistry.
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Thank you for making it obvious that you don’t know what you’re talking about.
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Please explain why, for unless you present your arguments in support of your assertion, you are the one who will look like the one who does not know what he is talking about.
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No. Most of the required information is in the V, D and J segments that preexist in the immunoglobulin genes. Granted, recombination and mutation are sources of additional information, but this additional information is minor compared to the information carried by the VDJ segments. Saying otherwise is like saying that thief 2 has a better chance of opening the safe than thief 1 in the following scenario:
Imagine a 15 wheels safe lock protecting a safe full of gold. Imagine that the set of winning combinations is as follow:
** 369373012279038*
** 369373532279038*
** 369373952279038*
** 369373272279038*
** 369373182279038*
You will note that in this set of winning combinations, positions 1 to 6 and 9 to 15 display the same numbers whereas positions 7 and 8 allow some variation.
Imagine now that two thieves are planning to steal the gold and that the first one knows positions 1 to 6 and 9 to 15 while the second one only has the information residing in positions 7 and 8.
What information is that? How are you measuring it? How does that information survive being chopped up and recombined?
In your analogy, that small amount of variation is all that is needed to produce a massive library of different protein-protein binding regions.
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I think you might be confusing sequence information with functional information. Which I find to be inconsistent with how you’ve previously been very focused on FI as the definition of information most apposite to biology.
Those VDJ combinations that don’t work to elicit an adaptive response have no FI despite consisting of segments of sequence that have high similarity to those that do work, so it’s just not clear to me that they have any FI if not found in the right order and combination.
Yes.
That’s empirically false. We’ve known that for more than forty years:
We don’t need a fatally flawed analogy, Gil. We have real data from real immune systems.
Why don’t you learn some basic immunology?
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You’re correct. The VDJ segments have no FI before they recombine and mutate to generate a functional immunoglobulin able to bind a particular epitope. However, just as thief 1 in my safe lock analogy has most of the information to open the lock, it can be said similarly that the VDJ segments have most of the information required to produce a functional immunoglobulin.
Then why does binding specificity differ so greatly between antibodies?
Once again, someone has an ID hypothesis that makes empirical predictions–in this case, that binding is a binary function.
The difference is that Gil is simply asserting his prediction as the data, whereas scientists test predictions.
This quote just serves as another example where Sanford is glaringly and embarrassingly factually wrong. Specifically, how many more functional nucleotide sites have been disrupted than established, under selection over the Covid epidemic? It’s not like this is happening under the radar; every single mutation of the virus is on the record for the world to access. It is not enough for Sanford to retract this claim, he must repent of it with heaving sobs of contrition.
Genetic Entropy.
The whole idea is that random mutation, single nucleotide replacements, indels, and recombination represent loss of information. Loss of information results in loss of function, loss of specificity. That is the entire zeitgeist of Genetic Entropy.
And yet, when an undeniable example of a random process which routinely results in functional proteins is put forward, the terabytes of information for hundreds of millions of shape spaces is held to be somehow contained in kilobytes of genetic code.
This requires a stunning degree of special pleading. Please define exactly what is meant by information in the immunoglobin genes, and how this information maps to the information defining the antibodies produced. If this cannot be done without invoking the same random processes which underlay genetic variation which drive evolution, the immune system stands as a conclusive counter-example to the claims of ID and Genetic Entropy.
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The way you depict the antibody generation process is misleading for it is not the case that it is a purely random process. As gpuccio rigthly noted in a post at uncommon descent, the truth is that the process « uses random variation in a controlled way to generate diversity », the word « controlled » making all the difference here.
You an roll a handful of dice in a controlled manner, but the outcome is still random.
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It’s no more or less controlled than the way in which whole organisms use it. The point is that the variation is random with respect to fitness and that the information is created later–it is not present in the germline.
You’ve provided no evidence to suggest that either you or gpuccio have any relevant knowledge/expertise in immunology, Gil, so what either of you claims doesn’t matter. What matters is the evidence.
And in your deep thinking about antibodies vs. other protein-protein interactions, how did you account for the much higher affinity of most antibody-antigen binding? Intuitively, shouldn’t that make them less frequent in sequence space?
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Even as an analogy, this breaks down. We are not dealing with one safe, but innumerable safes each with their own unique combination. These combinations will be essentially random in respect to any given position. Returning to antibodies, the lesson Behe took from the Gregory Winter experiments was that antibody specificity can be one in the hundreds of millions. The immune system has no idea what is going to walk through that front door. The information demanded to define this immense shape space does not and cannot pre-exist in the immunoglobulin genes.
Do they have FI if they are not able to bind a particular epitope? Do they have no FI one day, and the next I am exposed to a new pathogen and the moment one binds, FI is suddenly created? If the virus escapes, does the FI then disintegrate? If it binds to tissue that it is not supposed to supposed to in an autoimmune disease, is binding then indicative of FI? It appears to me that every antibody that exists embodies the information defining its shape, regardless of the existence of an antitope, and that FI in regards to binding is a very squirrelly concept intended to be malleable to the ID need of the moment.
That antibodies are generated by VDJ segments does not imply that the information pre-exists, any more than information pre-exists for the balls in a » controlled « lottery machine. You could randomly draw from a bucket of amino acids to string together a protein sequence, and that would not make the bucket some repository of information. Neither for antibodies is the whole the same as the recombined and mutated parts contributed, and the sheer number of distinct antibodies produced reflects the degree of randomization involved.
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Okay, let’s assume you are right, let’s assume that antibody specificity is one on the hundreds of millions. Since antibody specificity comes entirely from the VH/VL variable regions, it means that one in the hundreds of millions VH/VL pairs will display a given specificity. VL and VH regions are about 120aa long and are produced through a process combining recombination of V and J segments (for VL) and of V, D and J segments (for VH), with some other factors. Now, take all possible 120 aa long polypeptides and ask yourself which proportion of them will display a given specificity in the same range than the average antibody. I have no doubt that this proportion will be much much less than one in the hundreds of millions, have you? If am correct here, and I am pretty confident I am, it means that most of the information required to produce an antibody with a given specificity is carried by the VDJ segments.
Any antibody able to bind whatever epitope with a biologically relevant threshold has FI (with respect to that precise epitope).
If an antibody has the potential to bind an epitope not yet present in the body, it nonetheless has FI with respect to that epitope.
No.
Yes
The function of an antibody, or, more precisely of the VH/VL régions of an antibody is to bind an epitope or a set of epitopes in a biologically relevant manner. If it could be demonstrated that an antibody is unable to bind a single epitope among all the possible epitopes in the universe, then it would have no FI. But of course, such demonstration is impossible.
There is a huge difference between randomly picking amino acids and randomly picking VDJ segments. In fact, about the same difference between randomly picking individual letters and randomly picking whole sentences.
There’s no need to assume anything here. It’s empirical.
It doesn’t. It comes from sloppy recombination and somatic mutation too.
If your claim was true, identical twins would make the same antibodies. They don’t.
Since your premise is empirically false, that doesn’t follow. Also, binding isn’t binary, so there’s no real “given specificity.” It’s a iterative process of variation and selection–Darwinian evolution.
Can you present evidence for your claim that the threshold for selecting a B-cell clone is the same as the threshold for function of a mature antibody?
And that definition of FI is meaningless.
Both happen in this iterative process. You’re ignoring the former.
Why engage in such gross misrepresentations of an empirically demonstrated mechanism that works in real time?
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No. There is nothing to indicate that any individual VDJ segment is closer in sequence space to matching a never before encountered antigen epitope than just any sequence pulled at random from sequence space(Edit: provided it is valid coding sequence of course). Rather the individual VDJ segments, when recombined in a new order, function more like very large-scale mutations (effectively like many simultaneous substitutions) that result in very large jumps in sequence space.
The strength of recombination isn’t so much that the sequences being recombined are already close to something putatively functional, rather it is their capacity to sample very far from the original sequence by entirely changing a large amount of sequence in one go, rather than accumulating individual substitutions over many, many generations.
Remember that the antigens that the antibodies bind to can have wildly different structures and sequences, and they can bind to many different types of foreign bodies, not just protein sequences from pathogens.
As such there is absolutely nothing that suggests there is some sort of universal similarity between the unfathomable diversity of molecules that antibodoes can adapt to bind, that makes it so the different VDJ segments will just always be “close” to effective binding sequences already, except perhaps in some extremely broad sense of having segments that exhibit different degrees of polarity and hydro-philicity/phobicity.
Different epitopes will have conflicting properties, so that VDJ segments that might be “close” in sequence space to something that can strongly bind one epitope X, will be much further from something that can bind another epitope Y.
This is why the information that matters, the FI, comes from the recombining and mutation process under selection, not from the pre-existing sequence. And the reason why the immune system is nevertheless able to adapt antibodies to foreign agents is that intermolecular binding actually isn’t that rare in protein sequence space, nor as exceedingly dichotomous in degree as many ID-proponents appear to think. But then this implies it really doesn’t take all that much to evolve towards effective binding in the first place, because it takes very little change in sequence to bring out those complementary electrostatic attractions that most contribute to binding affinity.
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