In Kairosfocus’ very good thread about functional complexity, I posted about antibody affinity maturation as an example of a very complex engineering process embedded in biological beings. Both Kairosfocus and Dionisio suggested that I could open a new thread to discuss the issue. When such good friends ask, I can only comply. 🙂
For lack of time, I will try to be very simple.
First of all, I paste here my original post (#6 in the original thread):
KF:
Thank you for the very good summary. Among many other certainly interesting discussions, we may tend to forget sometimes that functionally specified complex information is the central point in ID theory. You are very good at reminding that to all here.
I would like to suggest a very good example of multilevel functional complexity in biology, which is often overlooked. It is an old favourite of mine, the maturation of antibody affinity after the initial immunological response.
Dionisio has recently linked an article about a very recent paper. The paper is not free, but I invite all those interested to look at the figures and legends, which can be viewed here:
http://www.nature.com/nri/jour…..28_ft.html
The interesting point is that the whole process has been defined as “darwinian”, while it is the best known example of functional protein engineering embedded in a complex biological system.
In brief, the specific B cells which respond to the epitope (antigen) at the beginning of the process undergo a sequence of targeted mutations and specific selection, so that new cells with more efficient antibody DNA sequences can be selected and become memory cells or plasma cells.
The whole process takes place in the Germinative Center of lymph nodes, and involves (at least):
1) Specific B cells with a BCR (B cell receptor) which reacts to the external epitope.
2) Specific T helper cells
3) Antigen presenting cells (Follicular dendritic cell) which retain the original epitope (the external information) during the whole process, for specific intelligent selection of the results
4) Specific, controlled somatic hypermutation of the Variable region of the Ig genes, implemented by the following molecules (at least):
a) Activation-Induced (Cytidine) Deaminase (AID): a cytosine:guanine pair is directly mutated to a uracil:guanine mismatch.
b) DNA mismatch repair proteins: the uracil bases are removed by the repair enzyme, uracil-DNA glycosylase.
c) Error-prone DNA polymerases: they fill in the gap and create mutations.
5) The mutated clones are then “measured” by interaction with the epitope presented by the Follicular DC. The process is probably repeated in multiple steps, although it could also happen in one step.
6) New clones with reduced or lost affinity are directed to apoptosis.
7) New clones with higher affinity are selected and sustained by specific T helper cells.
In a few weeks, the process yields high affinity antibody producing B cells, in the form of plasma cells and memory cells.
You have it all here: molecular complexity, high control, multiple cellular interactions, irreducible complexity in tons, spacial and temporal organization, extremely efficient engineering. The process is so delicate that errors in it are probably the cause of many human lymphomas.
Now, that’s absolute evidence for Intelligent Design, if ever I saw it.
The most interesting answers came from Aurelio Smith and sparc. I have already answered AS’s comment in the original thread. Spark’s comments were more specific, so I paste them here (#58 and 59):
You haven’t looked up evolution of AID, did you?
and
BTW, you let out the part of the B-cell development that occurs without any antigen. Lots of mutations, rearragements and selection. Where and how does ID interfere in these processes. Especially, in cases of man made synthetic artificial antigens that were not present 50 years ago?
OK, I will make just a couple of comments on these two points here, and let the rest to the discussion:
a) My point was not specifically about the evolution of the individual proteins in the system, but about the amazing complexity of the whole system. So, I have not done any detailed analysis of the individual proteins I quote. However, I will look at that aspect. As sparc seems aware of specific information about the evolution of AID, I invite him ot provide some references, and we can certainly go on from there.
b) I did not “let out” the part of the B-cell development. I simply focused on affinity maturation. However, the part sparc alludes to is extremely interesting too, so I will mention here in very general lines how it works, and why it is another wonderful example of intelligent engineering. And we can obviously discuss this second aspect too.
In brief, the adaptive immune system must solve the problem of reacting t a great number of potential antigens/epitope, which are not known in advance (I will use “epitope” from now on, because that is the immulogically active part of an antigen).
So, the two branches of the adaptive immune system (B system and T system) must be “prepared” to recognized possible epitopes coming from the outer world. They do that by a “sensor” which is the B cel receptor (BCR) in the B system, and the T cell receptor (TCR) in the T system.
Let’s focus the discussion on the B system.
To recognize the greatest number of possible epitopes (IOWs, of possible small biochemical configurations, mainly of proteins but also of other molecules), the B immune system builds what is usually known as the “basic repertoire”.Very simply, B cells underso a process of somatic genetic differentiation, essentially based on the recombination of VDJ genes, which generates a basic repertoire of different B clones with specific variable genes for the heavy and light chain, IOWs a specific BCR. In that sense, immune cells are different from other somatic cells, because they have a specific genetic recombination of the variable chains of the BCR (and therefore of the antibody that they will produce.
No one knows exactly how big that repertoire is in each individual, but new techniques are helping much in studying it quantitatively. From what I have read, I would say that the size is probably somewhere between 10^6 and 10^9 (more or less the total number of B cells in an organism).
Now, what is the purpose of this basic BCR (antibody) repertoire? We can consider it as a “network” of lower affinity antibodies covering in a loose way the space of possible epitope configurations. That repertoire is generated blindly (IOWs, without any information about specific antigens) by a process of sophisticated genetic engineering (VDJ recombination and other factors), which again uses random variation in a controlled way to generate diversity.
So, to sum up. two different complex algorithms act to ensure efficient immune responses.
1) The first one generates a “blind” repertoire of lower affinity antibodies covering as well as possible the whole space of configurations of possible epitopes.
2) The second one (affinity maturation) refines the affinity of the B cells selected in the primary response (from the basic repertoire) so that they become high affinity, specialized memory cells. This is the process I described in the beginning, in my post.
Both processes are wonderful examples of sophisticated engineering and irreducibly complex systems, and they are completely different one from the other. Both processes work together in sequence in a sophisticated and irreducibly complex meta-system.
Both use controlled random variation to generate diversity. The second process also uses intelligent selection based on existing information from the environment (the epitope conserved in the Follicular GC cell).
All that is very brief, and in no way covers the whole complexity of what is known. So, let’s open the discussion.