Re: Speculation on the immune system

Walter ReMine (wjremine@mmm.com)
Fri, 01 Sep 1995 16:00:44 -0500

Abstract: This is a continuation of the chat with Steve Clark about my
speculation on the immune system, the potential role of gene conversion, and
information flow. Steve's last post, in my view, offered bits of positive
support for the idea. I here identify and allay his objections.

Steve wrote:
>In fact I didn't intend to make an argument one way or the other. I think
>that you are trying to paint me into a corner to which I will not go.

I didn't paint Steve into a corner, he did that on his own. His original
response made only one central argument, at the time he thought it
compelling -- compelling enough to use against me. ... Well, then it's
compelling enough to use against him. Here are Steve's words again.

>It is doubtful that any heritable mutation would be adequate to
>provide a mammalian defense system capable of adapting to
>newly arising pathogens. With their faster generation times,
>viruses et al. often stay one convenient step ahead of even the
>most adaptable component the immune system, which is the
>antigen receptor genes that undergo a high rate of somatic
>mutation when they encounter foreign antigen. However,
>this somatic mutation is not heritable.

He made a fair argument for why the immune system must have been designed,
and could not have originated by evolution. Yet his latest post trys to
brush aside his own words as if they have no importance. He obscures the
issue by diverting our attention into extraneous matters. He argues that:
1) Theism and evolution are compatible.
2) Randomness is not the same as purposelessness.
3) Natural selection is not a random process.
Those are tired old saws, and none of them can save him from his own
argument above.

******

>Depending on one's definition of information in biological systems, I
>contend that "random mutation" is not as inocuous as you imply and that it
>involves information. So what is it that you mean here?

If Steve were to insist that "random mutation" amounts to serious
information, then we have a profound disagreement. The 'information' I am
talking about is distinctly different from random mutation. Within the
mechanism I have suggested, it would *preferentially* tune the immune system
toward improved performance by non-randomly informing the MHC genes about
the prefered direction to change. This is distinctly different from the
random-mutation/selection model of the neo-Darwinians.

******

Steve agrees with a key step in my mechanism, the idea that:

>> The virus preferentially attacks certain genes, and
>>creates pseudogenes. The very EXISTENCE of that PARTICULAR pseudogene,
>>signals the existence of the virus, and conveys information about its
>>identity. For example, hemoglobin pseudogenes may signal that hemoglobin
>>genes are under assault by viruses. In this way pseudogenes can convey real
>>information about particular viruses.
>
>This sort of "attack" has been documented and well studied. Such attack can
>also cause inappropriate expression of cellular genes and lead to a
>pathogenic state.

Steve allows additional room for my idea, when he admits:

>But this doesn't mean it [Walter's mechanism] couldn't happen.

Later Steve leaves still more room for my idea:

>>Above I discussed two examples where the mechanism might be
>>confined solely to the MHC genes and MHC-like pseudogenes.
>>On the other hand, it might conceivably work for many varieties
>>of pseudogenes throughout the genome.
>
>Perhaps, perhaps not. We probably can't answer this question
>at this stage because it is very hard to show gene conversion in
>higher mammals. The nature of the MHC genetic complex is very
>unique and made it easier to identify gene conversion in this instance.

Then Steve again admits that a key step in my idea is possible:

>>For example, the virus might directly turn an MHC gene into
>>an MHC-like pseudogene.
>
>That is possible, but would be detectable. There are many examples of
>cellular genes being interrupted by "viral" sequences, but again, this
>involves the general category of transposable elements that have very
>characteristic fingerprints.

>A few viruses can integrate into the mammalian genome and there
>exist transposable genetic elements that are rudimentary viruses.
> ***All of these have a characteristic fingerprint that allows us to
> follow them around in the genome.***
(wjr: my emphasis above)

In other words, Steve admits that key steps in my idea are possible, but it
would be easily DETECTABLE if it occurred, and since we havn't detected it,
it must not occur.

I can respond. If the viral sequences "have very characteristic
fingerprints" (as Steve says), then the cell might potentially identify
those sequences and extract them. Leaving -- voila' -- an MHC-like
pseudogene! Just like the ones that exist! This MHC-like pseudogene would
have the characteristics I require. It conveys information that when merged
(via gene conversion) with other MHC genes will tweak them in the direction
of the ORIGINALLY attacked MHC gene.

Here is a key question: Will such an informed tweak to the MHC genes tend
to IMPROVE immune system response, particularly to the original virus or its
relatives? For me, this is the biggest remaining question in my idea. It
requires no additional steps. It only requires an answer.

For extra clarity let me list all the steps (in this simplest version) of my
idea:
1) A virus preferentially attacks certain MHC alleles,
thus creating an MHC-like pseudogene from that allele.
According to Steve this pseudogene would then contain
"very characteristic fingerprints" of such viruses.
2) Some mechanism scans the MHC-like pseudogene for the
"very characteristic fingerprints", and excises them.
3) Gene conversion then merges the new MHC-like pseudogene
with the MHC genes, thus tweaking the MHC genes toward the
previously attacked MHC allele.

Steve has already given full or partial credence to mechanisms 1 and 3. The
only missing mechanism is #2. This is conceptually an easy one. It is no
more difficult than the genetic mechanisms that Steve already believes in.

******

>I also hope that you recognize that this is only speculation and
>that you have offered no evidence for your scenario.

I gave the evidence for my scenario in my original post. Briefly again: 1)
gene conversion is a mechanism that can 'filter' information and merge it
together from two genetic sequences. (That is not a point of dispute
between Steve and I. Rather the existence and nature of that information is
the issue.) 2) There is (in mammals at least) a tight one-to-one
connection between an information flow mechanism (i.e. gene conversion) and
the MHC genes of the immune system, the very genes that (by Steve's own
admission) could benefit from the injection of information:

>Certainly, sequence changes in the two outer domains of the MHC proteins
>affect the way that they fold and present antigen to the immune cells.
>Thus, gene conversion can contribute changes to the sequence of the MHC
>molecules which, in turn, can dramatically change what type of antigens the
>immune system can recognize. Thus, by changing the sequence information,
>function is altered.

******

>Further, you are wrong that gene conversion is random.

I never said gene conversion is random. On the contrary.

>Gene conversion doesn't work by injecting random mutation.

I never said gene conversion works by injecting random mutation. On the
contrary.

Steve is thrashing out disputes that don't exist. My idea assumes the
standard notion of gene conversion -- EXACTLY as expressed by Steve. Gene
conversion is not the issue. Gene conversion merely merges genetic
sequences into the MHC genes, thereby changing the MHC genes. The issue is:
Are those changes ultimately random (as Steve and the current theory says)
and therefore rarely likely to be helpful? Or are those changes ultimately
substantially non-random and more likely to improve the immune system (as I
suggest).

Walter ReMine