If antibody production was not randomized, then it would not be effective. Our genomes cannot code for the millions / billions of antibody variants we make routinely. The antigen binding domains of antibodies (and T cell receptors, for that matter) arise from a randomized process - V, D and J segments are mixed and matched, and the process involves adding random nucleotides to the joint of each V, D, or J segment. So, yes - the antigen binding sites of antibodies and T cell receptors are randomized. After the randomization step, selection comes into play - and for an antibody, somatic hypermutation (SHM) is involved. This process preferentially targets the antigen binding region, but does not specify what nucleotides are mutated. Mutation and selection combine to select antibodies with high affinity for their target.
So, as it pertains to the sequence search issue, yes - the binding sites of antibodies are randomized. Yet vertebrates routinely use them to form new protein-protein binding sites. Thatâs how we use them to combat pathogens. The immune system as a whole is not a âpurely random search processâ of course, but the part relevant to your claim is.
Of course, evolution is not a âpurely random searchâ either, since every search, since the origin of life, has started from a successfully replicating entity. Itâs not a random shot in the dark, itâs random modification and selection of a previously successful sequence.
Targets arenât selected - randomized antibodies that bind to foreign antigens are selected for - the cells making them undergo proliferation, while cells making antibodies that donât bind foreign antigens are not selected for and remain quiescent. Cells that make antibodies that bind to self (i.e. our own proteins, etc) are selected against, and are removed from the population.
I do think you have an interesting argument, however equating an engineered mechanism that does restricted hyper searches to the RMNS of neo darwinism is a big stretch.
Random searches are ok for small chains but fail for long chains where the combinatorial explosion comes into effect.
If I need to dial a friend and his number has 2 digits a random search is ok. If his number has 13 digits I will likely never reach him unless I know the number.
In the RMNS model single proteins are not necessarily selected for, simply by successfully binding a single protein. The action of binding must create a survival advantage. It may take binding to dozens of proteins to get an advantage
Although I donât think your argument supports the RMNS model, it is an interesting idea and may help unlock the âhowâ of evolution going forward.
Hello Bill,
What prompted you to insert the adjective âpurelyâ?
You seem to be moving the goalposts. Neither Dennis nor I are stretching anything here.
You were claiming that the vastness of sequence space precludes the possibility of any randomized process finding a new protein binding event, remember? Very little sequence space is being searched here and the search is virtually always successful. Axeâs claims about sequence space have no factual basis.
It seems that way because Dennis has used a straw man argument so I am just returning the goal posts to the original position. Difficult and impossible are very different words.
If I used impossible in the past I misspoke and apologize.
As we explore this idea the main point is how much help is studying the immune system in helping us understand how diversity evolved? I think Dennis has surfaced a very good idea.
Hi Bill, I havenât equated anything here - we were discussing the exploration of sequence space. The âsequence space problemâ, however, is the same for the immune system as it is for evolution in general.
Did you know that the variable region of antibodies is about 110 amino acids long? Thatâs a pretty long chain. Random mutation and selection can easily find new protein-protein interactions within that 110 amino acid space. No problem at all.
The example I gave you earlier, which I donât think youâve interacted with yet, shows an example of one new protein-protein binding event, that required 4 amino acid changes. It was of huge selective benefit to the organism.
I agree this is very interesting and I would like to know more about how this mechanism works. At 110 amino acids a purely random search with one solution is out. Are their a library of sequences for the cell to draw from? Is the binding area smaller then 110 amino acids? Are the amino acids that are hyper mutated a subset of the 110 amino acid chain?
Can you make an argument that this is the result of lots of solutions in this search space? Even if you could establish that you had 10^40 ways to bind to a particular protein claiming this is a random search of 110 amino acids until the protein successfully binds is a stretch.
How much do you think this brides the gap between mutational adaption, which we all agree with, and generating a new genetic innovation like a flagellar motor?
[quote=âBillcole, post:90, topic:9418â]
It seems that way because Dennis has used a straw man argument so I am just returning the goal posts to the original position. Difficult and impossible are very different words.[/quote]
I disagree.
I was paraphrasing. Hereâs your claim:
Your premise is simply, utterly, empirically false. Why did you make such a claim?
[quote]As we explore this idea the main point is how much help is studying the immune system in helping us understand how diversity evolved? I think Dennis has surfaced a very good idea.
[/quote]Youâre trying to make it something that it is not. Itâs simply a direct, factual refutation of your false claim quoted above. Your claim was only about binding, see?
[quote=âBillcole, post:94, topic:9418â]
I agree this is very interesting and I would like to know more about how this mechanism works. At 110 amino acids a purely random search with one solution is out.[/quote]
Has that not been made clear to you yet, Bill? How is it that you keep overlooking the essential and nonrandom role of selection?
Yes, but youâd need to learn about recombination and abandon your focus on mutation to grasp this major source of variation in this system (and in evolution).
Areas are 2-dimensional. This is 3-dimensional.
[quote]Even if you could establish that you had 10^40 ways to bind to a particular protein claiming this is a random search of 110 amino acids until the protein successfully binds is a stretch.
[/quote]Thatâs not what is being claimed.
First, you need to distinguish between fact and speculation.
If you immunize genetically-identical individuals with the same antigen, then select and clone the B-cells producing the antibody, the V regions have different sequences.
This is done every day in the process of making monoclonal antibodies. Itâs the foundation of an enormous amount of medical diagnostics. It was in undergraduate immunology textbooks 30 years ago.
Thus, your premise that âspecific binding requires specific sequencesâ is objectively false. Does that change your position?
Might that make you think about why Axe and Behe donât mention this?
Itâs not mere conjecture. The DNA evidence is of the same type and strength that we use to observe legally that âBilly Bob is the father of this child (a past event), Bobby Joe isnât.â Do you object to those too?
Your formation, in that you arose from gametes from your two parents, is an unobserved past event. Nonetheless I would be quite confident that if I sequenced the genomes of your two parents, I would find evidence that would be convincing to all that you did indeed arise through this process. Presumably you wouldnât have a problem if I said, upon sequencing your genome and those of your parents, that in your motherâs cells a specific crossover event took place here, or there; likewise for your dad, etc. So the issue isnât speaking concretely about past, unseen events - it hinges on how reliable you think the evidence is.
Ok, let me put it this way: the enzymes that do VDJ recombination in vertebrates bear an uncanny resemblance to transposases, and they even are able to function as transposases (!). Why might that be the case, do you think? Could it be that they are exapted transposases from mobile DNA? Biologists are convinced, even if that âconvincedâ state is always open to advances in knowledge.
Another example: I have no problem saying âhumans and chimpanzees descend from an common ancestral population.â Should I forever couch that in subjunctive prose, and never the indicative? Your complaint seems like a dressed-up version of the âwere you there?â rebuttal.
If youâre interested in the nuts and bolts of immunology there are plenty of resources available online. Iâm sorry but I donât have the time to teach you this information, unless you sign up for a class at TWU.
The question you need to wrestle with is this: yes, this is a random search, and yes, it works incredibly well. Why might that be the case? What might it tell me about protein sequence space?
On the lambda J / OmpF interaction, did you know that Behe claims that this number of mutations (4 amino acid substitutions in this case) is beyond the reach of evolutionary mechanisms?
